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A study of X-linked mental retardation in British Columbia Herbst, Diana Shawn 1980

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A STUDY OF X-LINKED MENTAL RETARDATION IN BRITISH COLUMBIA by DIANA SHAWN HERBST B.A., U n i v e r s i t y o f C a l i f o r n i a , R i v e r s i d e , 1969 M . S c , Simon F r a s e r U n i v e r s i t y , 1975 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES (Department of M e d i c a l G e n e t i c s ) We a c c e p t t h i s t h e s i s as con f o r m i n g t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1980 (c) Diana Shawn H e r b s t , 1980 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 D E - 6 B P 75-51 1 E ABSTRACT An e x c e s s o f males among the m e n t a l l y r e t a r d e d has been noted i n p r a c t i c a l l y a l l s u r v e y s of a m e n t a l l y r e t a r d e d popu-l a t i o n . I t has been h y p o t h e s i z e d t h a t X - l i n k e d genes may account f o r t h i s e x c e s s . The main purpose o f t h i s s t u d y was t o t e s t the h y p o t h e s i s u s i n g d a t a on the m e n t a l l y r e t a r d e d i n B r i t i s h C o l u m b i a . A second purpose was t o c a l c u l a t e the f r e q u e n c y o f n o n - s p e c i f i c X - l i n k e d m e n t a l r e t a r d a t i o n i n the p o p u l a t i o n . In a d d i t i o n , an attempt was made t o d e l i n e a t e c l i n i c a l t y p e s of X - l i n k e d m e n t a l r e t a r d a t i o n . Data on the m e n t a l l y r e t a r d e d i n B r i t i s h Columbia were o b t a i n e d from the B.C. H e a l t h S u r v e i l l a n c e R e g i s t r y . The R e g i s t r y a l s o p r o v i d e d i n f o r m a t i o n on s i b s h i p s w i t h two or more s i b s a f f e c t e d w i t h n o n - s p e c i f i c m e n t a l r e t a r d a t i o n . F a m i l y h i s t o r i e s on s i b s h i p s w i t h two or more a f f e c t e d males were o b t a i n e d from the Department o f M e d i c a l G e n e t i c s , i n s t i t u t i o n s f o r the m e n t a l l y r e t a r d e d , namely Woodlands S c h o o l and T r a n q u i l l e , and i n some c a s e s p e r s o n a l i n t e r v i e w s . The number o f m o t h e r s : i n B r i t i s h Columbia g i v i n g b i r t h t o two or more sons i n a d e f i n e d b i r t h c o h o r t was r e t r i e v e d from the l i n k e d f a m i l y r e c o r d s o f the B.C. Record L i n k a g e P r o j e c t . F a m i l i e s w i t h a p a t t e r n of X - l i n k e d i n h e r i t a n c e f o r n o n - s p e c i f i c mental r e t a r d a t i o n were a s c e r t a i n e d w h i l e f a m i l y h i s t o r i e s on s i b s h i p s w i t h two or more a f f e c t e d males were b e i n g r e c o r d e d and by r e v i e w i n g f i l e s o f o t h e r n o n - s p e c i f i c m e n t a l l y r e t a r d e d males i n the Department of M e d i c a l G e n e t i c s , Woodlands S c h o o l and T r a n q u i l l e . C l i n i c a l and p s y c h o l o g i c a l c h a r a c t e r i s t i c s of the m e n t a l r e t a r d a t i o n i n males from these f a m i l i e s were o b t a i n e d from m e d i c a l f i l e s from the same s o u r c e s . Among the m e n t a l l y r e t a r d e d i n B r i t i s h C o lumbia, t h e r e i s an o v e r a l l 28.2% exc e s s of males. The e x t e n t o f t h i s e x c e s s i s s i m i l a r t o t h a t o b s e r v e d i n o t h e r s t u d i e s . T h i s e x c e s s o f males i s seen a t a l l l e v e l s o f r e t a r d a t i o n e x c e p t a t the p r o f o u n d l e v e l . M e n t a l r e t a r d a t i o n o f known causes does not s i g n i f i c a n t -l y c o n t r i b u t e t o the e x c e s s , which i s due p r i m a r i l y t o non-s p e c i f i c m e n t a l r e t a r d a t i o n . N o n - s p e c i f i c m e n t a l r e t a r d a t i o n i n two or more s i b s may be g e n e t i c i n o r i g i n . Data from s i b s h i p s w i t h both males and females a f f e c t e d do not s u p p o r t an h y p o t h e s i s o f m u l t i f a c t o r i a l i n h e r i t a n c e w i t h s p e c i f i c sex t h r e s h o l d s a c c o u n t i n g f o r the ex c e s s of m e n t a l l y r e t a r d e d males. A r a t i o o f 3.1:1 o f s i b -s h i p s w i t h two or more a f f e c t e d males t o s i b s h i p s w i t h two or more a f f e c t e d females s u g g e s t s t h a t X - l i n k e d i n h e r i t a n c e may account f o r the e x c e s s of male a f f e c t e d s i b s h i p s . F a m i l y h i s -t o r y d a t a on s i b s h i p s w i t h two or more a f f e c t e d males p r o v i d e e v i d e n c e t h a t X - l i n k e d genes can account f o r the e x c e s s o f male a f f e c t e d s i b s h i p s . A minimum f r e q u e n c y of 1.83 per 1,000 males f o r X - l i n k e d m ental r e t a r d a t i o n i n the p o p u l a t i o n o f B r i t i s h Columbia was - i v -c a l c u l a t e d u s i n g s i b s h i p d a t a . T h i s f r e q u e n c y can account f o r the e n t i r e e x c e s s of n o n - s p e c i f i c m e n t a l l y r e t a r d e d males i n the p r o v i n c e . M e n t a l r e t a r d a t i o n i n h e r i t e d i n an X - l i n k e d p a t t e r n may be due t o e i t h e r s i n g l e genes on the X chromosome or autosomal dominant genes w i t h s e x - l i m i t e d e x p r e s s i o n . D i s t i n g u i s h i n g be-tween the two types o f genes was not p o s s i b l e i n the p r e s e n t s t u d y . S p e c i f i c c l i n i c a l subtypes o f X - l i n k e d m ental r e t a r d a t i o n c o u l d n o t be d i f f e r e n t i a t e d due t o a l a r g e amount of v a r i a -b i l i t y which was found n ot o n l y i n the l e v e l of r e t a r d a t i o n but a l s o i n a s s o c i a t e d p s y c h o l o g i c a l , n e u r o l o g i c a l and p h y s i c a l c h a r a c t e r i s t i c s . A l t h o u g h f u r t h e r c l i n i c a l , b i o c h e m i c a l and c y t o g e n e t i c i n v e s t i g a t i o n s of a f f e c t e d males i n f a m i l i e s w i t h X - l i n k e d mental r e t a r d a t i o n may e l u c i d a t e subtypes of non-spe-c i f i c m e ntal r e t a r d a t i o n , v a r i a b i l i y i n p h e n o t y p i c e x p r e s s i o n has been i d e n t i f i e d as an i m p o r t a n t f e a t u r e of X - l i n k e d m ental r e t a r -d a t i o n . - V -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES i x LIST OF FIGURES x i ACKNOWLEDGEMENTS x i i CHAPTER I - INTRODUCTION A. R a t i o n a l e f o r Study 1 B. L i t e r a t u r e Review 8 1. X - l i n k e d MR 8 a. f a m i l y p e d i g r e e s 8 b. a s p e c t s o f IQ 9 c. e x p r e s s i o n i n females 10 d. v a r i a b l e minor anomalies 10 e. m a c r o - o r c h i d i s m 11 f . CNS anomalies 12 g. speech d e f e c t s 12 h. b e h a v i o r a l d i s o r d e r s 13 i . d e r m a t o g l y p h i c s .. . .' 13 j . b r a i n p a t h o l o g y a t autopsy 14 k. marker X chromosome 14 1. marker X chromosome and m e g a l o t e s t e s 15 m. l i n k a g e w i t h X g a 15 n. progeny o f X - l i n k e d m e n t a l l y r e t a r d e d males .. 16 2. Frequency o f X - l i n k e d MR 17 a. t h e o r e t i c a l e s t i m a t e 17 b. g e n e r a l f a m i l y s u r v e y s 18 c. males w i t h n o n - s p e c i f i c MR 20 d. m u l t i p l y a f f e c t e d s i b s h i p s 22 C. Summary 24 - v i -CHAPTER I I - METHODS Page A. D e f i n i t i o n s 25 1. MR 2 5 2. L e v e l s o f MR 26 3. P a t t e r n of X - l i n k a g e 29 B. A s c e r t a i n m e n t 30 1. MR i n B r i t i s h Columbia 30 2. S i b s h i p Data 33 3. F a m i l y H i s t o r i e s 34 4. A s s o c i a t e d C l i n i c a l F e a t u r e s o f X - l i n k e d MR 35 5. B r i t i s h Columbia F a m i l y Data 36 C. A n a l y s i s 36 1. Sex R a t i o 36 2. S t a t i s t i c a l T e s t s 37 3. C a l c u l a t i o n s 38 CHAPTER I I I - RESULTS A. MR i n B r i t i s h Columbia 40 B. Minimum I n c i d e n c e of N o n - s p e c i f i c MR 44 C. N o n - s p e c i f i c MR i n Two or more S i b s 46 D. A n a l y s i s o f S i b s h i p s w i t h Two or more A f f e c t e d Males .. 50 1. F a m i l y H i s t o r i e s 5 0 2. S i z e of S i b s h i p s 52 3. Sex R a t i o i n S i b s h i p s 52 4. MR i n S i b s h i p s 55 5. A n a l y s i s of S i b s i n Index S i b s h i p s 55 - v i i -Page 6. A n a l y s i s of M a t e r n a l S i b s 57 7. Ages of Grandparents a t Time of P a r e n t s ' B i r t h .... 59 E. P e r s o n a l I n t e r v i e w s 61 1. V e r i f i c a t i o n of F a m i l y H i s t o r i e s 61 2. Concern f o r G e n e t i c R i s k s 63 F. Frequency o f X - l i n k e d MR i n B r i t i s h Columbia 64 G. F a m i l i e s w i t h X - l i n k e d MR 66 H. C l i n i c a l F e a t u r e s o f X - l i n k e d MR 70 1. C l i n i c a l I n f o r m a t i o n 70 2. M e n t a l , V e r b a l and S o c i a l A b i l i t i e s 70 a. v a r i a t i o n i n MR 70 b. IQ s t r e n g t h s and weaknesses 72 c. s p e c i f i c speech d e f e c t s 72 d. s o c i a l a d a p t a b i l i t y 75 3. B e h a v i o r a l D i s o r d e r s 75 4. B i r t h H i s t o r y 79 5. N e u r o l o g i c a l C h a r a c t e r i s t i c s ". 81 a. s e i z u r e s 81 b. motor c o n t r o l 81 6. P h y s i c a l C h a r a c t e r i s t i c s 83 a . h e i g h t 83 b. head c i r c u m f e r e n c e 83 c. u n u s u a l p h y s i c a l f e a t u r e s 83 7. Summary o f C l i n i c a l F e a t u r e s 87 CHAPTER IV - DISCUSSION A. MR i n B r i t i s h Columbia 89 B. F a m i l y S t u d i e s 94 C. Frequency o f X - l i n k e d MR 97 - v i i i -Page D. X - l i n k e d Genes 98 E. A Marker X Chromosome 101 F. C l i n i c a l F e a t u r e s o f X - l i n k e d MR 103 G. G e n e t i c C o u n s e l l i n g I m p l i c a t i o n s 109 H. Summary I l l BIBLIOGRAPHY ' 112 APPENDIX I - P u b l i s h e d X - l i n k e d M e n t a l R e t a r d a t i o n P e d i g r e e s as o f End of Year, 1978 121 APPENDIX I I - Forms and Q u e s t i o n n a i r e 129 APPENDIX I I I - L i v i n g Cases of M e n t a l R e t a r d a t i o n i n B r i t i s h Columbia R e g i s t e r e d i n the H e a l t h S u r -v e i l l a n c e R e g i s t r y a t Year-end, 1977, and C a t e g o r i z e d by Degree of R e t a r d a t i o n , E t i o l o g y , Age-group, and Sex 136 APPENDIX IV - P e d i g r e e s o f K i n d r e d s w i t h X - l i n k e d M e n t a l R e t a r d a t i o n 140 - i x -LIST OF TABLES Table Page I Male-Female R a t i o s from S e l e c t e d S t u d i e s of M e n t a l R e t a r d a t i o n (MR) 5 I I Male-Female R a t i o s of S i b s h i p s w i t h Two or More A f f e c t e d S i b s 6 I I I L e v e l s of MR 27 IV L e v e l s of A d a p t i v e B e h a v i o r 28 V C l a s s i f i c a t i o n o f MR i n the H e a l t h S u r v e i l l a n c e R e g i s t r y 32 VI L i v i n g I n d i v i d u a l s _< 19 y e a r s o l d w i t h MR R e g i s -t e r e d i n the H e a l t h S u r v e i l l a n c e R e g i s t r y Recorded a t Year-end, 1977 41-42 V I I Cases of N o n - s p e c i f i c MR i n B.C. whose B i r t h d a t e s are between 1950-1969 i n c l u s i v e and Who are R e g i s t e r e d , e i t h e r A l i v e or Dead, a t Year-end, 1977, i n the H e a l t h S u r v e i l l a n c e R e g i s t r y 45 V I I I Number of S i b s h i p s w i t h N o n - s p e c i f i c MR i n Two or More S i b s Recorded i n the H e a l t h S u r v e i l l a n c e R e g i s t r y 47 IX D i s t r i b u t i o n o f MR among F a m i l i a l Cases where Two or More S i b s are A f f e c t e d 49 X Comparison of S e v e r i t y o f MR between A f f e c t e d Males and Females from S i b s h i p s w i t h both Males and Females Retarded 51 XI F a m i l y H i s t o r y I n f o r m a t i o n of S i b s h i p s w i t h Two or More A f f e c t e d M a l e s . I S i z e of S i b s h i p s 53 X I I F a m i l y H i s t o r y I n f o r m a t i o n of S i b s h i p s w i t h Two or More A f f e c t e d M a l e s . I I M e n t a l S t a t u s o f S i b l i n g s 54. X I I I Summary of Data on I n t e r v i e w s made t o V e r i f y and Update F a m i l y H i s t o r i e s 62 - x -Table Page XIV M a t e r n a l E t h n i c Background 67 XV F a m i l i e s w i t h a Presumptive X - l i n k e d MR D e f e c t .... 69 XVI L e v e l o f MR i n Males w i t h X - l i n k e d MR 71 XVII IQ S t r e n g t h s and Weaknesses i n Males w i t h X - l i n k e d MR , 73 X V I I I S p e c i f i c Speech D i s a b i l i t y i n Males w i t h X - l i n k e d MR 74 XIX S o c i a l Q u o t i e n t (SQ) i n Males w i t h X - l i n k e d MR ....76-77 XX A s p e c t s o f B e h a v i o r A s s o c i a t e d w i t h X - l i n k e d MR ... 78 XXI B i r t h H i s t o r y of Males w i t h X - l i n k e d MR 80 XXII N e u r o l o g i c a l F e a t u r e s i n Males w i t h X - l i n k e d MR ... 82 X X I I I H e i g h t of Males w i t h X - l i n k e d MR 84 XXIV Head C i r c u m f e r e n c e of Males w i t h X - l i n k e d MR ...... 85 XXV P h y s i c a l C h a r a c t e r i s t i c s A s s o c i a t e d w i t h X - l i n k e d MR 86 - x i -LIST OF FIGURES F i g u r e Page 1 T h e o r e t i c a l D i s t r i b u t i o n o f I n t e l l i g e n c e T e s t S c o r e s f o r the Age Group 10 t o 14 Years i n the T o t a l P o p u l a t i o n 2 2 T h e o r e t i c a l D i s t r i b u t i o n o f I n t e l l i g e n c e T e s t S c o r e s f o r the T o t a l P o p u l a t i o n 3 3 Ages o f Grandparents a t B i r t h of P a r e n t of Two or More M e n t a l l y R etarded Males 60 - X I 1 -ACKNOWLEDGEMENTS I am v e r y g r a t e f u l t o the many people who k i n d l y and e n t h u s i a s t i c a l l y h e l p e d me w i t h t h i s p r o j e c t . S p e c i a l thanks goes t o Dr. J.R. M i l l e r , my s u p e r v i s o r , f o r h i s p a t i e n t s u p p o r t and v a l u a b l e a d v i c e . Other members of my t h e s i s committee, Dr. H.G. Dunn, Dr. D.G. Holm, Dr. R.B. Lowry, Dr. P. J . MacLeod and the l a t e Dr. G.W. R o b e r t s , have a l s o been s u p p o r t i v e of t h i s p r o j e c t . T h e i r a d v i c e and encouragement are most a p p r e c i a t e d . Dr. R o b e r t s w i l l be c o r d i a l l y remember f o r h i s f r i e n d l y i n t e r e s t i n t h i s s t u d y and f o r h i s most h e l p f u l s u g g e s t i o n s r e g a r d i n g the d a t a a n a l y s i s and d e s i g n o f s e v e r a l t a b l e s . I w i s h t o thank the f o l l o w i n g people whose k i n d co-opera t i o n made t h i s p r o j e c t p o s s i b l e . W i t h o u t t h e i r a s s i s t a n c e , t h i s s t u d y would never have m a t e r i a l i z e d : 1) the s t a f f o f the B.C. H e a l t h S u r v e i l l a n c e R e g i s t r y ; e s p e c i a l l y Mrs. H. C o l l s , A d m i n i s t r a t o r , even i n cramped c o n d i t i o n s she always found a desk f o r me t o use, Mr. D.H.G. Renwick, Research O f f i c e r , f o r p r e v a l e n c e t a b u l a t i o n s , and Mrs. L. K e i l l o r f o r her p a t i e n c e , and c o - o p e r a t i o n i n c h e c k i n g q u e s t i o n a b l e d i a g n o s e s and f a m i l i a l r e l a t i o n s h i p s . 2) the s t a f f o f Woodlands S c h o o l ; e s p e c i a l l y Dr. B. T i s c h l e r , M e d i c a l D i r e c t o r , f o r her h e l p f u l s u p p o r t and k i n d p e r m i s s i o n t o have a c c e s s t o m e d i c a l f i l e s , M i s s Henshaw and o t h e r M e d i c a l Records s t a f f f o r t h e i r a s s i s t a n c e i n s e a r c h i n g through the w e l l o r g a n i z e d m e d i c a l f i l e s and c o n t a c t i n g f a m i l i e s . 3) the s t a f f o f T r a n q u i l l e f o r t h e i r f r i e n d l y h o s p i -t a l i t y and i n t e r e s t d u r i n g my v i s i t ; e s p e c i a l l y Dr. J . Bower, E x e c u t i v e D i r e c t o r (now r e t i r e d ) , - x i i i -f o r h i s k i n d a s s i s t a n c e , the M e d i c a l Records s t a f f f o r t h e i r h e l p i n s e a r c h i n g t h rough f i l e s , and K. F r e e b u r y , O u t p a t i e n t Department C o - o r d i n a t o r , f o r t r a c i n g and c o n t a c t i n g a number of f a m i l i e s . 4) Mr. S.H. Uh f o r d a t a from the B.C. Record L i n k a g e P r o j e c t . 5) and e s p e c i a l l y a l l o f the f a m i l i e s who were i n t e r -viewed f o r t h e i r c o n c e r n , i n t e r e s t and k i n d c o -o p e r a t i o n i n the p r o j e c t . F i n a n c i a l a s s i s t a n c e from the K i l l a m F o u n d a t i o n , N a t i o n a l I n s t i t u t e of M e n t a l R e t a r d a t i o n and a t e a c h i n g a s s i s t a n t s h i p through Dr. J.J.R. Campbell i n M i c r o b i o l o g y are g r a t e f u l l y acknowledged. A s s i s t a n c e from M i s s S. Manning who drew the p e d i g r e e s and Mrs. P. G r a b i who typed the m a n u s c r i p t i s most a p p r e c i a t e d . L a s t l y , I e x p r e s s l o v i n g a p p r e c i a t i o n t o Tom f o r h i s encouragement and u n d e r s t a n d i n g and t o C h r i s who would c h e e r -f u l l y s t a y w i t h h i s b a b y s i t t e r so Mommy c o u l d complete t h i s p r o j e c t . - 1 -CHAPTER I INTRODUCTION A. RATIONALE FOR STUDY M e n t a l r e t a r d a t i o n (MR) i s a s e r i o u s p o o r l y u n d e r s t o o d h a n d i c a p . I t may a c c u r a t e l y be termed a symptom o f some under-l y i n g d e f e c t ; y e t , i n most c a s e s , the d e f e c t and i t s e t i o l o g y are unknown. In the g e n e r a l p o p u l a t i o n MR i s more common than might be ex p e c t e d on the assumption o f a normal G a u s s i a n d i s -t r i b u t i o n f o r i n t e l l i g e n c e (Penrose, 1972, pp 25-30 and 5 0 ) . However, the a c t u a l d i s t r i b u t i o n o f i n t e l l i g e n c e i s not p r e -c i s e l y known. There are v e r y few s t u d i e s o f the d i s t r i b u t i o n of i n t e l l i g e n c e t e s t s c o r e s t h a t admit t o u n b i a s e d s a m p l i n g of the g e n e r a l p o p u l a t i o n . Penrose e s t i m a t e d an e x c e s s o f 0.29% of i n d i v i d u a l s a t the lower l i m i t s of i n t e l l i g e n c e which c o u l d not be accounted f o r by a normal d i s t r i b u t i o n c u r v e i n a sample of the B r i t i s h p o p u l a t i o n aged 10-14 y e a r s . He suggested t h a t a s i n g l e skewed c u r v e , as i n F i g u r e 1, c o u l d a c c u r a t e l y r e p r e s e n t the d i s t r i b u t i o n o f i n t e l l i g e n c e i n the g e n e r a l p o p u l a t i o n . Dingman and T a r j a n (1960) suggested t h a t a t r u n c a t e d normal curve w i t h a s h o u l d e r a t the lower l i m i t s , as i n F i g u r e 2, c o u l d more a c c u r a t e l y f i t the e m p i r i c a l d a t a . - 2 -F i g u r e 1 T h e o r e t i c a l D i s t r i b u t i o n of I n t e l l i g e n c e T e st Scores f o r the Age Group 10 t o 14 Years i n the T o t a l P o p u l a t i o n (Penrose, 1972, p. 29) t based on a p o p u l a t i o n of 100,290 * I n t e l l i g e n c e Q u o t i e n t ** s t a n d a r d d e v i a t i o n - 3 -F i g u r e 2 T h e o r e t i c a l D i s t r i b u t i o n of I n t e l l i g e n c e T e s t Scores f o r the T o t a l P o p u l a t i o n (Dingman and T a r j a n , 1960) T h e o r e t i c a l d i s t r i b u t i o n t based on a t o t a l p o p u l a t i o n o f 175,000,000 * IQ - I n t e l l i g e n c e Q u o t i e n t ** sd - s t a n d a r d d e v i a t i o n - 4 -In any c a s e , most a u t h o r s agree t h a t a normal d i s t r i b u t i o n of i n t e l l i g e n c e cannot account f o r a l l cases o f MR (Thomson, 1953; L a r s s o n and S j o g r e n , 1954; C a v a l l i - S f o r z a and Bodmer, 1971, p 515). F u r t h e r m o r e , s t u d i e s o f the p r e v a l e n c e o f MR, a sample of which i s l i s t e d i n Table I , r e v e a l t h a t t h e r e i s an ex c e s s o f m e n t a l l y r e t a r d e d males. T h i s e x c e s s o f males i s independent of the mode o f a s c e r t a i n m e n t s i n c e i t i s found i n i n s t i t u t i o n a l , p o p u l a t i o n , and f a m i l y s u r v e y s . A s i m i l a r e x c e s s of m e n t a l l y r e t a r d e d males i s observed i n s t u d i e s o f f a m i l y groups o f two or more a f f e c t e d s i b l i n g s (Table I I ) . These s i b s h i p s suggest t h a t MR may have an under-l y i n g g e n e t i c component. In f a m i l i e s of index c a s e s w i t h one or more s i b l i n g s , W o r t i s , e t a l • (1966) found t h a t 13.4% o f male p a t i e n t s , but o n l y 5.7% of female p a t i e n t s , had a m e n t a l l y r e t a r d e d or m e n t a l l y d i s t u r b e d s i b l i n g . The s t u d i e s by W r i g h t , e t a l . (1959) and P r i e s t , e t . a l . (1961) d i d not d i f f e r e n t i a t e MR i n s i b s h i p s w i t h r e s p e c t t o e t i o l o g y or degree o f s e v e r i t y . In a d d i t i o n , W o r t i s , e t a l . (1966) i n c l u d e d v a r i o u s c a s e s of mental d i s o r d e r s w i t h those o f MR. Turner and Turner (1974) e x c l u d e d those c a s e s whose MR was due t o Down Syndrome or whose IQ was 56 or more. On the o t h e r hand, Davison (1973), who s e l e c t e d o n l y those f a m i l i e s w i t h a f f e c t e d s i b s o f IQ 50 or l e s s , e x c l u d e d as many c a s e s w i t h known causes o f MR as was p o s s i b l e u s i n g i n f o r m a t i o n from m e d i c a l f i l e s and p h y s i c a l e x a m i n a t i o n s . In any c a s e , a l l s t u d i e s show a t l e a s t a 2:1 - 5 -Table I Male-Female R a t i o s from S e l e c t e d S t u d i e s o f M e n t a l R e t a r d a t i o n (MR) number number % Male Study o f males'of females e x c e s s A. I n s t i t u t i o n a l S t u d i e s 1. I n s t i t u t i o n a l r e s i d e n t s i n _ 1 n ,._„ „ R England (Penrose, 1938) /±u:5/u Zb 2. I n s t i t u t i o n a l r e s i d e n t s i n U.S. i n 1965 (U.S. 107,709:88,937 21 P u b l i c H e a l t h S e r v i c e , 1967) B. P o p u l a t i o n S t u d i e s 1. M e n t a l l y r e t a r d e d r e p o r t e d i n S t a t e n n r „ n n n „ • . • ~, -, 3 ,706 : 2,970 25 R e g i s t r y i n Rhode ' I s l a n d (Wunsch, 1951) 2. M e n t a l l y r e t a r d e d i n V i c t o r i a , A u s t . 114.7:94.7 21 ( S t o l l e r , 1965) (per 100,000) 3. M e n t a l l y r e t a r d e d i n E d i n b u r g h , S c o t . 1950- 7 o n 1956 ( D r i l l i e n , e t a l . , J U : i / b 5 L 1966) 4. M e n t a l l y r e t a r d e d i n B r i t i s h I s l e s , E n g l i s h R o y a l Commission, 1904 6,685:5,435 23 ( i n s t i t u t i o n a l a s c e r -tainment ) (Tredgold , 1914, p. 18) C. F a m i l y S t u d i e s 1. M i n n e s o t a f a m i l i e s over s e v e r a l g e n e r a t i o n s 867:583 49 (Reed and Reed, 1965) 2. I n s t i t u t i o n a l r e s i d e n t s w i t h a f f e c t e d s i b s i n n u • a. / T > - 4 . 223: 164 36 Washington ( P r i e s t , e t a l . , 1961) 3. C a l i f o r n i a i n s t i t u t i o n a l r e s i d e n t s and a f f e c t e d , n o r , _ . , r 7 - v . . -i 108:53 104 s i b s ( W r i g h t , et. a l . , 1959) - 6 -Table I I Male-Female R a t i o s o f S i b s h i p s w i t h Two or More A f f e c t e d S i b s T o t a l number A s c e r t a i n m e n t S$ :¥$ :<?$ * of s i b s h i p s P a c i f i c S t a t e H o s p i t a l , 26: 6:29 61 C a l i f o r n i a ( W r i g h t , e t a l . , 1959) R a i n i e r S c h o o l , Washington 26:10:39 75 ( P r i e s t , e t a l . , 1961) New York O u t p a t i e n t P s y c h i -a t r i c C l i n i c , New York 19: 2: 9 30 ( W o r t i s , e t a l . , 1966) Ox f o r d a r e a , England ( m u l t i p l e a s c e r t a i n m e n t ) 50:21:70 141 (Da v i s o n , 1973) New South Wales, A u s t . ( s c h o o l a s c e r t a i n m e n t ) 58:22 80** (Turner and T u r n e r , 1974) * 38 - s i b s h i p s w i t h o n l y males a f f e c t e d %% - s i b s h i p s w i t h o n l y females a f f e c t e d S% - s i b s h i p s w i t h males and females a f f e c t e d ** s < i s i b s h i p s were not i n c l u d e d i n r e p o r t - 7 -r a t i o of- f a m i l i e s w i t h o n l y males a f f e c t e d v e r s u s f a m i l i e s w i t h o n l y females a f f e c t e d . Such r a t i o s suggest t h e r e are g e n e t i c f a c t o r s t h a t a f f e c t the o v e r a l l e x c e s s of MR i n males. Goddard (1914, p. 554) was the f i r s t t o r e f e r t o s e x -l i m i t e d i n h e r i t a n c e as an e x p l a n a t i o n f o r the e x c e s s o f men-t a l l y r e t a r d e d males. However, Ro s a n o f f (1931) f i r s t s u ggested t h a t a f a c t o r on the X chromosome might be r e s p o n s i b l e f o r the exces s of m e n t a l l y r e t a r d e d males obse r v e d i n h i s stu d y of t w i n s . Lehrke (1974), upon r e v i e w i n g much o f the l i t e r a t u r e on'MR, h y p o t h e s i z e d t h a t genes on the X chromosome may account f o r the o v e r a l l e x c e s s o f m e n t a l l y r e t a r d e d males i n the popu-l a t i o n . The p r e s e n t s t u d y t e s t s t h i s h y p o t h e s i s by r e v i e w i n g c ases of MR i n B r i t i s h C o lumbia. G e n e r a l i n f o r m a t i o n on MR i n the p r o v i n c e and s i b s h i p d a t a were o b t a i n e d from the B.C. H e a l t h S u r -v e i l l a n c e R e g i s t r y . M e d i c a l r e c o r d s from Woodlands S c h o o l and T r a n q u i l l e , which are i n s t i t u t i o n s f o r the m e n t a l l y r e t a r d e d , and from the M e d i c a l G e n e t i c s Department, U.B.C., as w e l l as p e r s o n a l i n t e r v i e w s , p r o v i d e d i n f o r m a t i o n on the f a m i l y h i s t o r y and e t i o l o g y o f the MR. The e s t i m a t e d minimum f r e q u e n c y o f males w i t h X - l i n k e d MR i s c a l c u l a t e d a l o n g w i t h the p o s s i b l e number o f X - l i n k e d genes t h a t can cause n o n - s p e c i f i c MR. The minimum number o f males w i t h p r o b a b l e X - l i n k e d MR and the ex c e s s number o f males w i t h MR i n a b i r t h c o h o r t i n the B r i t i s h Columbia p o p u l a t i o n are then compared. Such a comparison t e s t s the - 8 -hypothesis that X - l i n k e d MR can account f o r a l l of the excess of m e n t a l l y r e t a r d e d males i n the p o p u l a t i o n . The c l i n i c a l f e a t u r e s a s s o c i a t e d with the MR found in f a m i l i e s showing a d e f i n i t e p a t t e r n of X - l i n k e d i n h e r i t a n c e have been t a b u l a t e d . The t a b u l a t i o n i s an attempt to i d e n t i f y s p e c i f i c c h a r a c t e r i s t i c s t h a t would be u s e f u l i n the d i a g n o s i s of t h i s type of MR i n s p o r a d i c cases where a f a m i l y h i s t o r y does not show any s p e c i f i c p a t t e r n of i n h e r i t a n c e or suggest any environmental f a c t o r s c o n t r i b u t i n g to the MR. B. LITERATURE REVIEW 1. X - l i n k e d MR a. f a m i l y pedigrees A p a t t e r n of n o n - s p e c i f i c MR c o n s i s t e n t with X - l i n k e d i n h e r i t a n c e has been documented i n over 40 k i n d r e d s . Appendix I summarizes the f i n d i n g s i n the f a m i l y pedigrees r e p o r t e d to year-end 1978. T h i s form of MR, a l s o c a l l e d M a r t i n - B e l l Syndrome or more commonly Renpenning Syndrome,is not a s s o c i a t e d with any known bi o c h e m i c a l d e f e c t or any major p h y s i c a l or n e u r o l o g i c a l a b n o r m a l i t i e s . I t i s a l s o d i s t i n c t from other s p e c i f i c X - l i n k e d syndromes or b i o c h e m i c a l d i s o r d e r s causing MR, such as Hunter Syndrome, Lesch-Nyhan " Syndrome or nephro-genic d i a b e t e s i n s i p i d u s . The f i r s t r e p o r t of a n o n - s p e c i f i c mental d e f e c t showing sex-linkage was by M a r t i n and B e l l i n 1943: a l a r g e kindred _ 9 -had eleven males i n s i x s i b s h i p s who were s e v e r e l y mentally r e t a r d e d . However, the p a t t e r n of i n h e r i t a n c e may be ques-tio n e d s i n c e the extended f a m i l y i s r e l a t e d through two b r o t h e r s who were repo r t e d by other f a m i l y members to be mentally normal. The authors e x p l a i n e d t h i s i n c o n s i s t e n c y as being due to sup-p r e s s i o n of the X - l i n k e d r e c e s s i v e gene i n these b r o t h e r s . The f i r s t f a m i l i e s that d e f i n i t e l y showed a p a t t e r n of X - l i n k e d r e c e s s i v e MR were those r e p o r t e d by Dunn, et a l . (1963) and Renpenning, e t a l . (1962) i n which 19 and 20 males r e s p e c t i v e l y were mentally r e t a r d e d . No major p h y s i c a l or CNS a b n o r m a l i t i e s were found in the a f f e c t e d males. The MR was not p r o g r e s s i v e and seemed to be present from b i r t h . No b i o c h e m i c a l abnormality was detected i n the a f f e c t e d males by u r i n e amino a c i d chromatography. b. aspects of IQ I t i s apparent from Appendix I that i n most kindreds the males were s e v e r e l y a f f e c t e d . However, i t should be noted that in a number of these s t u d i e s (Turner, e t a l . , 1971; Turner, e t a l . , 1972; Davison,*1973) ascertainment was l i m i t e d to males with an IQ or 50 or l e s s . In l a r g e r kindreds, a wide range of MR i n males i s more apparent. For example, in the f a m i l y r e p o r t e d by Dunn, et a l . (1963), four males were pro-foundly, e i g h t s e v e r e l y , s i x moderately and one m i l d l y r e t a r d e d . In most cases the i n t e l l e c t u a l c a p a c i t i e s of the a f f e c t e d males were not f u r t h e r d i f f e r e n t i a t e d . However, a number of - 10 -a u t h o r s have commented on a s t r i k i n g v e r b a l e x p r e s s i o n d e f i c i t i n a t l e a s t some of the a f f e c t e d males (Appendix I , nos. 1, 2, 5, 6, 9, 12, 14, 21, 23, 24; and 2 5 ) . Lehrke (1974) r e p o r t e d the WAIS v e r b a l and performance s c o r e s f o r 11 o f 20 a f f e c t e d males i n the f a m i l y f i r s t r e p o r t e d by O p i t z , e t a l . (1965) as 65 ± 8 and 78 ± 11 r e s p e c t i v e l y . NeuhSuser, e t a l . (1969) commented on the normal s o c i a l a d a p t a b i l i t y o f a f f e c t e d males i n one f a m i l y . S o c i a l q u o t i e n t s (SQ) of 93 and 95 ( V i n e l a n d S o c i a l M a t u r i t y S c a l e ) were measured i n two a f f e c t e d males whose IQ's were 57 and 50 r e s p e c t i v e l y . c. e x p r e s s i o n i n females Not o n l y does the p e n e t r a n c e of the gene f o r MR seem t o be v a r i a b l e i n males, t h e r e seems t o be p a r t i a l e x p r e s s i o n i n some females as w e l l . A number of the r e p o r t s l i s t e d i n Appendix I d e s c r i b e d c a r r i e r females as " m i l d l y r e t a r d e d " , " f e e b l e - m i n d e d " , "slow", "backward", " b o r d e r l i n e " , "not t o o b r i g h t " , " s i m p l e " or "of l i m i t e d IQ". There were a l s o known c a r r i e r females who were of average or above average i n t e l l i g e n c e (Dunn, e t a l . , 1963; Snyder and R o b i n s o n , 1969). P a r t i a l e x p r e s s i o n of a p r o b a b l e X - l i n k e d r e c e s s i v e gene i n some females i s c o m p a t i b l e w i t h the Lyon h y p o t h e s i s which s u g g e s t s t h a t random X i n a c t i v a t i o n t a k e s p l a c e i n the e a r l y s t a g e s o f a female embryo .(Lyon, 1962). d. v a r i a b l e minor a n o m a l i e s One of the p e c u l i a r a s p e c t s o f t h i s type o f MR i s the l a c k of a s s o c i a t e d major p h y s i c a l , CNS, or b i o c h e m i c a l - 11 -a n o m a l i e s . Even a n o m a l i e s , which may be c o n s i d e r e d m i n o r , such as prominent jaw, l a r g e e a r s or h i g h a r c h e d p a l a t e , were not r e p o r t e d i n a l l a f f e c t e d members of the same k i n d r e d (Appendix I , nos. 4, 5, 1, 13, 14, 17, 19, 22 and 23). Most s t u d i e s r e p o r t a normal head c i r c u m f e r e n c e . However, most of the a f f e c t e d ) m a l e s examined i n one f a m i l y (Renpenning, e t a1., 1962) had a low normal head c i r c u m f e r e n c e (mean 50.0 ± 1.5 cm). A l s o , s p o r a d i c cases o f m i c r o c e p h a l y were r e p o r t e d t o occur i n some f a m i l i e s (Appendix I , nos. 6, 7, 9 and 1 7 ) . e. m a c r o - o r c h i d i s m Most a u t h o r s have not commented on the s i z e of the g e n i -t a l i a of a f f e c t e d males. However, m e g a l o t e s t e s were r e p o r t e d i n s e v e r a l f a m i l i e s (Appendix I , nos. 10, 12, 18, 19, 20 and Cantu, et... a l . , 1975). In these c a s e s t h e r e was no apparent u n d e r l y i n g e n d o c r i n e d i s t u r b a n c e but the t e s t i c u l a r volume was u s u a l l y g r e a t e r than 30 ml. The t e s t i c u l a r volume f o r t e s t e s i n normal males a t 18 y e a r s o f age has b e e n ' r e p o r t e d t o be 18.2 ± 4.7 ml (Zachmann, e t a l . , 1974). R e s u l t s from t e s t i c u l a r b i o p s i e s have v a r i e d . Cantu, e t a l . (1976) r e p o r t e d hyposper.matogenesis i n some s e m i n i f e r o u s t u b u l e s and a d i m i n i s h e d number of L e y d i g c e l l s . T u r n e r , e t  a l . (1975), found t h i c k e n e d basement membranes and an i n c r e a s e i n p e r i t u b u l a r c o l l a g e n f i b e r s . R u v a l c a b a , e t a l . (1977b), on the o t h e r hand, found o n l y normal t e s t i c u l a r t i s s u e , and c o n c l u d e d t h a t the i n c r e a s e i n volume was a p p a r e n t l y due t o e x c e s s f l u i d c o n t e n t . - 12 -The m a c r o - o r c h i d i s m , which seemed t o be p r e s e n t b e f o r e p u b e r t y i n a f f e c t e d males, was not p r e s e n t i n u n a f f e c t e d male r e l a t i v e s . Not a l l a f f e c t e d males i n f a m i l i e s w i t h X - l i n k e d MR had. m a c r o - o r c h i d i s m . One su r v e y r e p o r t e d t h a t i n s i x out of s i x t e e n f a m i l i e s i n v e s t i g a t e d , the p r o p o s i t i were found t o have e n l a r g e d t e s t e s ( T u r n e r , e t a l . , 1978). In another s u r v e y , o n l y one of the s i x f a m i l i e s i n v e s t i g a t e d had a f f e c t e d males w i t h t h i s anomaly (Jacobs, e t - a l . , 1979). f . CNS anomalies A few CNS anomalies o c c u r r e d s p o r a d i c a l l y i n these f a m i l i e s . S e i z u r e s might be a s s o c i a t e d w i t h the MR but were not p r e s e n t i n the m a j o r i t y of a f f e c t e d males (Appendix I , nos. 4, 5, 6,7, 18, 21, 22 and 2 3');. Hydrocephalus was r e p o r t e d i n two f a m i l i e s i n two of s i x and one of twenty-one a f f e c t e d males ( F r i e d , 1972 and Deroover, e t a l . , 1977 r e s p e c t i v e l y ) . T h i s h y d r o c e p h a l u s seemed t o be d i f f e r e n t from the s e x - l i n k e d h y d r o c e p h a l u s r e -p o r t e d by Edwards (1961) which i s due t o s t e n o s i s o f the aque-d u c t o f S y l v i u s . H y p o t o n i a and poor g r o s s or f i n e motor c o -o r d i n a t i o n were p r e s e n t i n some, but a g a i n not i n a l l , r e t a r d e d f a m i l y members (Appendix I , nos. 5, 6, 7, 8, 13, 21, 2.2 and 23) . g. speech d e f e c t s S p e c i f i c speech d e f e c t s , m a i n l y poor a r t i c u l a t i o n , have been noted i n some of the a f f e c t e d males (Appendix I , nos. 2,5, - 13 -9, 16, 21, 2 3 and 24) . However, speech d e f e c t s are r e p o r t e d t o occur i n 5 t o 94% o f a heterogenous m e n t a l l y r e t a r d e d p o p u l a -t i o n - the f r e q u e n c y b e i n g dependent on the p o p u l a t i o n t e s t e d , the examiner, and the a r b i t r a r y d e f i n i t i o n o f a "speech d e f e c t " (Matthews, 1974). T h e r e f o r e , f i n d i n g speech d e f e c t s i n some males a f f e c t e d w i t h X - l i n k e d MR might not be r e l e v a n t . Howard-P e e b l e s , e t a l . (1978) c o n c l u d e d t h a t poor a r t i c u l a t i o n might s i m p l y be due t o g e n e r a l d e l a y e d development. h. b e h a v i o r a l d i s o r d e r s B e h a v i o r a l d i s o r d e r s were not predominant among the a f f e c t e d males. M a r t i n and B e l l (1943) d e s c r i b e d two a f f e c t e d males as p s y c h o t i c , one p a r a n o i d and another s c h i z o i d , , among e l e v e n males w i t h X - l i n k e d MR. H y p e r a c t i v i t y has been d e s c r i b e d o n l y s p o r -a d i c a l l y (Appendix I , nos. 12, 18' and 21). i . d e r m a t o g l y p h i c s Other than the r e p o r t e d s p o r a d i c t r a n s v e r s e palmar c r e a s e (Dunn, e t a l . , 1963), d e r m a t o g l y p h i c s have been g e n e r a l l y unremarkable among a f f e c t e d males (Appendix I , nos. 9, 14 and 21). Davison (1973) r e p o r t e d a s l i g h t , though i n s i g n i f i c a n t , d e c r e a s e i n the t o t a l f i n g e r r i d g e c o u n t s f o r X - l i n k e d m e n t a l l y r e t a r d e d males compared t o o t h e r m e n t a l l y r e t a r d e d males. Two of the fou r m e n t a l l y r e t a r d e d males r e p o r t e d by Yarbrough and Howard-Pe e b l e s (1976) a l s o had r e l a t i v e l y low t o t a l f i n g e r r i d g e c o u n t s . The o t h e r two had t o t a l f i n g e r r i d g e c o u n t s s i m i l a r t o those of t h e i r p a r e n t s . - 14 -j . b r a i n p a t h o l o g y a t autopsy Only one autopsy of an a f f e c t e d male has been r e p o r t e d (Dunn, e t a l . , 1963). The w e i ght of the b r a i n was below a v e r -age. There were no g r o s s d e v e l o p m e n t a l anomalies i n the c o r t e x , a l t h o u g h t h e r e was some ev i d e n c e of d e l a y of n e u r o b l a s t i c m i g r a -t i o n i n f e t a l l i f e . A l s o r e p o r t e d were p a r t i a l l o s s of m y e l i n i n the centrum s e m i o v a l e i n both hemispheres and marked s i d e r -o s i s of the g l o b u s p a l l i d u s . k. marker X chromosome There are r e p o r t s t h a t i n some f a m i l i e s the MR might be a s s o c i a t e d w i t h a f r a g i l e s i t e on the X chromosome. Chromo-somes have been r e p o r t e d as normal i n a l l f a m i l i e s e x c e p t the e a r l y r e p o r t s p u b l i s h e d p r i o r t o k a r y o t y p i n g ( M a r t i n and B e l l , 1943; A l l a n , e t a l . , 1944) and those by Lubs (1969), Harvey, e t , a l . (1977) and Howard-Peebles, et,. a l . (1978) where a t e r -m i n a l f r a g i l e s i t e on the l o n g arm o f the X chromosome was ob-s e r v e d . G i r a u d , e t a l . (1976) found a s i m i l a r f r a g i l e s i t e on the X chromosome a s s o c i a t e d w i t h MR and d e l a y e d speech w i t h or w i t h o u t f a c i a l dysmorphy i n s i x s u b j e c t s . The f r a g i l e s i t e , o b s e r v e d as a c o n s t r i c t i o n a t Xq 27 or 28, may show d i s t i n c t b r eaks i n some c e l l s . T h i s marker was seen o n l y a t low f r e q u e n c i e s . In 26 a f f e c t e d males, i t was seen i n 4 t o 50% of the c e l l s (median 21%) and i n 17 o b l i g a t e c a r -r i e r females i n a range of 0 t o 28% (median 3%) o f the c e l l s . The f r e q u e n c y o f the marker seemed dependent p a r t l y on the type - 15 -of c u l t u r e medium used ( S u t h e r l a n d , 1977a, 1977b). By c o n t r o l -l i n g c u l t u r e c o n d i t i o n s and r e f i n i n g h a r v e s t i n g t e c h n i q u e s , the marker X c o u l d be demonstrated n o t o n l y i n lymphocyte c u l t u r e s but a l s o i n f i b r o b l a s t c u l t u r e s (Jacky and D i l l , 1980). 1. marker X chromosome and m e g a l o t e s t e s T u r n e r , e t a l . (1978) r e i n v e s t i g a t e d s i x t e e n f a m i l i e s w i t h a p a t t e r n o f X - l i n k e d MR i n which a f f e c t e d males had e a r l i e r demonstrated normal k a r y o t y p e s . Under r e v i s e d c u l t u r e c o n d i -t i o n s the marker a t Xq 27 or 28 was shown i n a f f e c t e d males from s i x of the f a m i l i e s . N o t a b l y , i n a l l s i x f a m i l i e s the MR and marker X chromosome were a s s o c i a t e d w i t h m e g a l o t e s t e s . F u r t h e r , of 14 males w i t h the marker r e p o r t e d by S u t h e r l a n d and A s h f o r t h (1979), 13 had t e s t e s l a r g e r than the 90th p e r c e n t i l e . T h i s e v i d e n c e suggested t h a t X - l i n k e d MR w i t h m a c r o - o r c h i d i s m and MR a s s o c i a t e d w i t h the f r a g i l e s i t e a t Xq 27 or 28 were one e n t i t y ( S u t h e r l a n d and A s h f o r t h , 1979). However, t h i s a s s o c i a t i o n might not be c o n s i s t e n t s i n c e the marker X chromosome has been found i n t h r e e f a m i l i e s i n which a f f e c t e d males d i d n o t have m a c r o - o r c h i d i s m (Jacobs, e t a l . , 1979). m. l i n k a g e w i t h X g a Nine f a m i l i e s have been i n v e s t i g a t e d f o r l i n k a g e o f a gene f o r MR w i t h the Xg b l o o d group l o c u s on the X chromosome (Appendix I , nos. 7, 8, 9, 13, 14, 18, 23, 2 5 ) . In most f a m i - ~ l i e s the Xg phenotypes were not i n f o r m a t i v e . In one f a m i l y - 16 -where the MR was a s s o c i a t e d w i t h h y d r o c e p h a l u s i n two o f e i g h t a f f e c t e d males, the i n v e s t i g a t o r s computed a r e c o m b i n a t i o n f r a c t i o n of 0.11 w i t h a maximum l i k e l i h o o d o f 20.2 between the MR l o c u s and the Xg l o c u s ( F r i e d and Sanger, 1973). In the f a m i l y r e p o r t e d by Wolf, e t a l . (1978) 2-3 recombinants were found out of f i v e c a ses s u g g e s t i n g independent a s s o r t m e n t between the two l o c i . I t i s of i n t e r e s t t h a t the Xg l i n k a g e group i s l o c a t e d on the s h o r t arm o f the X chromosome w h i l e the f r a g i l e s i t e found i n some f a m i l i e s i s a t the d i s t a l end of the l o n g arm. N e i t h e r f a m i l y w i t h Xg l i n k a g e i n f o r m a t i o n demonstrated a marker X chromosome; however, o n l y s t a n d a r d lymphocyte c u l t u r e c o n d i t i o n s were used. n. progeny o f X - l i n k e d m e n t a l l y r e t a r d e d males A l t h o u g h X - l i n k e d MR i n some f a m i l i e s may be a s s o c i a t e d w i t h a marker X chromosome, t h e r e i s s t i l l the q u e s t i o n of whether the MR i s due t o an X - l i n k e d r e c e s s i v e gene or an a u t o -somal dominant gene w i t h s e x - l i m i t e d e x p r e s s i o n . Another t e s t f o r l i n k a g e o t h e r than the use of markers on the X chromosome i s t o examine the progeny of a f f e c t e d males. I f the MR i s due t o a r e c e s s i v e gene on the X chromosome, o n l y normal sons and c a r r i e r d a u g h t e r s are ex p e c t e d among the progeny of a f f e c t e d males. I f i t i s due t o a s e x - l i m i t e d autosomal dominant gene, h a l f of the sons would be ex p e c t e d t o be m e n t a l l y r e t a r d e d and h a l f of the da u g h t e r s t o be c a r r i e r s . - 17 -There are two reasons why such a t e s t i s not p r a c t i c a l . F i r s t , m e n t a l l y r e t a r d e d males do not n o r m a l l y r e p r o d u c e . Second, i f they do have c h i l d r e n , mating i s u s u a l l y a s s o r t a t i v e w i t h r e s p e c t t o IQ. A s s o r t a t i v e mating may cause c o n f u s i o n i n r e c o g n i z i n g the e t i o l o g y o f the MR found i n any o f f s p r i n g . Progeny from a f f e c t e d males were r e p o r t e d , i n ' two k i n d r e d s . One a l l e g e d m e n t a l l y r e t a r d e d male i n a f a m i l y r e p o r t e d by Lehrke (1974) was m a r r i e d and had a daughter d e s c r i b e d as "not too b r i g h t " . The k i n d r e d r e p o r t e d by Deroover, e t a l . (1977), i n c l u d e d one r e t a r d e d male who was m a r r i e d w i t h f o u r d a u g h t e r s , two of whom were d e s c r i b e d as "f e e b l e - m i n d e d " . Among the daugh-t e r s ' o f f s p r i n g t h e r e were s i x a f f e c t e d males, f o u r normal males and twelve f e m a l e s , t h r e e of whom are m i l d l y r e t a r d e d . Such a r a t i o i s more c o m p a t i b l e w i t h the h y p o t h e s i s t h a t the MR i s due t o a r e c e s s i v e gene on the X chromosome than t o a s e x - l i m i t e d autosomal dominant gene. However, s e x - l i m i t e d autosomal dom-i n a n t i n h e r i t a n c e s t i l l cannot be d i s r e g a r d e d . Other e v i d e n c e f o r X - l i n k a g e comes from a f a m i l y d e s c r i b e d by T u r n e r , e t a l . (1971b), i n which a s e v e r e l y m e n t a l l y r e t a r d e d female w i t h Turner Syndrome (45,XO k a r y o t y p e ) , whose MR was c o m p a t i b l e w i t h X - l i n k a g e , was p r e s e n t . 2. Frequency of X - l i n k e d MR a. t h e o r e t i c a l e s t i m a t e A l t h o u g h the p u b l i s h e d p e d i g r e e s p r o v i d e e v i d e n c e t h a t a r e c e s s i v e gene (or genes) on the X chromosome (or s e x - l i m i t e d - 18 -autosomal dominant genes) cause MR, t h e r e i s s t i l l the q u e s t i o n of how f r e q u e n t t h i s p a r t i c u l a r p a t t e r n of MR i s . Lehrke (1974) attempted t o e s t a b l i s h a t h e o r e t i c a l range of the i n c i d e n c e o f an X - l i n k e d mental d e f e c t . H i s e s t i m a t e t h a t 33-1/3 t o 47% o f a l l MR i n males i s due t o X - l i n k e d genes i s n o t r e l i a b l e because of two unfounded and v e r y l i k e l y i n a c -c u r a t e a s s u m p t i o n s . He assumed the o v e r a l l e x c e s s of m e n t a l l y r e t a r d e d males t o be 50% which was r o u g h l y the median p e r c e n t a g e from s i x t e e n s t u d i e s - some o f which were o b v i o u s l y b i a s e d i n a s c e r t a i n m e n t . He a l s o assumed t h a t males w i t h an X - l i n k e d m ental d e f e c t are as r e p r o d u c t i v e l y f i t as normal males which i s not the c a s e . Because o f the absence o f any b i o c h e m i c a l or c o n s i s t e n t chromosomal a b n o r m a l i t y , and because of the v a r i a b i l i t y and u n o b t r u s i v e n e s s • o f a s s o c i a t e d a n o m a l i e s , f a m i l y h i s t o r i e s are the o n l y means of i d e n t i f y i n g X - l i n k e d MR. T h e r e f o r e , any study a t t e m p t i n g t o c a l c u l a t e the f r e q u e n c y o f X - l i n k e d MR must use f a m i l y h i s t o r y d a t a . b. g e n e r a l f a m i l y s u r v e y s S e v e r a l f a m i l y s u r v e y s of MR have been used t o e s t i m a t e the fr e q u e n c y o f v a r i o u s t y p e s o f MR. The most n o t a b l e are the C o l c h e s t e r study by Penrose (1938) and the Mi n n e s o t a f a m i l y study by Reed and Reed (1965). However, n e i t h e r study was de-s i g n e d t o a c c u r a t e l y c o n s i d e r the f r e q u e n c y of X - l i n k e d MR. - 19 -Penrose c o l l e c t e d i n f o r m a t i o n on s i b s , p a r e n t s , g r a n d -p a r e n t s and o t h e r c l o s e r e l a t i v e s of 1280 i n s t i t u t i o n a l r e s i -d e nts (710 males, 570 females) who were a heterogenous group e t i o l o g i c a l l y . The MR l e v e l of probands was d e t e r m i n e d by s t a n d a r d t e s t s w h i l e the m ental s t a t u s of r e l a t i v e s was d e t e r -mined l a r g e l y by i n t e r v i e w . Penrose d i d not s e p a r a t e the f a m i l i e s e t i o l o g i c a l l y f o r a n a l y s i s , but c o n s i d e r e d them as a whole. In o r d e r t o t e s t f o r s e x - l i n k e d genes, he compared the mental grades of the p a r e n t s w i t h those of the p a t i e n t s and t h e i r s i b s but c o u l d f i n d no s i g n i f i c a n t t r e n d s . A c c o r d i n g l y , he c o n c l u d e d t h e r e was i n s u f f i c i e n t e v i d e n c e t o s u p p o r t the view t h a t s e x - l i n k e d genes p l a y a s i g n i f i c a n t p a r t i n the e t i o l o g y o f mental r e t a r d a t i o n . Other a n a l y s e s of the C o l c h e s t e r d a t a (Dewey, e t a l . , 1965 and Morton, e t a l . , 1977) were i n c o n c l u s i v e w i t h r e s p e c t t o the f r e q u e n c y of s e x - l i n k e d genes. I t must be noted t h a t Penrose l i s t e d the m e n t a l s t a t u s of o n l y s i b s , p a r e n t s and g r a n d p a r e n t s f o r each proband s e p a r a t e l y . He grouped a l l o t h e r r e l a t i v e s t o g e t h e r ; i n such a heterogenous group any f a m i l y h i s t o r y of X - l i n k e d MR would not be d e t e c t a b l e . Reed and Reed (1965) p u b l i s h e d an e x t e n s i v e f o l l o w u p s t u d y on the f a m i l i e s of 289 persons who were i n The S t a t e S c h o o l and H o s p i t a l a t F a i r b a u l t , M i n n e s o t a d u r i n g the y e a r s 1911 t o 1918. A g a i n , t h i s sample of 289 probands from 1500 p a t i e n t s was h e t e r -ogenous w i t h r e s p e c t t o the e t i o l o g y of the m ental d e f e c t . - 20 -However, a s c e r t a i n m e n t was o b v i o u s l y b i a s e d even f o r an i n s t i -t u t i o n a l p o p u l a t i o n , e.g. any proband w i t h a h i s t o r y o f s e i z u r e s p r i o r t o i n s t i t u t i o n a l i z a t i o n was e l i m i n a t e d from the s t u d y . E x t e n s i v e p e d i g r e e s and IQ s c o r e s of many f a m i l y members were p u b l i s h e d f o r each proband. Over 80,000 i n d i v i d u a l s were i n c l u d e d i n the c h a r t s o f whom 1450 were r e t a r d e d (867 males and 583 f e m a l e s ) . P a u l s and Anderson (1972) and F r e i r e - M a i a , e t  a l . (1974) a n a l y s e d these d a t a and found them c o m p a t i b l e w i t h a s e x - m o d i f i e d m u l t i f a c t o r i a l t h r e s h o l d h y p o t h e s i s f o r MR. No attempt was made i n e i t h e r a n a l y s i s t o omit those f a m i l i e s i n which the cause f o r the MR was known or i n which the h i s t o r y sug-ge s t e d a s i n g l e X - l i n k e d gene as the e t i o l o g y . As F r e i r e - M a i a , e t a l . (1974) p o i n t e d out / ' e t i o l o g y of mental r e t a r d a t i o n i s o b v i o u s l y heterogeneous?, and none of the [ t h r e e m u l t i f a c t o r i a l t h r e s h o l d ] models [ t e s t e d ] i s l i k e l y t o be t r u e f o r more than a p r o p o r t i o n of f a m i l i e s a t most". A b e t t e r i n d i c a t i o n o f the f r e q u e n c y of X - l i n k e d MR might be o b t a i n e d by p e r s o n a l e x a m i n a t i o n of the 289 p e d i g r e e s . Such an e x a m i n a t i o n r e v e a l e d . t h a t 31 f a m i l i e s (11%) had an X - l i n k e d p a t t e r n of i n h e r i t a n c e and no o t h e r d e f i n i t e cause f o r the MR. Another 23 f a m i l i e s (8%) had a f f e c t e d males i n o n l y one g e n e r a t i o n . c. males w i t h n o n - s p e c i f i c MR Turner and c o l l e a g u e s c o n s i d e r e d the q u e s t i o n of the f r e -quency of X - l i n k e d MR i n s e v e r a l d i f f e r e n t s t u d i e s ( T u r n e r , - 21 -e t a l . , 1971b;Turner, e t a l . , 1972 and Turner and T u r n e r , 1974). Over a two year p e r i o d , 148 m o d e r a t e l y r e t a r d e d (IQ 36-51) males ( e x c l u d i n g c a s e s of Down Syndrome) were a s c e r t a i n e d from the r e c o r d s o f a d i a g n o s t i c and e v a l u a t i o n c l i n i c i n Sydney, A u s t r a l i a (Turner, e t a l . , 1970;; T u r n e r , e t a l . , 1971b). Seventeen (11%) o f the 148 males had n e i t h e r a major p h y s i c a l a b n o r m a l i t y nor d e f i n i t e d i a g n o s i s . Of the s e seven-t e e n , f i v e had a f a m i l y h i s t o r y c o m p a t i b l e w i t h X - l i n k a g e w h i l e s i x more had a s i m i l a r l y a f f e c t e d b r o t h e r . In c o n t r a s t , o f the 131 males w i t h major p h y s i c a l a b n o r m a l i t i e s or a d e f i n i t e d i a g -n o s i s , o n l y 23 had a s i m i l a r l y a f f e c t e d s i b , of whom ten were b r o t h e r s , and none had a f a m i l y h i s t o r y s u g g e s t i n g an e t i o l o g y of X - l i n k e d genes. Turner and her c o l l e a g u e s thus c o n c l u d e d t h a t t h e r e was an e n t i t y (termed Renpenning Syndrome) o f X-l i n k e d MR w i t h o u t major p h y s i c a l a b n o r m a l i t i e s which c o u l d a c -count f o r a p p r o x i m a t e l y 10% o f m o d e r a t e l y r e t a r d e d males. As f u r t h e r e v i d e n c e t h a t X - l i n k e d MR i s common, e i g h t e e n a f f e c t e d b r o t h e r p a i r s were a s c e r t a i n e d from 488 male p a t i e n t s of the Peat and M i l s o n I s l a n d H o s p i t a l i n New South Wales (Turner, e t a l . , 1972). Of the e i g h t e e n s i b s h i p s , e l e v e n c o n s i s t e d of males who showed no major p h y s i c a l s t i g m a t a and s i x of these had a f a m i l y h i s t o r y w i t h a p a t t e r n of X - l i n k e d i n h e r i t a n c e . - 22 -d. m u l t i p l y a f f e c t e d s i b s h i p s In order to o b t a i n a more homogeneous group whose MR was l i k e l y to be due to g e n e t i c causes, s e v e r a l r e s e a r c h e r s l i m i t e d t h e i r study to i n s t i t u t i o n a l r e s i d e n t s who had s i m i l a r l y a f -f e c t e d s i b l i n g s (Wright, et. a l . , 1959; P r i e s t , et a l . , 1961; Wortis, et a l . , 1966). In a l l three s t u d i e s there was a g r e a t -er preponderance of f a m i l i e s i n which only male s i b l i n g s were ment a l l y r e t a r d e d compared to f a m i l i e s with only females a f -f e c t e d . The r a t i o s of s i b s h i p s with o n l y males a f f e c t e d com-pared to s i b s h i p s with o n l y females a f f e c t e d were 26:6 (Wright, e t a l . , 1959), 26:10 ( P r i e s t , e t a l . , 1961) and 15:2 (Wortis, et a l . , 1966). The l a s t r a t i o excluded p s y c h i a t r i c cases i n c l u d e d with MR i n the o r i g i n a l study. In a l l three s t u d i e s over 80% of the mentally r e t a r d e d cases with a s i m i l a r -l y a f f e c t e d s i b l i n g had no s p e c i f i c e t i o l o g y other than " c u l -t u r a l - f a m i l i a l " or " c o n g e n i t a l not f u r t h e r s p e c i f i e d " . R e s u l t s from a l l three s t u d i e s suggest t h a t X - l i n k e d genes may be a frequent cause of n o n - s p e c i f i c MR i n males. Davison (1973) conducted a more thorough study than any up to that time. She a s c e r t a i n e d f a m i l i e s with two or more s e v e r e l y subnormal (IQ 50 or l e s s ) s i b l i n g s i n the Oxford, England r e g i o n through the Mental Health Departments of L o c a l A u t h o r i t i e s , the h o s p i t a l s admitting mentally d e f e c t i v e pa-t i e n t s and: g e n e r a l p r a c t i t i o n e r s . T h i r t y out of 171 f a m i l i e s , in which the MR was of known e t i o l o g y , were e l i m i n a t e d from the - 23 -s t u d y . Each proband was g i v e n a s t a n d a r d c l i n i c a l e x a m i n a t i o n , a b u c c a l smear and hand p r i n t s were taken whenever p o s s i b l e . U r i n e samples from 67% o f the probands were t e s t e d by amino a c i d chromatography and i n 60 c a s e s the u r i n e of the mothers was t e s t e d f o r p h e n y l k e t o n u r i a . Of the 141 f a m i l i e s w i t h non-s p e c i f i c s e v e r e l y subnormal MR, 50 f a m i l i e s had o n l y males a f -f e c t e d w h i l e 21 f a m i l i e s had o n l y females a f f e c t e d . E i g h t o f the 50 f a m i l i e s i n which o n l y males were a f f e c t e d had p e d i g r e e e v i d e n c e s u g g e s t i n g X - l i n k a g e . D a v ison c o n s i d e r e d her d a t a as e v i d e n c e f o r a s u b s t a n t i a l c o n t r i b u t i o n t o i d i o p a t h i c severe s u b n o r m a l i t y by X - l i n k e d r e c e s s i v e genes. However, because of i n c o m p l e t e a s c e r t a i n m e n t i n a p o o r l y d e f i n e d p o p u l a t i o n ' , she d i d not attempt t o c a l c u l a t e the f r e q u e n c y of such genes. By u s i n g d a t a of m e n t a l l y r e t ar d e d c h i l d r e n (TQ 30-55) who were born over a t e n year p e r i o d i n New South W.ales and who were a t t e n d -i n g s p e c i a l s c h o o l s or i n s t i t u t i o n s , Turner and Turner (1974) e s t i m a t e d t h a t 20% o f a l l m e n t a l l y r e t a r d e d males may have X-l i n k e d MR. They c a l c u l a t e d a p r e v a l e n c e r a t e o f 0.74/1000 f e -males f o r female c a r r i e r s o f X - l i n k e d MR. Though i t was not r e p o r t e d , such an e s t i m a t e i m p l i e s t h a t 0.55/1000 males i n the p o p u l a t i o n may have X - l i n k e d MR. These e s t i m a t e s were based on the assumption t h a t X - l i n k e d genes account f o r a l l o f the e x c e s s of s i b s h i p s w i t h o n l y a f -f e c t e d males among s i b s h i p s w i t h two or more a f f e c t e d s i b s of the same sex. In o t h e r words, they assumed t h a t a l l of the - 24 -mothers of the excess male a f f e c t e d s i b s h i p s are c a r r i e r s of X- l i n k e d r e c e s s i v e genes f o r MR. Since f a m i l y h i s t o r i e s were not r e p o r t e d , such an assumption may or may not be v a l i d . A l s o , in c a l c u l a t i n g the prevalence r a t e , Turner and Turner d i d not exclude probands with MR of known e t i o l o g y other than Down Syndrome. T h e r e f o r e , t h e i r estimated frequency of X - l i n k e d MR may not be a c c u r a t e . C. SUMMARY In summary, p o p u l a t i o n data on i n t e l l i g e n c e present a skewed or shouldered curve with more mentally r e t a r d e d i n d i v i -d u als than expected from a simple m u l t i f a c t o r i a l mode of i n -he r i t a n c e f o r i n t e l l i g e n c e . S t u d i e s of the frequency of MR i n a p o p u l a t i o n show an excess of males who are a f f e c t e d . MR i n h e r i t e d i n an X - l i n k e d r e c e s s i v e manner has been reported i n a number of f a m i l i e s . The c l i n i c a l f e a t u r e s a s s o c i a t e d with t h i s p a t t e r n of MR seem to be minor anomalies with v a r i a b l e ex-p r e s s i o n among a f f e c t e d males i n the same f a m i l y . The most d i s t i n g u i s h i n g and c o n s i s t e n t of •"' the f e a t u r e s apparent i n some f a m i l i e s (not n e c e s s a r i l y i n the same family) may be lack of v e r b a l a b i l i t y , m a c r o - g e n i t a l i a and a marker X chromosome. The frequency of t h i s type of MR has not been a c c u r a t e l y estimated nor has the q u e s t i o n of whether or not the frequency of X-l i n k e d MR can account f o r the excess ive -proportion o f _ m e n t a l l y ret a r d e d males'been answered. The present study of X - l i n k e d MR i n B r i t i s h Columbia examines these questions and attempts to answer them. - 25 -CHAPTER I I METHODS A. DEFINITIONS 1. MR T h i s s t u d y has adopted the d e f i n i t i o n of MR used by the American A s s o c i a t i o n on M e n t a l D e f i c i e n c y (AAMD) which d e f i n e s i t i n the f o l l o w i n g manner: M e n t a l r e t a r d a t i o n r e f e r s t o s i g n i f i c a n t l y sub-average g e n e r a l i n t e l l e c t u a l f u n c t i o n i n g e x i s t i n g c o n c u r r e n t l y w i t h d e f i c i t s i n a d a p t i v e b e h a v i o r and m a n i f e s t e d d u r i n g the d e v e l o p m e n t a l p e r i o d (AAMD, 1973, p. 11) I n t e l l e c t u a l f u n c t i o n i n g may be a s s e s s e d on any o f the s t a n d a r d i z e d t e s t s . A measured I n t e l l i g e n c e Q u o t i e n t (IQ) of more than two s t a n d a r d d e v i a t i o n s below the mean - l e s s than 68 on S t a n f o f d - B i n e t and C a t t e l l s c a l e s or l e s s than 70 on the Wechsler s c a l e - i s c o n s i d e r e d s i g n i f i c a n t l y subaverage. The IQ s c o r e s are based i n i t i a l l y on the assumption t h a t i n t e l l e c -t u a l f u n c t i o n i n g measured by these t e s t s i s d i s t r i b u t e d a c c o r d -i n g t o a normal p r o b a b i l i t y c u r v e i n the g e n e r a l p o p u l a t i o n . A d a p t i v e b e h a v i o r i s d e f i n e d as the e f f e c t i v e n e s s or de-gree w i t h which the i n d i v i d u a l meets the s t a n d a r d s o f p e r s o n a l independence and s o c i a l r e s p o n s i b i l i t y e x p e c t e d of h i s age and c u l t u r a l group ( i b i d • , p. 1 1 ) . I t i s o b v i o u s l y v e r y d i f f i c u l t - 26 -q u a n t i f y and measure f u n c t i o n i n g i n s p e c i f i c a r e a s such as s e l f - h e l p , communication, and s o c i a l i z a t i o n a l t h o u g h some t e s t s , such as the V i n e l a n d S o c i a l M a t u r i t y S c a l e , attempt t o p r o v i d e an o v e r a l l g e n e r a l i n d e x , the S o c i a l Q u o t i e n t (SQ). The AAMD s t r e s s e s t h a t both s i g n i f i c a n t l y subaverage i n t e l -l e c t u a l f u n c t i o n i n g and d e f i c i t s i n a d a p t i v e b e h a v i o r are neces-s a r y t o make a d i a g n o s i s of MR, a l t h o u g h MR i s o f t e n s i m p l y d e s c r i b e d i n terms of an IQ s c o r e i n the l i t e r a t u r e . 2. L e v e l s of MR T h i s s t u d y r e f e r s t o the same l e v e l s of MR adopted by the World H e a l t h O r g a n i z a t i o n (WHO) and the AAMD namely, m i l d , moderate, severe and p r o f o u n d . These c a t e g o r i e s are s c a l e d i n terms of s t a n d a r d d e v i a t i o n u n i t s s i g n i f i c a n t l y below the mean on s t a n d a r d i z e d i n t e l l i g e n c e t e s t s . The IQ ranges f o r t h r e e f r e q u e n t l y used i n t e l l i g e n c e t e s t s and the c o r r e s p o n d i n g l e v e l s of m e n t a l r e t a r d a t i o n are p r e s e n t e d i n Table I I I . The b o r d e r -l i n e c a t e g o r y (IQ v a l u e s between one and two s t a n d a r d d e v i a t i o n s below the mean), used e a r l i e r i n AAMD and WHO c l a s s i f i c a t i o n systems, has been dropped from t h i s c l a s s i f i c a t i o n , ( i b i d . , p. 18; I n t e r n a t i o n a l C l a s s i f i c a t i o n of D i s e a s e s , 1977, pp. 212-213). SQ v a l u e s from the V i n e l a n d S o c i a l M a t u r i t y S c a l e measur-in g a d a p t i v e b e h a v i o r are comparable t o IQ v a l u e s . They are a l s o c a t e g o r i z e d i n t o L e v e l s I through IV as p r e s e n t e d i n Table IV. With a s t a n d a r d d e v i a t i o n o f 16 the l e v e l s b e g i n one - 27 -Table I I I L e v e l s o f MR I n t e l l i g e n c e Q u o t i e n t (IQ) L e v e l S t a n f o r d - B i n e t and C a t t e l l S c a l e s (sd*=16) Wechsler S c a l e (sd*=15) M i l d Moderate Severe Profound 3sd<IQ<2sd 4sd<IQ<3sd 5sd<IQ<4sd IQ<5sd 67-52 51-36 35-20 19 and below 69-55 54-40 39-25 ( e x t r a p o l a t e d ) 24 and below ( e x t r a p o l a t e d ) * sd = s t a n d a r d d e v i a t i o n - 28 -Table IV L e v e l s o f A d a p t i v e B e h a v i o r S o c i a l Q u o t i e n t (SQ) V i n e l a n d S o c i a l M a t u r i t y S c a l e L e v e l (sd*=16) I 83-64 I I 63-44 I I I 43-24 IV 23 and below * sd - s t a n d a r d d e v i a t i o n - 29 -s t a n d a r d d e v i a t i o n below the mean. Each of the l e v e l s i n c l u d e s one and o n e - f o u r t h s t a n d a r d d e v i a t i o n u n i t s , or 20 p o i n t s ( D o l l , 1947) . Numerous c l a s s i f i c a t i o n systems f o r MR have been used i n the p a s t and are s t i l l f r e q u e n t l y r e f e r r e d t o i n the l i t e r a t u r e as w e l l as i n m e d i c a l f i l e s . A comparison of c l a s s i f i c a t i o n systems by G e l o f (1963) has been u s e f u l i n s t a n d a r d i z i n g the r e p o r t s on m e n t a l l y r e t a r d e d i n d i v i d u a l s . 3. P a t t e r n o f X - l i n k a g e An X - l i n k e d r e c e s s i v e t r a i t i s n o r m a l l y i n h e r i t e d e i t h e r through an u n a f f e c t e d h e t e r o z y g o u s " c a r r i e r " female or through a hemizygous a f f e c t e d male. Among the c h i l d r e n of a h e t e r o -zygous female and normal male, a l l o f the d a u g h t e r s w i l l be p h e n o t y p i c a l l y n o r m a l , a l t h o u g h one h a l f w i l l a l s o be c a r r i e r s , and one h a l f of the males w i l l e x p r e s s the t r a i t w h i l e the o t h e r h a l f w i l l be n o r m a l . In the case o f a t r a i t l i k e MR, v e r y few of the a f f e c t e d males r e p r o d u c e , so such p a t t e r n s of X - l i n k a g e through an a f f e c t e d male can e s s e n t i a l l y be i g n o r e d . I t i s v e r y d i f f i c u l t t o d i s t i n g u i s h between i n h e r i t a n c e due t o an autosomal dominant gene w i t h s e x - l i m i t e d e x p r e s s i o n and i n h e r i t a n c e due t o an X - l i n k e d gene w i t h s i m i l a r phenotype i f a f f e c t e d males do not r e p r o d u c e . T h e r e f o r e , even though the terms X - l i n k e d i n h e r i t a n c e and X - l i n k e d genes are used f o r the sake of s i m p l i c i t y t h r o u g h o u t the s t u d y , autosomal dominant - 30 -genes w i t h s e x - l i m i t e d e x p r e s s i o n remain an e q u a l l y p o s s i b l e e t i o l o g y . In t h i s s t u d y two c r i t e r i a are used t o i d e n t i f y a f a m i l y w i t h X - l i n k e d MR. In a k i n d r e d m e n t a l l y r e t a r d e d males must be found i n a t l e a s t two s i b s h i p s i n which the mothers are r e l a t e d and may have a t l e a s t one X chromosome i n common. A l s o , the MR must have no o t h e r a p p arent e t i o l o g y . B. ASCERTAINMENT 1. MR i n B r i t i s h Columbia Data on MR i n B r i t i s h Columbia were o b t a i n e d from the B.C. H e a l t h S u r v e i l l a n c e R e g i s t r y ( f o r m e r l y the R e g i s t r y f o r Handicapped C h i l d r e n and A d u l t s ) , which h e r e a f t e r w i l l be r e -f e r r e d t o as the R e g i s t r y , up t o the end o f 1977. S i n c e the R e g i s t r y has m u l t i p l e s o u r c e s of a s c e r t a i n m e n t and i t s a s c e r -t ainment has been an ongoing procedure s i n c e the R e g i s t r y ' s i n c e p t i o n i n 1952, the r e g i s t r a t i o n of c a s e s of MR i n o l d e r c h i l d r e n and young a d u l t s among B r i t i s h Columbian r e s i d e n t s would approach complete a s c e r t a i n m e n t . Cases of MR a s c e r -t a i n e d among young c h i l d r e n w i l l be low because MR cannot n o r -m a l l y be d i a g n o s e d a t b i r t h and many c h i l d r e n are not brought t o the a t t e n t i o n of a p p r o p r i a t e a g e n c i e s u n t i l s c h o o l age. S i n c e the R e g i s t r y r e g i s t e r e d o n l y c h i l d r e n from 1952 t o A p r i l , 1960, the t o t a l number of m e n t a l l y r e t a r d e d a d u l t s r e g i s t e r e d i s l i k e l y t o be low. - 31 -D u r i n g the y e a r s 1975 t o 1977 when i n f o r m a t i o n was r e -t r i e v e d , the R e g i s t r y used the c l a s s i f i c a t i o n system f o r MR recommended by the 8 t h R e v i s i o n of the I n t e r n a t i o n a l C l a s s i f i - c a t i o n o f D i s e a s e s , Adapted (ICDA) p r e s e n t e d i n Table V. The c a ses a t the b o r d e r l i n e l e v e l (310 c a t e g o r y ) of MR have not been i n c l u d e d among the index c ases i n t h i s s t u d y f o r two r e a s o n s . F i r s t , i n d i v i d u a l s w i t h an IQ i n the b o r d e r l i n e range are not n o r m a l l y c o n s i d e r e d m e n t a l l y r e t a r d e d by c u r r e n t d e f i -n i t i o n . Second, because of t:he;mild h a n d icap of an IQ between 68-85, a s c e r t a i n m e n t would be low and p o s s i b l y b i a s e d towards those w i t h a s s o c i a t e d h a n d i c a p s . Those index c a s e s regar d e d as h a v i n g n o n - s p e c i f i c MR i n c l u d e d a l l those w i t h the f o u r t h d i g i t s u b d i v i s i o n s of .4, .6, .8 and .9 (Table V) . The R e g i s t r y p r o v i d e d i n f o r m a t i o n on the numbers of men-t a l l y r e t a r d e d p ersons l i v i n g i n B r i t i s h Columbia a t y e a r - e n d , 1977. The c a s e s were c a t e g o r i z e d by degree of MR, e t i o l o g i c a l f o u r t h d i g i t s u b d i v i s i o n , age group, and sex. Cases of MR i n c h i l d r e n (<_ 19 y e a r s ) were f u r t h e r a n a l y z e d and were c l a s s i f i e d i n t o those w i t h n o n - s p e c i f i c MR and those whose MR had a s p e c -i f i e d e t i o l o g y . In o r d e r t o c a l c u l a t e a minimum i n c i d e n c e r a t e of non-s p e c i f i c MR i n g e n e r a l , d a t a on p ersons w i t h n o n - s p e c i f i c MR from a b i r t h c o h o r t were used. The b i r t h c o h o r t i n c l u d e d a l l i n d i v i d u a l s w i t h n o n - s p e c i f i c MR who were born between 1950 and - 32 -Table V C l a s s i f i c a t i o n of MR i n the H e a l t h S u r v e i l l a n c e R e g i s t r y * C a t e g o r y Degree of MR IQ 310 B o r d e r l i n e 68-85 311 M i l d ' 52-67 312 Moderate 36-51 313 Severe 20-35 314 P r o f o u n d <20 315 U n s p e c i f i e d The f o l l o w i n g f o u r t h d i g i t s u b d i v i s i o n s are used s i g n i f y i n g e t i o l o g y : .0 F o l l o w i n g i n f e c t i o n s and i n t o x i c a t i o n s .1 F o l l o w i n g trauma or p h y s i c a l agents .2 With d i s o r d e r s o f m e t a b o l i s m , growth or n u t r i t i o n .3 A s s o c i a t e d w i t h g r o s s b r a i n d i s e a s e ( p o s t n a t a l ) .4 A s s o c i a t e d w i t h d i s e a s e s and c o n d i t i o n s due t o (unknown) p r e n a t a l i n f l u e n c e .5 With chromosomal a b n o r m a l i t i e s .6 A s s o c i a t e d w i t h p r e m a t u r i t y .7 F o l l o w i n g major p s y c h i a t r i c d i s o r d e r .8 With p s y c h o - s o c i a l ( e n v i r o n m e n t a l ) d e p r i v a t i o n .9 Other and u n s p e c i f i e d * Coded i n c o n f o r m i t y w i t h the 8th R e v i s i o n o f the I n t e r -n a t i o n a l C l a s s i f i c a t i o n o f D i s e a s e s , Adapted - 33 -1969 i n c l u s i v e i n B r i t i s h Columbia and who were r e g i s t e r e d i n the R e g i s t r y whether a l i v e or dead a t year-end 1977. I t was d e c i d e d t o use the twenty year p e r i o d of 1950-1969 because cases born i n B r i t i s h Columbia d u r i n g t h i s p e r i o d were l i k e l y t o be a s c e r t a i n e d by the R e g i s t r y by 1977. 2. S i b s h i p Data Data on s i b s h i p s w i t h two or more n o n - s p e c i f i c m e n t a l l y r e t a r d e d s i b s were o b t a i n e d by a hand s e a r c h o f the r e g i s t r a t i o n c a r d s of c a s e s a t a l l l e v e l s of MR w i t h the s u b d i v i s i o n s o f .4, .6, .8 and .9 i n the R e g i s t r y (Table V ) . H a l f - s i b l i n g s w i t h the same mother were c o n s i d e r e d t o be i n one s i b s h i p . Twins or t r i p l e t s were counted as one s i b l i n g and were not i n c l u d e d u n l e s s another s i b l i n g was a l s o r e g i s t e r e d as m e n t a l l y r e t a r d e d . S i b s h i p s where the MR was of unknown cause i n one s i b but of known c a u s e , i . e . Down Syndrome, i n another s i b , were a l s o o m i t t e d . I f upon f u r t h e r i n v e s t i g a t i o n a case of MR r e g i s t e r e d as n o n - s p e c i f i c was found t o have a s p e c i -f i c e t i o l o g y or be a s s o c i a t e d w i t h muscular d y s t r o p h y , i t , t o o , was o m i t t e d from the s i b s h i p sample. The s i b s h i p s w i t h two or more n o n - s p e c i f i c m e n t a l l y r e -t a r d e d s i b s were d i v i d e d i n t o t h r e e c a t e g o r i e s : those w i t h o n l y males a f f e c t e d ; those w i t h o n l y females a f f e c t e d ; and those w i t h males and females a f f e c t e d . A g a i n , i n o r d e r to e l i m i n a t e any a s c e r t a i n m e n t b i a s e s i n the o l d e r and younger age groups a s i m i l a r b i r t h c o h o r t was - 34 -used f o r s i b s h i p s . The a f f e c t e d s i b s must have been born i n B r i t i s h Columbia and a t l e a s t one must have been born between 1950-1969 i n c l u s i v e . 3. F a m i l y H i s t o r i e s In o r d e r t o d e t e c t those f a m i l i e s w i t h a p a t t e r n of X - l i n k e d i n h e r i t a n c e of n o n - s p e c i f i c MR, f a m i l y h i s t o r i e s were o b t a i n e d on n o n - s p e c i f i c m e n t a l l y r e t a r d e d males who were r e g i s t e r e d as h a v i n g another a f f e c t e d r e l a t i v e . F a m i l y i n f o r m a t i o n was ob-t a i n e d from s e v e r a l s o u r c e s : m e d i c a l f i l e s a t Woodlands S c h o o l , T r a n q u i l l e , and the Department of M e d i c a l G e n e t i c s , U.B.C. and by p e r s o n a l i n t e r v i e w s . I n f o r m a t i o n e x t r a c t e d from the m e d i c a l f i l e s i n c l u d e d s u s -p e c t e d e t i o l o g y of the MR i n the proband, p e r t i n e n t p e r s o n a l h i s t o r y , v i t a l d a t a and mental s t a t u s of s i b s , p a r e n t s , a u n t s , u n c l e s , and g r a n d p a r e n t s . S i m i l a r i n f o r m a t i o n was a l s o r e c o r d e d f o r n i e c e s , nephews, and c o u s i n s i f a v a i l a b l e . Much of t h i s i n f o r m a t i o n was c o m p i l e d i n the m e d i c a l f i l e a t the time of d i a g n o s i s and/or ad m i t t a n c e of a proband i n t o an i n s t i t u t i o n f o r the m e n t a l l y r e t a r d e d , such as Woodlands S c h o o l or T r a n -q u i l l e . In o r d e r t o check the a c c u r a c y of the f a m i l y h i s t o r i e s o b t a i n e d from m e d i c a l f i l e s and t o update the f a m i l y i n f o r m a -t i o n , i n t e r v i e w s were conducted e i t h e r i n person or by t e l e -phone. F a m i l i e s w i t h two or more males w i t h n o n - s p e c i f i c MR i n - 35 -one s i b s h i p , or- w i t h a p a t t e r n of X - l i n k e d i n h e r i t a n c e f o r the MR, were c o n t a c t e d t h rough the agency through which the proband had been a s c e r t a i n e d . I f the agency was Woodlands S c h o o l , a l e t t e r e x p l a i n i n g the s t u d y and a s k i n g f o r t h e i r p a r t i c i p a t i o n was s e n t to the f a m i l y a l o n g w i t h a c o v e r i n g l e t t e r from Dr. B. T i s c h l e r , M e d i c a l D i r e c t o r of Woodlands S c h o o l . A form t o be f i l l e d out i n d i c a t i n g t h e i r i n t e r e s t and a p r e p a i d r e p l y envelope were a l s o included... C o p i e s of" these . l e t t e r s and the form are i n Appendix I I . I f the c o n t a c t agency was T r a n q u i l l e , a s o c i a l worker t h e r e i n i t i a l l y c o n t a c t e d the f a m i l y . I f the f a m i l y was i n t e r e s t e d i n p a r t i c i p a t i n g i n the s t u d y , p e r m i s s i o n was then g r a n t e d by Dr. J . Bower, E x e c u t i v e D i r e c t o r of T r a n q u i l l e , t o c o n t a c t the f a m i l y d i r e c t l y . I n t e r v i e w s were conducted e i t h e r i n person or by t e l e p h o n e . At t h a t time a q u e s t i o n n a i r e , a copy of which i s i n Appendix I I , was g i v e n o r a l l y and completed by the i n t e r v i e w e r . A f t e r the i n t e r v i e w , comments r e g a r d i n g the i n t e r v i e w e e ' s a t t i t u d e s and c o n c e r n s f o r the MR i n the f a m i l y were noted on the back of the q u e s t i o n n a i r e . A note e x p r e s s i n g a p p r e c i a t i o n and thanks f o r t h e i r c o - o p e r a t i o n was s u b s e q u e n t l y s e n t t o each p a r t i c i -p a t i n g f a m i l y . 4. A s s o c i a t e d C l i n i c a l F e a t u r e s of X - l i n k e d MR In f a m i l i e s w i t h a p a t t e r n o f n o n - s p e c i f i c MR s u g g e s t i n g X - l i n k e d i n h e r i t a n c e , i n f o r m a t i o n r e g a r d i n g the c l i n i c a l - 36 -f e a t u r e s of a f f e c t e d males was o b t a i n e d from the m e d i c a l f i l e s a t Woodlands S c h o o l , T r a n q u i l l e and the Department of M e d i c a l G e n e t i c s , U.B.C.. I n f o r m a t i o n r e c o r d e d i n c l u d e d : r e s u l t s of b i o c h e m i c a l t e s t s , k a r y o t y p e , IQ t e s t s c o r e s , IQ s t r e n g t h s or weaknesses, speech d e f e c t s , SQ t e s t s c o r e s , b i r t h h i s t o r y , h e i g h t , head c i r c u m f e r e n c e , h i s t o r y of e p i l e p s y , motor c o n t r o l , u n u s u a l or abnormal p h y s i c a l f e a t u r e s and b e h a v i o r a l d i s o r d e r s . A sample of the form used t o r e c o r d t h i s i n f o r m a t i o n i s i n Appendix 11. 5. B r i t i s h Columbia F a m i l y Data Data from the B r i t i s h Columbia Record L i n k a g e P r o j e c t were used i n o r d e r t o g e t an e s t i m a t e o f the number of mothers who gave b i r t h t o two or more sons i n B r i t i s h C o lumbia, a t l e a s t one of whom was born between 1950-1969 i n c l u s i v e . The Record L i n k -age P r o j e c t has c o m p i l e d a l l B r i t i s h Columbia v i t a l r e c o r d s of m a r r i a g e and b i r t h s from 1946 t o 1970 i n t o f a m i l y groups o r , i f no m a r r i a g e r e c o r d was a v a i l a b l e , i n t o s i b g r o u p s ( T r i m b l e , 1976). The number of the mothers meeting the above c r i t e r i a was then used t o c a l c u l a t e the e s t i m a t e d f r e q u e n c y o f X - l i n k e d MR i n B r i t i s h C o lumbia. C. ANALYSIS 1. Sex R a t i o A c c o r d i n g t o B r i t i s h Columbia p o p u l a t i o n v i t a l s t a t i s t i c s , the male-female r a t i o f o r c h i l d r e n (<: 19 y e a r s ) i n the p r o v i n c e - 37 -i s 1.04:1 ( B r i t i s h Columbia Dept. o f H e a l t h , 1974, p. 3 0 ) . There i s no d i f f e r e n c e i n outcome i n u s i n g the 1.04:1 r a t i o i n s t e a d of a 1:1 r a t i o i n t e s t i n g the sex r a t i o o f v a r i o u s groups i n t h i s s t u d y . T h e r e f o r e , an e x p e c t e d 1:1 sex r a t i o i s used i n a n a l y z -i n g d a t a f o r the sake of s i m p l i c i t y . 2. S t a t i s t i c a l T e s t s S t a n d a r d s t a t i s t i c a l t e s t s have been used t o t e s t appro-p r i a t e d a t a . A comparison o f the v a r i a t i o n i n " l e v e l s -of MR between males and females was t e s t e d by a n a l y s i s o f v a r i -ance. A s i m i l a r comparison of the d i s t r i b u t i o n between cases o f n o n - s p e c i f i c MR and. c a s e s o f MR w i t h a s p e c i f i e d e t i o l o g y was a l s o made. A d i f f e r e n c e i n d i s t r i b u t i o n s was r e g a r d e d s i g n i f i -c a n t a t the 5% l e v e l . C h i square t e s t s have been used t o t e s t the s i g n i f i c a n c e of the d e v i a t i o n from e x p e c t e d numbers of males and females and from e x p e c t e d numbers of m e n t a l l y r e t a r d e d and normal s i b s . Be-cause of the d i f f i c u l t y i n d i a g n o s i n g MR i n young c h i l d r e n , 5 y e a r s of age was a r b i t r a r i l y s e t as the minimum d i a g n o s a b l e age f o r MR. Those s i b s who d i e d b e f o r e 5 y e a r s o f age were o m i t t e d from the sample b e f o r e the i n i t i a l c h i square a n a l y s i s was p e r -formed. I f the p r o b a b i l i t y o f the outcome was between .05 and .01 the d e v i a t i o n was c o n s i d e r e d q u e s t i o n a b l y s i g n i f i c a n t . I f the p r o b a b i l i t y was l e s s than or e q u a l t o .01, the d e v i a t i o n was r e g a r d e d t o be h i g h l y s i g n i f i c a n t . - 38 -In o r d e r t o i n v e s t i g a t e the p o s s i b i l i t y o f a g r e a t e r than e xpected number of mothers c a r r y i n g an X - l i n k e d MR gene due t o new m u t a t i o n s , the g r a n d p a r e n t s ' ages a t the time the mother was born were a n a l y z e d . A n a l y s i s of v a r i a n c e was used t o com-pare the m a t e r n a l g r a n d p a r e n t s ' ages a t the time of the mother's b i r t h w i t h c o n t r o l s . The p a t e r n a l g r a n d p a r e n t s ' ages a t the time the f a t h e r was born were used as i n t r a - p e d i g r e e c o n t r o l s . 3. C a l c u l a t i o n s The minimum i n c i d e n c e o f n o n - s p e c i f i c MR was c a l c u l a t e d f o r males and females u s i n g d a t a on c a s e s of n o n - s p e c i f i c MR f o r the 1950-1969 b i r t h c o h o r t from the R e g i s t r y . The number of l i v e b i r t h s f o r the same p e r i o d was o b t a i n e d from the B r i t i s h Columbia Dept. of H e a l t h (1974). The minimum f r e q u e n c y of X - l i n k e d MR was c a l c u l a t e d u s i n g the method of Turner and Turner (1974). The e x c e s s number of s i b s h i p s w i t h two or more males w i t h n o n - s p e c i f i c MR i n the 1950-1969 b i r t h c o h o r t were used t o e s t i m a t e the number of mothers c a r r y i n g a gene f o r X - l i n k e d MR. That e s t i m a t e and . the number of mothers g i v i n g b i r t h t o two or more sons i n t h a t same p e r i o d were used i n c a l c u l a t i n g the f r e q u e n c y of females c a r r y i n g a gene f o r X - l i n k e d MR i n the B r i t i s h Colum-b i a p o p u l a t i o n . S i n c e , i n an X - l i n k e d r e c e s s i v e l e t h a l d i s e a s e i n a p o p u l a t i o n a t e q u i l i b r i u m , the i n c i d e n c e of a f f e c t e d males i s t h r e e - f o u r t h s t h a t o f the i n c i d e n c e of female c a r r i e r s - 39 -( C a r t e r , 1969, p. 4 7 ) , the f r e q u e n c y of males w i t h X - l i n k e d MR was thus c a l c u l a t e d . T h i s f r e q u e n c y was then t e s t e d t o see i f i t c o u l d account f o r the e x c e s s of n o n - s p e c i f i c m e n t a l l y r e -t a r d e d males i n the p o p u l a t i o n of B r i t i s h C olumbia. - 40 -CHAPTER I I I RESULTS A. MR IN BRITISH COLUMBIA The R e g i s t r y p r o v i d e d i n f o r m a t i o n on the numbers o f men-t a l l y r e t a r d e d persons l i v i n g i n B r i t i s h C o lumbia. In Appendix I I I , the l i v i n g c a s e s r e c o r d e d a t y e a r - e n d , 1977, are c a t e -g o r i z e d by degree of MR, e t i o l o g i c a l f o u r t h d i g i t s u b d i v i s i o n , age group, and sex. S i n c e r e g i s t r a t i o n s o f handicapped a d u l t s are l i k e l y t o be low owing t o a s c e r t a i n m e n t b i a s , Table VI summarizes the d a t a on i n d i v i d u a l s £ 19 y e a r s o l d o n l y . With r e s p e c t t o degree of MR, the moderate group i s l a r g e s t f o r both males and females w h i l e the p r o f o u n d l y r e t a r d e d group i s s m a l l e s t f o r both s e x e s . The d i s t r i b u t i o n o f males among the v a r i o u s l e v e l s does not d i f f e r s i g n i f i c a n t l y a t the 5% l e v e l from the d i s t r i b u t i o n o f f e m a l e s . With r e s p e c t t o e t i o l o g y t h e r e are more MR c a s e s (1867 o f 2994 or 62.3%) i n the .9, unknown or u n s p e c i f i e d c a t e g o r y * t h a n i n any o t h e r . In P a r t B of T a b l e V I , 827 of the 2994 cases (27.6%) are grouped as MR w i t h a s p e c i f i c e t i o l o g y (subcodings .0, .1, .2, .3, .5 and . 7 ) . T h i s group c o m p r i s e s 26.2% of the m e n t a l l y r e t a r d e d males and 29.4% o f the m e n t a l l y r e t a r d e d f e -males. The o t h e r s u b c o d i n g s (.4, .6, .8, .9) are vaguer i n TABLE VI Living Individuals <19 years old with MR Registered in the Health Surveillance Registry Recorded at Year-end, 1977 A. Categorized by degree of retardation, etiological fourth digit subdivision and sex (#/$.) Degree of MR .0 .1 .2 .3 Etiological subdivision .4 .5 .6 .7 .8 .9 Sub total Percent of subtotals (J* + £ Total Percent of totals 311 Mild .3/3 1/1 2/1 1/1 9/5 16/22 3/0 0/0 2/0 294/189 331/222 19.7/16.9 553 18.5 312 Moderate 3/0 3/0 4/1 1/1 15/18 252/218 2/2 0/0 3/0 256/186 539/426 32.0/32.5 965 32.2 313 Severe 2/2 2/2 3/2 0/2 33/32 39/17 3/0 0/0 0/0 141/91 223/148 13.3/11.3 371 12.4 314 Profound 6/4 0/2 2/1 1/0 24/38 17/12 0/1 0/0 0/0 99/81 149/139 8.8/10.6 288 9.6 315 Unspecified 2/1 0/1 6/7 2/4 55/54 73/81 1/0 0/0 0/0 301/229 440/377 26.2/28.7 817 27.3 Sub total 16/10 6/6 17/12 5/8 136/147 397/350 9/3 0/0 5/0 1091/776 1682/1312 100/100 2994 100 <f + 5 Total 26 12 29 13 283 747 12 0 5 1867 2994 TABLE VI (cont'd) B. Categorized by degree of MR, s p e c i f i c (.0, .1, .2, .3, .5, .7) and non-sp e c i f i c (.4, .6, .8, .9) e t i o l o g y and sex (J/j) Degree of MR S p e c i f i c E t i o l o q y Non-specific E t i o l o g y T o t a l % of Number excesst of cases Percent males % of Number excesst of cases Percent males % of Number excess of cases Percent males Mild Moderate Severe Profound Unspecified 23/28 5.2/7.3 263/220 59.7/56.9 46/25* 10.4/6.5 84.0 26/19 5.9/4.9 83/94 18.8/24.4 308/194** 24.8/20.9 25.9 276/206** 22.2/22.2 34.0 177/123** 14.3/13.3 43.9 123/120 9.9/13.0 357/283** 28.8/30.6 26.1 331/222** 19.7/16.9 21.5 | 539/426** 32.0/32.5 26.5 ** 223/148** 13.3/11.3 50.7 | 149/139 8.8/10.6 440/377* 26.2/28.7 16.7 Subtotal 441/386 100/100 1241/926** 100/100 34.0 1682/1312** 100/100 28.2 Percent of su b t o t a l 26.2/29.4 73.8/70.6 100/100 c? + £ t o t a l 827 2167 2994 Percent of t o t a l 27.6 72.4 100 t % excess males = — T - ^ - x 100 d e v i a t i o n from 1:1 r a t i o of if to j i s s i g n i f i c a n t .01 <_ p < .05 de v i a t i o n from 1:1 r a t i o of cf to $ i s highl y s i g n i f i c a n t p < .01 - 43 -e t i o l o g y and are c a t e g o r i z e d as n o n - s p e c i f i c MR. T h i s group i n c l u d e s 72.4% o f the t o t a l number of MR c a s e s , or i n o t h e r words 73.8% o f the m e n t a l l y r e t a r d e d males and 70.6% o f the m e n t a l l y r e t a r d e d f e m a l e s . A g a i n , t h e r e i s no s i g n i f i c a n t d i f f e r e n c e i n d i s t r i b u t i o n i n degree of MR between males and females e i t h e r i n the group w i t h a s p e c i f i c e t i o l o g y or i n the group w i t h a n o n - s p e c i f i c e t i o l o g y . However, i f the d i f f e r e n c e i n d i s t r i b u t i o n i n MR l e v e l s i s compared between the s p e c i f i c and n o n - s p e c i f i c e t i -o l o g y g r o u p s , then t h e r e i s a s i g n i f i c a n t d i f f e r e n c e a t the 5% l e v e l . When the i n d i v i d u a l MR l e v e l s are compared between each group, i t i s apparent t h a t t h e r e are fewer m o d e r a t e l y r e t a r d e d c a ses and more m i l d l y r e t a r d e d c a s e s w i t h a n o n - s p e c i f i c e t i o l o g y which, i n p a r t , a c c o u n t s f o r the s i g n i f i c a n t d i f f e r e n c e i n d i s t r i -b u t i o n . An exc e s s of males i s apparent i n the s u b t o t a l s a t a l l l e v e l s of MR i r r e s p e c t i v e o f e t i o l o g y . In f a c t , i n a l l c a t e -g o r i e s , e x c e p t the profound MR l e v e l , the r a t i o of males t o females d e v i a t e s s i g n i f i c a n t l y from an expected 1:1 r a t i o . Among the l e v e l s o f MR w i t h a s p e c i f i c e t i o l o g y , t h e r e i s o n l y one s i g n i f i c a n t d e v i a t i o n i n the sex r a t i o s . There i s a s i g n i f i c a n t e x c e s s of males found a t the severe MR l e v e l . The e x c e s s may be due t o the g r e a t e r number o f males w i t h the .5 subcoding of severe MR a s s o c i a t e d w i t h chromosomal abnor-m a l i t i e s . In t h a t c a t e g o r y t h e r e are 39 males t o 17 f e m a l e s . - 44 -With such s m a l l numbers the deviation..may simply._be due t o chance. For c a s e s of n o n - s p e c i f i c MR the d e v i a t i o n from an expected 1:1 sex r a t i o i s h i g h l y s i g n i f i c a n t i n a l l l e v e l s e x c e p t i n the p r o f o u n d MR group. In f a c t , the p a t t e r n of sex r a t i o s i n the n o n - s p e c i f i c MR group i s s i m i l a r t o t h a t i n the o v e r a l l MR p o p u l a t i o n . T h e r e f o r e , i t i s r e a s o n a b l e t o c o n c l u d e t h a t the e x c e s s o f MR males p r e s e n t i n the t o t a l MR p o p u l a t i o n i s m a i n l y due t o n o n - s p e c i f i c or unknown c a u s e s . B. MINIMUM INCIDENCE OF NON-SPECIFIC MR Cases o f males and females w i t h n o n - s p e c i f i c MR who were born between 1950 and 1969 i n c l u s i v e and who were r e g i s t e r e d i n the R e g i s t r y , whether a l i v e or dead a t y e a r - e n d , 1977, are t a b u l a t e d i n Table V I I . A comparison of the r a t i o s of males t o females i n Table V I I with- those i n Table V I , which i n c l u d e o n l y those aged 19 y e a r s and under l i v i n g a t y e a r - e n d , 1977, shows a s i m i l a r e x c e s s of males w i t h n o n - s p e c i f i c MR. In o r d e r t o c a l c u l a t e the minimum i n c i d e n c e r a t e of non-s p e c i f i c MR, the number of male and female l i v e b i r t h s d u r i n g t h i s t i m e p e r i o d are used. S i n c e t h e r e were 356,387 males born i n B.C. d u r i n g t h i s p e r i o d , the minimum i n c i d e n c e o f non-s p e c i f i c MR i n males i s 6.48/1000 male l i v e b i r t h s . W ith 340,345 female l i v e b i r t h s , the minimum i n c i d e n c e r a t e of n o n - s p e c i f i c MR i n females i s 5.08/1000 female l i v e b i r t h s . - 45 -Table V I I Cases o f N o n - s p e c i f i c MR i n B.C. whose B i r t h d a t e s are between 1950-1969 i n c l u s i v e and Who are R e g i s t e r e d , e i t h e r A l i v e or Dead, a t Year-end, 1977 i n the H e a l t h S u r v e i l l a n c e R e g i s t r y Degree of MR Number of males/number of females P e r c e n t males/ p e r c e n t females % e x c e s s males M i l d Moderate Severe Profound U n s p e c i f i e d T o t a l 606/436* 515/343* 296/215* 268/246 625/488* 2310/1728* 26.2/25.2 22.3/19.9 12.8/12.5 11.6/14.2 27.1/28.2 100/100 39.0 50 .1 37.7 28 .1 33.7 * d e v i a t i o n from 1:1 sex r a t i o i s h i g h l y s i g n i f i c a n t , p < .01. - 46 -These i n c i d e n c e r a t e s must be c o n s i d e r e d minimums s i n c e MR i s not d i a g n o s a b l e a t b i r t h , MR cases are not n o r m a l l y a s c e r t a i n e d by the R e g i s t r y i n p r e - s c h o o l y e a r s , and i t i s l i k e l y t h a t some m e n t a l l y r e t a r d e d c h i l d r e n do not l i v e t o a t e s t a b l e age. C. NON-SPECIFIC MR IN TWO OR MORE SIBS F a m i l i a l c a s e s of MR suggest t h e r e i s a g e n e t i c component i n the e t i o l o g y . Hence, s i b s h i p s w i t h two or more s i b s w i t h n o n - s p e c i f i c MR were i n v e s t i g a t e d . They are d i v i d e d i n t o t h r e e c l a s s e s : 1) s i b s h i p s w i t h o n l y males a f f e c t e d , 2) s i b s h i p s w i t h o n l y females a f f e c t e d , and 3) s i b s h i p s w i t h both males and females a f f e c t e d . Table V I I I shows the number of s i b s h i p s i n each o f these c l a s s e s as w e l l as the number of m e n t a l l y r e -t a r d e d s i b s per s i b s h i p . Most o f the s i b s h i p s i n c l u d e two or t h r e e m e n t a l l y r e t a r d e d s i b s . Only a s m a l l p r o p o r t i o n of s i b -s h i p s c o n t a i n more than t h r e e . Among a l l f a m i l i a l c a s e s r e c o r d e d i n the R e g i s t r y , the r a t i o o f male a f f e c t e d s i b s h i p s t o female a f f e c t e d s i b s h i p s i s 131 t o 48 or 2.7:1. Among the group of f a m i l i e s w i t h a t l e a s t one a f f e c t e d s i b born between 1950 and 1969 i n c l u s i v e , the r a t i o i s 107 t o 35 or 3.1:1. S i n c e t h e r e are 35 s i b s h i p s w i t h j u s t females a f f e c t e d , one would e x p e c t 35 of the 107 male a f f e c t e d s i b s h i p s t o have MR t h a t was due t o f a c t o r s t h a t a f f e c t both males and females - 47 -Table V I I I Number o f S i b s h i p s w i t h N o n - s p e c i f i c MR i n Two or More S i b s Recorded i n the H e a l t h S u r v e i l l a n c e R e g i s t r y Type of s i b s h i p * Number o f s i b s h i p s w i t h each number of s i b s . w i t h .MR T o t a l number of s i b s h i p s A. Among a l l 88 118 8 4 0 1 131 f a m i l i a l c a s e s 41 6 0 1 0 48 99 102 37 7 1 1 148 B. Among f a m i l i e s w i t h a t l e a s t one s i b born between 1950-1969 i n c l u s i v e 88 8% 96 6 4 0 1 107 29 5 0 1 0 35 77 32 6 1 0 116 * 88 --8? -s i b s h i p s w i t h o n l y males a f f e c t e d s i b s h i p s w i t h o n l y females a f f e c t e d s i b s h i p s w i t h males and females a f f e c t e d - 48 -e q u a l l y . But a d i f f e r e n t e x p l a n a t i o n i s n e c e s s a r y t o account f o r the exce s s of 72 male a f f e c t e d s i b s h i p s . Such d a t a on m u l t i p l y a f f e c t e d s i b s h i p s s u ggest n ot o n l y t h a t t h e r e may be a g e n e t i c component t o n o n - s p e c i f i c MR, but a l s o , t h a t e i t h e r m u l t i f a c t o r i a l i n h e r i t a n c e w i t h a d i f f e r e n c e i n sex t h r e s h o l d s or X - l i n k e d r e c e s s i v e genes may account f o r a p o r t i o n o f these f a m i l i a l c a s e s . The d i s t r i b u t i o n o f l e v e l s of MR i n the a f f e c t e d i n d i v i d u a l s i b s i s p r e s e n t e d i n Table IX. The p a t t e r n of d i s t r i b u t i o n does not s i g n i f i c a n t l y d i f f e r from one type of s i b s h i p t o another or between s e x e s . However, t h e r e i s a s i g n i f i c a n t i n -c r e a s e i n the p r o p o r t i o n of m i l d m e n t a l l y r e t a r d e d f a m i l i a l c a s es compared t o the o v e r a l l n o n - s p e c i f i c MR p o p u l a t i o n p r e -s ented i n Table VI or V I I . I f i t i s assumed t h a t m u l t i f a c t o r i a l i n h e r i t a n c e w i t h d i f -f e r e n t t h r e s h o l d s f o r males and females c o u l d account f o r a s i g n i f i c a n t p r o p o r t i o n o f the e x c e s s of male a f f e c t e d s i b s h i p s , a s i g n i f i c a n t e x c e s s of a f f e c t e d males would be e x p e c t e d among f a m i l i e s w i t h both m e n t a l l y r e t a r d e d males and f e m a l e s . How-e v e r , t h a t does n ot seem t o be the c a s e . The r a t i o o f a f f e c t e d males t o a f f e c t e d females among these s i b s h i p s i s 181:173 i n the o v e r a l l 148 s i b s h i p s and 146:133 i n the 116 s i b s h i p s i n the b i r t h c o h o r t . A f t e r s u b t r a c t i n g one a f f e c t e d male and one a f f e c t e d female as index c a s e s i n each s i b s h i p , the sex r a t i o s of 33:25 and 30:17 s t i l l do not d e v i a t e s i g n i f i c a n t l y from a Table IX A. Among a l l f a m i l i a l c a s e s B. Among f a m i l i e s w i t h a t l e a s t one s i b born between 1950-1969 i n c l u s i v e Type of s i b -s h i p s * ?* ** 9* s i b s h i p s w i t h o n l y males a f f e c t e d s i b s h i p s w i t h o n l y females a f f e c t e d s i b s h i p s w i t h males and females a f f e c t e d F a m i l i a l Cases : where Two or More S i b s are A f f e c t e d Number o f . s i b s •at each l e v e l of MR (percent) Sex of Mod- P r o - Unspec number S i b s M i l d e r a t e Severe found i f i e d of s i b i o" 116 51 36 17 62 282 (41) (18) (13) (6) (22) (100) g 46 20 13 7 20 106 (43) (19) (12) (7) (19) (100) 89 29 10 13 40 18,1 (49) (16) (6) (7) (22) (100) 81 24 13 11 44 173 (47) (14) (8) (6) (25) (100) 98 42 '27 14 51 232 (42) (18) (12) (6) (22) (100) 0 28 16 11 7 17 79 +• (35) (20) (14) (9) (22) (100) <? 71 25 S8 12 30 146 (49) (17) (5) (8) (21) (100) 0 65 19 10 9 30 133 (49) (14) (7) (7) (23) (100) - 50 -1:1 r a t i o . T h e r e f o r e , the r a t i o of a f f e c t e d males t o a f f e c t e d females i n m u l t i p l y a f f e c t e d s i b s h i p s does not s u p p o r t the m u l t i f a c t o r i a l h y p o t h e s i s . A comparison can a l s o be made of the s e v e r i t y of the MR i n males and f e m a l e s . With an h y p o t h e s i s o f m u l t i f a c t o r i a l i n h e r i t a n c e w i t h s e x - c o n t r b l l e d t h r e s h o l d s - . a c c o u n t i n g f o r the e x c e s s of male a f f e c t e d s i b s h i p s , i t might be ex p e c t e d t o f i n d males more s e v e r e l y a f f e c t e d than f e m a l e s . However, as a l r e a d y n o t e d , the d i s t r i b u t i o n of l e v e l s o f MR among f a m i l i a l c a s es does not d i f f e r s i g n i f i c a n t l y a t the 5% l e v e l between males and f e m a l e s . A comparison o f the s e v e r i t y of MR between a f f e c t e d males and a f f e c t e d females i n the male and female a f -f e c t e d s i b s h i p s i s p r e s e n t e d i n Table X. There i s no s i g n i f i c a n t e x c e s s o f s i b s h i p s i n which the male s i b i s more s e v e r e l y a f -f e c t e d compared t o s i b s h i p s i n which the female s i b i s more s e v e r e l y a f f e c t e d . T h e r e f o r e , i t seems r e a s o n a b l e t o co n c l u d e t h a t m u l t i f a c -t o r i a l i n h e r i t a n c e w i t h a d i f f e r e n c e i n sex t h r e s h o l d s cannot account f o r the e x c e s s o f male a f f e c t e d s i b s h i p s . I t i s pos-s i b l e t h a t X - l i n k e d genes may account f o r the e x c e s s o f s i b -s h i p s w i t h two or more males w i t h n o n - s p e c i f i c MR. D. ANALYSIS OF SIBSHIPS WITH TWO OR MORE AFFECTED MALES 1. F a m i l y H i s t o r i e s G iven the s i g n i f i c a n t e x c e s s of male a f f e c t e d s i b s h i p s , i t can be h y p o t h e s i z e d t h a t a l l of the exce s s of s i b s h i p s w i t h two Table X Comparison o f S e v e r i t y of MR between A f f e c t e d Males and Females from s i b s h i p s w i t h both Males and Females Retarded* Number of s i b s h i p s Male more s e v e r e l y a f f e c t e d than female Female more s e v e r e l y a f f e c t e d than male L e v e l o f MR e q u a l i n both c? & $ L e v e l of MR u n s p e c i f i e d i n male and/ or female Among a l l <f$ s i b s h i p s 37 32 27 52 Among s i b s h i p s w i t h a t l e a s t one s i b born between 1950 and 1969 i n c l u s i v e 30 27 23 36 W i t h i n each s i b s h i p the MR l e v e l s of the most s e v e r e l y a f f e c t e d male and female are compared. - 52 -or more a f f e c t e d males i s due t o X - l i n k e d MR. A t p r e s e n t the main c r i t e r i o n used t o d e t e c t X - l i n k e d MR i s a f a m i l y h i s t o r y o f n o n - s p e c i f i c MR i n a p a t t e r n s u g g e s t i n g X - l i n k e d i n h e r i t a n c e . T h e r e f o r e , i n o r d e r t o t e s t t h i s h y p o t h e s i s , the f a m i l y h i s -t o r i e s of these s i b s h i p s were i n v e s t i g a t e d . Of the 135 s i b s h i p s w i t h two or more a f f e c t e d m ales, f a m i l y h i s t o r y i n f o r m a t i o n was o b t a i n e d f o r 68. T a b l e s XI and X I I p r e s e n t i n f o r m a t i o n on the s i b s , p a r e n t s , m a t e r n a l s i b s , and p a t e r n a l s i b s i n these f a m i l i e s . Not a l l 68 f a m i l y h i s t o r i e s c o n t a i n e d complete i n f o r m a t i o n on sex and me n t a l s t a t u s o f a l l members of the index s i b s h i p s , as w e l l as m a t e r n a l and p a t e r n a l s i b s h i p s . I f the sex of s i b s was not known, the s i b s h i p - w a s not i n c l u d e d i n the a n a l y s i s . T h e r e f o r e , the number of s i b -s h i p s i n each c a t e g o r y i s l e s s than 68. 2. S i z e o f S i b s h i p s I n f o r m a t i o n i n T a b l e XI g i v e s an i n d i c a t i o n o f the s i z e o f s i b s h i p s i n these f a m i l i e s . The index s i b s h i p s have from two t o over t w e l v e s i b s . Many o f the m a t e r n a l and p a t e r n a l s i b -s h i p s a l s o have more than two or t h r e e s i b s which may be ex-p l a i n e d n o t o n l y by f a m i l i a l t r e n d s but a l s o by c u l t u r a l t r e n d s f o r t h a t g e n e r a t i o n . 3. Sex R a t i o i n S i b s h i p s From Table X I I i t i s apparent t h a t the r a t i o of males t o females ( e x c l u d i n g index c a s e s t o e l i m i n a t e b i a s ) among the T a b l e X I F a m i l y H i s t o r y I n f o r m a t i o n o f S i b s h i p s w i t h Two o r M o r e A f f e c t e d M a l e s I S i z e o f S i b s h i p s Number o f s i b s h i p s w i t h e a c h number :of s i b s T o t a l number o f 1 2 2 1 5 6 7 8 9 1 0 1 1 12+ s i b s h i p s A . S i b s h i p s w i t h two o r more a f f e c t e d m a l e s 9 18 14 7 3 5 6 2 0 0 1 65 B . P a t e r n a l s i b s h i p s * 5 6 7 11 3 2 6 1 1 2 2 1 47 C . M a t e r n a l s i b s h i p s * * 4 4 9 10 9 2 4 4 3 1 1 3 54 * t h e f a t h e r o f i n d e x s i b s h i p a n d h i s s i b l i n g s *.* t h e m o t h e r o f i n d e x s i b s h i p a n d h e r s i b l i n g s -+ * a fl) — cn fD ^ cn H- cr cn cn X H- X H- 3 H-H- H- NJ H-O 3 cr O 3 cr Qj l-i CT rl" cr 1 I 1 I—• DJ w HQiOl fl) rr w 3" H- w C fl) C fl) X 3" 3 w a 3 a x 0 D i X 0 CT S CL 0 H- fl) C m M i fD M i 3 0 0 » fD M l CT < 3 a 3 QJ M l DJ M i M X 01 H - D " — 0 3 — DJ M i M 3 fD H -SD CD rt 0 rr DJ fl) W X 3 3 £ ft l-l 3* rr 3" rr fl) DJ O DJ Q i 3" H- ft) 3* fD 3" o M l 1—1 H" fl) 0 o OJ • M fD l-S fD 0 rr C fl) X 3 l-h i-i 3 fD OJ W QJ M l fl) 3 H- M i n> QJ OJ ( D u n — h-1 a O rt fD 3 n> W cr a fD I—1 M l •• H -0 M (0 -J UJ Ul Total number fl) w 3 m o of sibships u i X f t a 1 Fathers with M 7s" 1 t \ J borderline IQ ( D O S DJ rt O M- H- s; a a 1 Mothers with WOP 1 VjO borderline IQ 0 M i W T3 l-i OJ 13 ft) oo CTi N) U) -J I—1 Sisters normal i n 0 cn fl) rr C 3 2 a Sisters with W fl) H - OJ borderline IQ IQ 3 rr H- O to M o o Sist e r s with MR M l ,H- cr O fl) M Sisters whose mental 3 3 O t \ J o U ) status i s not knownt n- o M s£> sO U l Brothers normal 3 U ) M U ) CU I—1 a i— 1 M M CO 3 M CO un M s£) oo I-1 00 Brothers with borderline IQ Brothers with MR Brothers whose mental status i s not knownt M 1—1 - J f O 00 Total number of O VJO - J 00 s i s t e r s M (-• >>0 .C* CO Total number of O CO brothers * * * * 1SJ —1 —1 *1 0) 3 H-w rr 0 M I—I 3 M l 0 i-i 3 DJ rr 3 fD 3 0 rr M l DJ h-1 cn i-3 cn CT OJ rr cn cr OJ 3* M rr fl) C in tn X 0 hH H M l H -rr cn 3" H-cr i-3 M H- o 3 iQ 0 W l-i M fD > M i M l fl) O rr fD a s DJ h-1 fD W Total number of sibs - frg -- 55 - \ s i b s h i p s does not s i g n i f i c a n t l y d e v i a t e from the exp e c t e d 1:1 r a t i o . 4. MR i n S i b s h i p s Two f a t h e r s and n i n e mothers were d e s c r i b e d as slow or o f b o r d e r l i n e i n t e l l i g e n c e . Among the s i b s o f the two index men-t a l l y r e t a r d e d males, t h e r e are 19 more males w i t h MR. Among the p a t e r n a l s i b s , t h e r e are two m e n t a l l y r e t a r d e d s i b s , one male and one femal e . However, t h e r e are two m e n t a l l y r e t a r d e d females and e l e v e n m e n t a l l y r e t a r d e d males among the m a t e r n a l s i b s . In a l l c a s e s t h e r e was no s p e c i f i c e t i o l o g y f o r the MR. Informa-t i o n on the mental a b i l i t i e s o f m a t e r n a l and p a t e r n a l s i b s was not d e t a i l e d enough t o d i s c e r n between those o f normal and those of b o r d e r l i n e i n t e l l i g e n c e . Those sibs,who d i e d i n i n -f a n c y or e a r l y c h i l d h o o d b e f o r e t h e i r mental a b i l i t y c o u l d be a s s e s s e d a c c u r a t e l y , a r e l i s t e d i n s e p a r a t e columns of Table X I I . 5. A n a l y s i s of S i b s i n Index S i b s h i p s I f s i b s born a f t e r the b i r t h of the second m e n t a l l y r e -t a r d e d male are a n a l y z e d w i t h r e s p e c t t o the X - l i n k e d MR hypo-t h e s i s , then a 2:1:1 r a t i o of females t o normal males t o men-t a l l y r e t a r d e d males, or s i m p l y a 1:1 r a t i o of normal males t o m e n t a l l y r e t a r d e d males,would be e x p e c t e d . Table X I I shows t h a t a t o t a l of 67 s i b s were born a f t e r the second m e n t a l l y r e t a r d e d male. Twenty-seven are females of normal or b o r d e r l i n e - 56 -i n t e l l i g e n c e and 40 are m ales, 17 of whom are of normal or b o r -d e r l i n e i n t e l l i g e n c e , 19 are m e n t a l l y r e t a r d e d and 4 d i e d b e f o r e a d i a g n o s a b l e age. These 4 s i b s were o m i t t e d b e f o r e a c h i square a n a l y s i s was performed. B e f o r e the s i b d a t a were a n a l y z e d , s t e p s were taken t o i n -sure t h a t the a n a l y s i s i n c l u d e d o n l y s i b s i n the e x c e s s o f male a f f e c t e d s i b s h i p s . S i n c e t h e r e are 35 female a f f e c t e d s i b s h i p s , then i n 35 of the 107 (33%) s i b s h i p s w i t h two or more m e n t a l l y r e t a r d e d males, the MR w i l l be due t o f a c t o r s t h a t a f f e c t both males and f e m a l e s . T h e r e f o r e , 33% of the s i b s was s u b t r a c t e d from each group so t h a t o n l y the s i b s i n the e x c e s s o f male a f f e c t e d s i b s h i p s would be a n a l y z e d . There are thus 18 f e m a l e s , 11 normal males and 13 m e n t a l l y r e t a r d e d males f o r a t o t a l of 42 s i b s among the e x c e s s male a f f e c t e d s i b s h i p s . There i s no s i g n i f i c a n t d e v i a t i o n e i t h e r from the e x p e c t e d 2:1:1 r a t i o of females t o normal males t o m e n t a l l y r e t a r d e d males or from the 1:1 r a t i o o f normal t o a f f e c t e d males. I f the 4 s i b s of unknown i n t e l l e c t u a l s t a t u s are i n c l u d e d i n the i n i t i a l t o t a l and c a t e g o r i z e d as e i t h e r a l l normal or a l l m e n t a l l y r e -t a r d e d or any c o m b i n a t i o n between, t h e r e are s t i l l no s i g n i f i -c a n t d e v i a t i o n s from the e x p e c t e d r a t i o s . T h e r e f o r e d a t a on the male a f f e c t e d s i b s h i p s are c o n s i s t e n t w i t h the h y p o t h e s i s t h a t the MR i n the e x c e s s o f s i b s h i p s w i t h two or more m e n t a l l y r e t a r d e d males i s due t o an X - l i n k e d r e c e s s i v e gene. - 57 -6. A n a l y s i s of M a t e r n a l S i b s As f u r t h e r e v i d e n c e f o r the X - l i n k e d MR h y p o t h e s i s s i m i l a r r a t i o s s h o u l d a l s o be found among a p o r t i o n of the m a t e r n a l s i b s . A g a i n , o n l y the s i b s of the mothers of the e x c e s s male a f f e c t e d s i b s h i p s s h o u l d be a n a l y z e d . I t has been shown t h a t i n a p o p u l a t i o n a t e q u i l i b r i u m one h a l f of the female h e t e r o z y g o t e s of an X - l i n k e d r e c e s s i v e l e t h a l d i s e a s e would be c a r r y i n g a new m u t a t i o n ( F r a n c k e , e t a l . , 1976). S i n c e m e n t a l l y r e t a r d e d males do not n o r m a l l y r e p r o d u c e , X - l i n k e d MR can be c o n s i d e r e d an X - l i n k e d r e c e s s i v e l e t h a l gene. T h e r e f o r e , o n l y one h a l f of the mothers of the e x c e s s male a f -f e c t e d s i b s h i p s would be e x p e c t e d t o have a f a m i l y h i s t o r y ex-p r e s s i n g a p a t t e r n of X - l i n k e d i n h e r i t a n c e . The m a t e r n a l s i b s l i s t e d i n T able X I I i n c l u d e 100 females and 119 males, 11 of whom are m e n t a l l y r e t a r d e d h y p o t h e t i c a l l y due t o an X - l i n k e d gene. F i r s t , the s i b s whose i n t e l l e c t u a l s t a t u s i s not known were s u b t r a c t e d from the t o t a l . Second, 33% of the s i b s were s u b t r a c t e d so t h a t o n l y the s i b s of the mothers o f the e x c e s s o f male a f f e c t e d s i b s h i p s were a n a l y z e d . I f one h a l f of the r e m a i n i n g s i b s are normal b r o t h e r s and s i s -t e r s of mothers c a r r y i n g a new m u t a t i o n , then t h e r e remain 34 f e m a l e s , 25 normal males and 11 m e n t a l l y r e t a r d e d males among the s i b s of mothers who s h o u l d have a h i s t o r y of X - l i n k e d MR. - 58 -There i s no s i g n i f i c a n t d e v i a t i o n from a 2:1:1 r a t i o o f females t o normal males t o m e n t a l l y r e t a r d e d males e x p e c t e d i f the h y p o t h e s i s i s c o r r e c t . I f the r a t i o o f normal males t o m e n t a l l y r e t a r d e d males i s t e s t e d a g a i n s t an e x p e c t e d 1:1 r a t i o , the d e v i a t i o n i s q u e s t i o n a b l y s i g n i f i c a n t (.05 > p > .01) . I t i s then of i n t e r e s t t o i n c l u d e those s i b s who d i e d be-f o r e 5 y e a r s of age i n o r d e r t o see i f t h e i r i n c l u s i o n i n e i t h e r the normal or a f f e c t e d group w i l l make a d i f f e r e n c e i n the a n a l y s i s . Among the 12 male s i b s i n q u e s t i o n , i f two or l e s s are c o n s i d e r e d m e n t a l l y r e t a r d e d and the r e s t n o r m a l , t h e r e i s s t i l l a s i g n i f i c a n t d e v i a t i o n from a 1:1 r a t i o of normal males t o m e n t a l l y r e t a r d e d males. However, i f t h r e e or more are c o n s i d e r e d m e n t a l l y r e t a r d e d and the r e s t n o r m a l , then the d e v i a t i o n from an e x p e c t e d 1:1 r a t i o i s not s i g n i f i c a n t . I t i s not u n r e a s o n a b l e t o assume t h a t a p o r t i o n of those males who d i e d i n e a r l y c h i l d h o o d would be m e n t a l l y r e t a r d e d . The o r i g i n a l d a t a on the m a t e r n a l s i b s do f i t a 2:1:1 r a t i o . As noted above, i f t h r e e or more of the undiagnosed males among the m a t e r n a l s i b s are presumed m e n t a l l y r e t a r d e d , the d e v i a t i o n from a 1:1 r a t i o of normal t o m e n t a l l y r e t a r d e d males i s a l s o i n s i g n i f i c a n t . T h e r e f o r e , i t i s r e a s o n a b l e t o conclude t h a t the d a t a from the m a t e r n a l f a m i l y h i s t o r i e s sub-s t a n t i a t e the h y p o t h e s i s t h a t the e x c e s s of male a f f e c t e d s i b -s h i p s i s due t o an X - l i n k e d r e c e s s i v e gene. - 59 -7. Ages of Grandparents a t Time of P a r e n t s ' B i r t h A l t h o u g h a n a l y s i s of the m a t e r n a l s i b s h i p s d a t a does not suggest an e x c e s s of mothers w i t h new X - l i n k e d m u t a t i o n s f o r MR, t h e r e has been some s u g g e s t i o n i n the l i t e r a t u r e t h a t the number of mothers w i t h sons h a v i n g an X - l i n k e d r e c e s s i v e l e t h a l d i s e a s e , such as H e m o p h i l i a A or Lesch-Nyhan D i s e a s e , and who are a l s o h e t e r o z y g o t e s , may be h i g h e r than e x p e c t e d ( F r a n c k e , e t a l . , 1976; B i g g s and R i z z a , 1976 ; R a t n o f f and J o n e s , 1977). The e x c e s s o f mothers c a r r y i n g m u t a t i o n s c o u l d be accounted f o r by s e v e r a l p o s s i b i l i t i e s , i . e . h e t e r o z y g o t e advantage, g e n e t i c d r i f t (Lange, e t a l . , 1978), or i n c r e a s e d m u t a t i o n r a t e i n males - namely i n the mother's f a t h e r (Francke, e t a l . , 1976). Francke and c o l l a b o r a t o r s argue t h a t an i n c r e a s e i n the p a t e r n a l age a t the time of the b i r t h o f the mother may account f o r an i n c r e a s e d m u t a t i o n r a t e c a u s i n g the e x c e s s o f mothers w i t h new m u t a t i o n s . In o r d e r t o i n v e s t i g a t e whether t h e r e might be an e x c e s s of mothers w i t h new m u t a t i o n s f o r X - l i n k e d M R , the ages of the m a t e r n a l and p a t e r n a l g r a n d p a r e n t s a t the time of b i r t h o f the p a r e n t were examined ( F i g u r e 3 ) . The ages of p a t e r n a l g r a n d p a r e n t s are used as i n t r a - p e d i g r e e c o n t r o l s . A l t h o u g h the average age o f the m a t e r n a l g r a n d f a t h e r s i s s l i g h t l y more than the average age o f the p a t e r n a l g r a n d -f a t h e r s , an a n a l y s i s o f v a r i a n c e of the two groups shows no s i g n i f i c a n t d i f f e r e n c e between them a t the 5% l e v e l . A s i m i l a r F i g u r e 3 Ages of Grandparents a t B i r t h of P a r e n t s of Two or More M e n t a l l y Retarded Males M a t e r n a l Grandmother no. = 38 average age ± sd = 28.0 ± 6.3 • • • o D n • • Q o a a n • • • • • • o o a u n t J o n o n a n o o D n o o n i i i > i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i I P a t e r n a l Grandmother no. = 28 average age ± sd = 28.1 ± 5.7 a • a n n a a o n a • • n a n • n o o a n n a n n a D O t i l i i i i i i i i i i i i i i i i • i i f i i i i i i • i i i M a t e r n a l G r a n d f a t h e r no. = 36 average age ± sd = 34.5 ± 7.1 a n a • • a >'• a a u a • • • a a . D . D D D O t l D D D • • • • D D • • • i .1 t i ' ' • ' ' ' ' » i i i i i* i i i i / . i . i i i i i i i • i , i i P a t e r n a l G r a n d f a t h e r no. = 3 0 average age ± sd = 31.3 ± 5.5 a a d a a • • • a o o o n • a n a • a a n a n a n a n a n a ' * I i ' ' t ' ' ' ' ' i i r i I i i i i 1 • i . . 1 i • i , 1 i f i l l 15 20 25 30 35 40 45 50 age i n y e a r s - 61 -comparison o f the ages o f the m a t e r n a l and p a t e r n a l g r a n d -mothers a l s o shows no s i g n i f i c a n t d i f f e r e n c e . These f i n d i n g s are c o n s i s t e n t w i t h the t h e o r e t i c a l c a l c u l a t i o n t h a t o n l y one h a l f of the mothers of the e x c e s s of male a f f e c t e d s i b s h i p s i s c a r r y i n g new m u t a t i o n s f o r X - l i n k e d MR. E. PERSONAL INTERVIEWS 1. V e r i f i c a t i o n o f F a m i l y H i s t o r i e s An attempt was made t o c o n t a c t 76 f a m i l i e s i n o r d e r t o v e r i f y the f a m i l y i n f o r m a t i o n used i n the s i b s h i p a n a l y s i s as w e l l as t o update, complete or v e r i f y o t h e r f a m i l y h i s t o r i e s , some of which suggested X - l i n k e d i n h e r i t a n c e o f MR. These 76 f a m i l i e s were s e l e c t e d because they c o n t a i n e d more than one male w i t h n o n - s p e c i f i c MR and they had had p r e v i o u s c o n t a c t w i t h e i t h e r T r a n q u i l l e or Woodlands S c h o o l . The r e s u l t s are p r e s e n t e d i n Table X I I I . Of the 76 f a m i l i e s , 55 were c o n t a c t e d of whom, 25 agreed t o p a r t i c i p a t e i n an i n t e r v i e w . Twenty-two o f those f a m i l i e s were s u b s e q u e n t l y i n t e r v i e w e d , 11 by te l e p h o n e and 11 by p e r -s o n a l v i s i t . In 16 o f the i n t e r v i e w s o n l y the mother p r o v i d e d the f a m i l y i n f o r m a t i o n . Other i n t e r v i e w e e s i n c l u d e d both p a r e n t s , a s i s t e r or a b r o t h e r o f the m e n t a l l y r e t a r d e d index male. Among the 22 f a m i l i e s , no m e n t a l l y r e t a r d e d females were found, but t h r e e f a m i l i e s r e p o r t e d a m e n t a l l y r e t a r d e d m a t e r n a l - 62 -Ta b l e X I I I Summary o f Data on I n t e r v i e w s made t o V e r i f y and Update F a m i l y H i s t o r i e s A. Among f a m i l i e s w i t h p a s t c o n t a c t w i t h T r a n q u i l l e or Woodlands S c h o o l : c o n t a c t e d 55 f a m i l i e s whereabouts not known 2_1 f a m i l i e s T o t a l 76 f a m i l i e s B. Among f a m i l i e s c o n t a c t e d : p o s i t i v e response 25 f a m i l i e s n e g a t i v e response 3 f a m i l i e s no response 2_7 f a m i l i e s T o t a l 55 f a m i l i e s C. Among f a m i l i e s w i t h p o s i t i v e r e s p o n s e : p e r s o n a l i n t e r v i e w 11 f a m i l i e s phone i n t e r v i e w 11 f a m i l i e s not i n t e r v i e w d _3 f a m i l i e s T o t a l 25 f a m i l i e s D. Among f a m i l i e s i n t e r v i e w d : F a m i l y H i s t o r i e s c o n f i r m e d as e a r l i e r r e p o r t e d e a r l i e r r e p o r t c o n f i r m e d but a l s o updated MR male found who had not been r e p o r t e d e a r l i e r normal male found who was e a r l i e r a l l e g e d t o be MR T o t a l 6 f a m i l i e s 11 f a m i l i e s 3 f a m i l i e s 2 f a m i l i e s 22 f a m i l i e s 2. A t t i t u d e s o f females of c h i l d - b e a r i n g age towards r e c u r r e n c e o f MR f e m a l e ( s ) concerned about r i s k s f e m a l e ( s ) d e c i d e d a l r e a d y not t o have c h i l d r e n f e m a l e ( s ) h a v i n g c h i l d r e n no females o f c h i l d - b e a r i n g age T o t a l 9 f a m i l i e s f a m i l i e s f a m i l i e s f a m i l i e s 22 f a m i l i e s - 63 -u n c l e or nephew who had not been r e p o r t e d e a r l i e r . I t was a l s o l e a r n e d t h a t two m a t e r n a l u n c l e s , e a r l i e r a l l e g e d t o be m e n t a l l y r e t a r d e d were of normal i n t e l l i g e n c e - one had severe f a m i l i a l d y s l e x i a , the o t h e r was p h y s i c a l l y and m e n t a l l y h e a l t h y u n t i l development of a l e t h a l b r a i n tumor a t age 35. T h e r e f o r e 1 of 22, or 4.5%,of the f a m i l y h i s t o r i e s o b t a i n e d from m e d i c a l f i l e s of male probands w i t h n o n - s p e c i f i c MR may have another m e n t a l l y r e t a r d e d male where the MR i s con-s i s t e n t w i t h a p a t t e r n o f X - l i n k e d i n h e r i t a n c e . 2. Concern f o r G e n e t i c R i s k s Of i n t e r e s t f o r g e n e t i c c o u n s e l l i n g are the a t t i t u d e s of the s i s t e r s of the a f f e c t e d males i n these s i b s h i p s . Seventeen of the 22 f a m i l i e s had females of c h i l d b e a r i n g age. In s i x f a m i l i e s the females were a l r e a d y h a v i n g c h i l d r e n . In n i n e of .the f a m i l i e s the females had not y e t had c h i l d r e n but e x p r e s s e d h e s i t a n c y and c o n c e r n about the p o s s i b i l i t y of h a v i n g a men-t a l l y r e t a r d e d c h i l d . S e v e r a l p a r e n t s s a i d t h e i r d a u g h t e r s had urged them t o p a r t i c i p a t e i n t h i s s tudy i n o r d e r t o f i n d out the e x a c t r i s k s i n h a v i n g a c h i l d w i t h MR. In two f a m i l i e s the s i s t e r s of a f f e c t e d males had a l r e a d y e x p r e s s e d a d e f i n i t e d e c i s i o n not t o have c h i l d r e n . Even though the e x a c t r i s k s o f h a v i n g an a f f e c t e d c h i l d were unknown, they f e l t t h a t any r i s k was too g r e a t t o t a k e . In a l l c a s e s these comments were u n s o l i c i t e d by the i n t e r v i e w e r , - f u r t h e r i m p l y i n g . a . - 64 -g r e a t concern about g e n e t i c r i s k s i n f a m i l i e s with mentally r e t a r d e d males. F. FREQUENCY OF X-LINKED MR IN BRITISH COLUMBIA Since data from the f a m i l y h i s t o r i e s of the male a f f e c t e d s i b s h i p s suggest that the mothers of the excess s i b s h i p s with a f f e c t e d males may be c a r r i e r s of X - l i n k e d MR, these were used to c a l c u l a t e the minimum frequency of X - l i n k e d MR. There i s an excess of 72 s i b s h i p s with two or more males who have non-s p e c i f i c MR i n which at l e a s t one of the a f f e c t e d males i s born between 1950 and 1969 i n c l u s i v e . The mothers of these 72 s i b s h i p s are thus assumed to be c a r r i e r s of an X - l i n k e d r e c e s s i v e gene f o r MR. I f a woman i n the g e n e r a l p o p u l a t i o n i s a c a r r i e r and has two or more sons, then i n a minimum of one-fourth of those s i b s h i p s would at l e a s t two of the sons be m e n t a l l y r e -tarded and thus be a s c e r t a i n e d i n t h i s s i b s h i p group. There-f o r e , approximately t h r e e - f o u r t h s of the mothers i n the g e n e r a l p o p u l a t i o n , who are c a r r i e r s and who have two or more sons, have not been a s c e r t a i n e d . Thus, an estimated 288 female c a r -r i e r s of X - l i n k e d MR gave b i r t h to two or more males i n B.C. with at l e a s t one being born between 1950 and 1969 i n c l u s i v e . From the B.C. Record Linkage P r o j e c t ' s m a r r i a g e - t o - b i r t h and b i r t h - t o - b i r t h l i n k a g e groups, an estimate was obtained of 117,831 mothers who gave b i r t h to two or more males i n B.C. with at l e a s t one being born d u r i n g the same 20 year p e r i o d . - 65 -T h e r e f o r e the minimum f r e q u e n c y of female c a r r i e r s of X - l i n k e d MR would be 2.44/1000 f e m a l e s . S i n c e w i t h an X - l i n k e d r e c e s -s i v e l e t h a l d i s e a s e i n a p o p u l a t i o n a t e q u i l i b r i u m the f r e -quency of a f f e c t e d males i s t h r e e - f o u r t h s t h a t o f the f r e q u e n c y of female c a r r i e r s ( C a r t e r , 1969, p. 4 7 ) , the minimum f r e q u e n c y of a f f e c t e d males i s 1.83/1000 males. The q u e s t i o n now a r i s e s : can t h i s e s t i m a t e d f r e q u e n c y of X - l i n k e d MR account f o r the e x c e s s of n o n - s p e c i f i c MR found i n a l l male c a s e s , not j u s t the f a m i l i a l ones? A c c o r d i n g t o the B. C. Department of H e a l t h V i t a l S t a t i s t i c s (1974) 356,387 males were born i n B r i t i s h Columbia from 1950 t o 1969 i n c l u s i v e . T a k i n g i n t o c o n s i d e r a t i o n the a g e - s p e c i f i c death r a t e s f o r c h i l d r e n under 5 y e a r s of age, 345,571 males reached 5 y e a r s of age, a d i a g n o s a b l e age f o r MR. The death r a t e s f o r males be-tween the ages of 5 and 19 i n c l u s i v e f o r the y e a r s 1950 t o 1969 v a r y from 1.5 t o 0.5 per 1000 males per year and would, t h e r e f o r e , make an i n s i g n i f i c a n t d i f f e r e n c e on the f o l l o w i n g c a l c u l a t i o n . The minimum number of males born i n B r i t i s h Columbia during.1950 t o 1969 i n c l u s i v e and l i v i n g t o a t l e a s t 5 y e a r s of age who may have X - l i n k e d MR i s : (1.83/1000) (345,571) = 632 males. S i n c e t h e r e are 2310 males (see Table V I I ) born d u r i n g t h a t 20 year p e r i o d who are r e g i s t e r e d w i t h n o n - s p e c i f i c MR', 632/2310, or 27.4%,of the n o n - s p e c i f i c MR i n males may be due t o an X - l i n k e d d e f e c t . That would l e a v e 1678 n o n - s p e c i f i c - 66 -m e n t a l l y r e t a r d e d males whose MR would be due t o f a c t o r s o t h e r than X - l i n k e d genes. There are 1728 females w i t h n o n - s p e c i f i c MR born d u r i n g the same time p e r i o d . The r a t i o o f 1678 males t o 1728 females does not s i g n i f i c a n t l y d e v i a t e from a 1:1 r a t i o . T h e r e f o r e , i t can be c o n c l u d e d t h a t X - l i n k e d MR can account f o r the e x c e s s of males w i t h n o n - s p e c i f i c MR. G. FAMILIES WITH X-LINKED MR T w e n t y - f i v e f a m i l i e s i n B r i t i s h C o lumbia, whose p e d i g r e e s are l i s t e d i n Appendix IV, were i d e n t i f i e d w i t h MR showing a p a t t e r n o f X - l i n k e d i n h e r i t a n c e . E l e v e n o f t h e s e f a m i l i e s have m e n t a l l y r e t a r d e d males i n a t l e a s t t h r e e s i b s h i p s . S i x f a m i -l i e s have m e n t a l l y r e t a r d e d males or o b l i g a t e c a r r i e r females i n two h a l f - s i b s h i p s * p l u s one o t h e r s i b s h i p . M e n t a l l y r e -t a r d e d males are i n o n l y two s i b s h i p s i n the r e m a i n i n g e i g h t f a m i l i e s . F i v e o t h e r f a m i l i e s w i t h p o s s i b l e X - l i n k e d MR are not i n c l u d e d because the second a f f e c t e d s i b s h i p i s not sub-s t a n t i a t e d by e i t h e r a m e d i c a l f i l e o f the person i n q u e s t i o n or by d i r e c t i n f o r m a t i o n from a f i r s t - d e g r e e r e l a t i v e . I n f o r m a t i o n on the m a t e r n a l e t h n i c background:.in these f a m i l i e s i s p r e s e n t e d i n Table XIV. A l t h o u g h the f a m i l i e s are not c l o s e l y r e l a t e d , i t i s o f i n t e r e s t t h a t t h e y are a l l o f n o r t h e r n European e x t r a c t i o n . The v a r i a t i o n i n backgrounds does not d i f f e r s i g n i f i c a n t l y from what would be e x p e c t e d g i v e n Two s i b s h i p s w i t h the same mother but d i f f e r e n t f a t h e r s . - 67 -Table XIV M a t e r n a l E t h n i c Background number of f a m i l i e s E n g l i s h 8 U k r a i n i a n 4 German 6 Swedish 2 F i n n i s h 1 Fre n c h 1 Hungarian 1 I r i s h 1 Welsh _1 T o t a l 25 - 68 -the s m a l l sample o f 25 f a m i l i e s and the f r e q u e n c i e s of e t h n i c groups i n B r i t i s h Columbia (Census o f Canada, P o p u l a t i o n : E t h n i c  Groups, 1971). However, t h e r e are a few more German and U k r a i n i a n f a m i l i e s r e p r e s e n t e d than would be ex p e c t e d s i m p l y from B. C. f r e q u e n c i e s . There are 79 s i b s h i p s c o m p r i s i n g 381 s i b s , i d e n t i f i e d as c a r r y i n g the X - l i n k e d d e f e c t among the 25 f a m i l i e s . I nforma-t i o n on the f a m i l y members i s summarized i n Table XV. There are 192 males, 185 females and 4 s i b s whose sex i s not known. The r a t i o of 192:185 does not d i f f e r s i g n i f i c a n t l y from an ex-pected 1:1 sex r a t i o . I f the s i b s , whose sex and m e n t a l s t a t u s are not known, are e x c l u d e d , t h e r e a re 182 f e m a l e s , 93 normal or b o r d e r l i n e males and 85 r e t a r d e d males which does not s i g -n i f i c a n t l y d i f f e r from a 2:1:1 r a t i o o f females t o h e a l t h y males t o a f f e c t e d males f o r an X - l i n k e d d i s e a s e . There i s no s i g n i -f i c a n t d e v i a t i o n from a 1:1 r a t i o o f normal t o m e n t a l l y r e t a r d e d males. I f the s i b s who d i e d b e f o r e a d i a g n o s a b l e age are i n c l u d e d i n the a n a l y s i s , i t makes no d i f f e r e n c e whether the 14 males are c o n s i d e r e d a l l normal or a l l m e n t a l l y r e t a r d e d or any com-b i n a t i o n between. There i s s t i l l no s i g n i f i c a n t d e v i a t i o n i n the a n a l y s i s of e i t h e r the 2:1:1 r a t i o or 1:1 r a t i o . There may be some q u e s t i o n whether the b o r d e r l i n e i n t e l -l i g e n c e i n the 13 males i s due t o the same X - l i n k e d d e f e c t presumably p r e s e n t i n the m e n t a l l y r e t a r d e d males or n o t . Table XV F a m i l i e s w i t h a Presumptive X - l i n k e d MR Defect fa c CO 0 Xi rH 4-> rtj •H S-i g 5 0 0 4-1 CO CO •H r—I CD ui b n £3 vi •H (T3 co a o g o f Vl .a -p 0) c vi CD •o I i" -p o c a KH I U C CD S Q rH m e vi o f • CO CD rH g CD C S-i CD X ! I CO 0 rH rc e a CD M fa >i -P 8 -P c CD a g H T CD I CO rQ CO 0 S-i 0 G rH (0 rH § (T3 -P CO O e CD e C CD U CD ^ fa fa e f CO CD 0 C CD i CO CD >1 -P o c a (0 •P O), CD O CO fti! CD -P I to _ 0 O rH 0 rH C a T3 g X 0 CO I -p X ! O •H C CO O C CO rH 0 OS rH -p m 0631 0534 0122 1671 2135 1274 1067 3788 2050 1007 0583 0224 0757 1201 0586 1742 0593 4252 1206 0 70 7 0992 0741 0084 1522 1906 T o t a l 2 4 2 3 5 3 4 2 4 2 3 2 2 5 7 4 4 4 3 3 2 2 2 3 2 79 1 4 2 3 5 3 4 2 3 3 2 2 5 6 4 2 4 3 3 .1 2 2 3 _2_ 171 1 2 1 2 5 7 6 •5 8 5 11 • .4 9 1 3 6 3 10 22 13 4 8 8 3 1 3 4 11 1 3 163 17 5 3 2 1 4 1 3 1 6 4 5 2 2 1 3 2 4 5 !lo 6 4 1 1 3 4 5 3 1 1 1 1 1 1 2 1 1 1 4 4 2 2 6 2 6 2 3 5 4 3 2 5 7 3 5 4 2 2 4 2 2 2 2 1 3 2 3 1 1 1 1 B0 13 85 14 7 7 6 5 10 5 13 4 9 2 3 6 3 10 27 .13 10 4 2 3 4 12 4_ 185 6 5 4 13 8 15 5 6 6 7 7 6 13 17 . 5 11 5 7 3 5 7 8 8 7_ 192 - 70 -Even i f they are i n c l u d e d w i t h the a f f e c t e d m ales, i t does not a f f e c t the s i g n i f i c a n c e of the r a t i o s . Nine (or 36%) o f the f a m i l i e s have females who are o f b o r d e r l i n e or r e t a r d e d i n t e l l i g e n c e . Seven (or 9%) o f the 79 mothers o f the s i b s h i p s c a r r y i n g the X - l i n k e d d e f e c t are de-s c r i b e d as slow. I f i t i s assumed t h a t one h a l f (or 91) o f the 182 f e m a l e s , who are among these s i b s h i p s and whose mental s t a t u s i s known, i s c a r r y i n g the X - l i n k e d d e f e c t , then 21% (19/91) of them may be p a r t i a l l y e x p r e s s i n g the X - l i n k e d d e f e c t . Such a phenonomenon i s c o m p a t i b l e w i t h random X i n a c t i v a t i o n i n the female. H. CLINICAL FEATURES OF X-LINKED MR I . C l i n i c a l I n f o r m a t i o n Data on the c l i n i c a l f e a t u r e s o f males w i t h MR or b o r d e r -l i n e i n t e l l i g e n c e i n the f a m i l i e s i d e n t i f i e d as h a v i n g X - l i n k e d MR are p r e s e n t e d i n T a b l e s XVI t o XXV. S i n c e m e d i c a l f i l e s were not a v a i l a b l e on a l l males and s i n c e i n those t h a t were a v a i l a b l e , the c l i n i c a l i n f o r m a t i o n v a r i e d c o n s i d e r a b l y , the number of males w i t h s p e c i f i c i n f o r m a t i o n i n any g i v e n t a b l e i s always l e s s than the t o t a l number of males i n the 25 f a m i l i e s . 2. M e n t a l , V e r b a l , and S o c i a l A b i l i t i e s a. v a r i a t i o n i n MR The degree of MR i n the a f f e c t e d males i n the X - l i n k e d f a m i l i e s i s p r e s e n t e d i n T a b l e XVI. The b o r d e r l i n e Table XVI L e v e l o f MR i n Males w i t h X - l i n k e d MR Number of males a t each l e v e l of MR F a m i l y T o t a l Study B o r d e r - Mod- P r o - Unspec- number number l i n e M i l d e r a t e Severe found i f i e d o f males 1) 0631 3 1 4 2) 0534 1 1 1 1 4 3) 0122 1 1 2 4) 1671 1 2 3 5) 2135 1 1 5 7 6) 1274 1 1 1 3 7) 1067 1 2 4 7 8) 3788 1 1 1 3 9) 2050 1 2 1 4 10) 1007 3 2 5 11) 0583 1 3 4 12) 0224 1 1 1 3 13) 0757 1 1 2 14) 1201 1 1 3 5 15) 0586 4 3 7 16) 1742 1 3 4 17) 0593 1 3 1 5 18) 4252 2 2 4 19) 1206 1 1 1 3 20) 0707 1 1 2 21) 0992 3 1 4 22) 0741 2 1 1 4 23) 0084 1 2 3 24) 1522 1 1 1 3 25) 1906 1 2 3 T o t a l number 13 19 23 16 6 21 98 of males - 72 -i n t e l l i g e n c e group has been i n c l u d e d a l t h o u g h i t i s q u e s t i o n -a b l e whether they a re a f f e c t e d or n o t . From the t a b l e i t i s apparent t h a t t h e r e i s a wide range o f MR a s s o c i a t e d w i t h X-l i n k e d i n h e r i t a n c e s i n c e t h e r e are 19 males w i t h m i l d MR, 23 males w i t h moderate MR, 16 w i t h severe MR.and 6 w i t h p r o f o u n d MR. T h i s v a r i a t i o n e x i s t s n o t o n l y among, but a l s o w i t h i n , f a m i l i e s . C o n s i d e r i n g the s p e c i f i e d l e v e l s of MR ( i n c l u d i n g the b o r d e r l i n e g r o u p ) , 15 f a m i l i e s (60%) have MR w i t h i n a range of one or two l e v e l s . Ten f a m i l i e s (40%) have a range o f t h r e e or more l e v e l s of MR i n the a f f e c t e d males. b. IQ s t r e n g t h s and weaknesses Re p o r t s from p s y c h o l o g i c a l exams on 21 a f f e c t e d males from 13 f a m i l i e s c o n t a i n e d comments on the a r e a s o f IQ s t r e n g t h s and weaknesses which are p r e s e n t e d i n T a b l e XVII . A l t h o u g h 11 males performed b e s t i n n o n - v e r b a l a r e a s , 8 males e i t h e r showed no s t r e n g t h s or weaknesses or performed b e s t i n the v e r -b a l a r e a . In t h r e e f a m i l i e s [nos. 12)0224, 16) 1742, and 21) 0992^] t h e r e a re a f f e c t e d males i n both c a t e g o r i e s . c. s p e c i f i c speech d e f e c t s A c c o r d i n g t o d a t a i n Table XVIII; on 38 males w i t h presumed X - l i n k e d MR among 20 f a m i l i e s , t h e r e i s no s p e c i f i c v e r b a l d i s a b i l i t y or speech d e f e c t commonly a s s o c i a t e d w i t h X - l i n k e d MR. Seventeen m e n t a l l y r e t a r d e d males show no v e r b a l d i s a b i l i t y or speech d e f e c t w h i l e 21 a f f e c t e d males do show a v a r i e t y o f Table XVII IQ S t r e n g t h s and Weaknesses i n Males w i t h X - l i n k e d MR Number of Males N o n - v e r b a l performance best No Poor Not s t r e n g t h s v i s u a l V e r b a l Poor o t h e r -F a m i l y or p e r c e p - p e r f o r m - e x p r e s - Poor wise No s t u d y weak- t u a l ance s i v e s p a t i a l spec- i n f o r -number nesses a r e a b e s t speech t r a n s f e r i f i e d m ation 1) 0631 1 3 2) 0534 1 1 2 3) 0122 2 4) 1671 2 1 5) 2135 7 6) 1274 3 7) 1067 7 8) 3788 3 9) 2050 1 3 10) 1007 5 11) 0583 4 12) 0224 1 1 1 13) 0757 1 1 14) 1201 1 4 15) 0586 1 6 16) 1742 1 2 1 17) 0593 2 3 18) 4252 1 3 19) 1206 1 2 20) 0707 2 21) 0992 1 1 1 1 22) 0741 4 23) 0084 3 24) 1522 3 25) 1906 3 T o t a l no. of males 4 2 4 5 2 4 77 - 74 -TABLE X V I I I S p e c i f i c Speech D i s a b i l i t y i n Males w i t h X - l i n k e d MR Number F a m i l y Study Number T o t a l no.I of males i *one male counted t w i c e , once f o r poor a r t i c u l a t i o n f o r s t u t t e r i n g and once - 75 -speech d e f e c t s . Three f a m i l i e s [nos. 11)0583, 15)0586, and 16)1742] c o n t a i n two or more m e n t a l l y r e t a r d e d males w i t h d i f -f e r e n t speech d i s a b i l i t i e s . In f o u r f a m i l i e s [nos. 4)1671, 18)4252, 21)0992, and 22)0741] t h e r e are males w i t h no v e r b a l d i s a b i l i t y and males w i t h a s p e c i f i c speech d e f e c t . d. s o c i a l a d a p t a b i l i t y The s o c i a l a d a p t a b i l i t y i n 18 of the m e n t a l l y r e t a r d e d males was measured by the V i n e l a n d S o c i a l M a t u r i t y S c a l e . The r e s u l t s , e x p r e s s e d as an SQ l e v e l , are r e c o r d e d i n T able XIX. There i s a wide sp r e a d of SQ l e v e l s s i m i l a r t o the range of IQ l e v e l s l i s t e d i n T able XVI.. A comparison i s made of SQ and IQ l e v e l s i n these 18 i n d i v i d u a l s i n P a r t B o f Table XIX. from which i t can be c o n c l u d e d t h a t a h i g h SQ s c o r e c o r r e l a t e s w e l l w i t h a m i l d degree of MR and a low SQ l e v e l c o r r e l a t e s w i t h a low l e v e l o f i n t e l l i g e n c e . 3. B e h a v i o r a l D i s o r d e r s J u s t over h a l f o f the X - l i n k e d m e n t a l l y r e t a r d e d males, 28 out o f 50, are d e s c r i b e d as h a v i n g some form of b e h a v i o r a l d i s o r d e r - d e v i a n t b e h a v i o r and h y p e r a c t i v i t y b e i n g the most common. However, as i s apparent i n Table XX,,- no p a r t i c u l a r b e h a v i o r a l d i s o r d e r i s e v i d e n t i n the m a j o r i t y of c a s e s or i s even c o n s i s t e n t i n any group of f a m i l i e s . - 76 -Table XIX S o c i a l Q u o t i e n t (SQ) i n Males w i t h X - l i n k e d MR A. Range of SQ Number of males a t SQ l e v e l s F a m i l y i n f o r m a t i o n study no. Normal I I I I I I IV No 1) 0631 1 3 2) 0534 2 2 3) 0122 2 4) 1671 3 5) 2135 7 6) 1274 1 2 7) 8) 1067 3788 7 3 9) 20 50 4 10) 1007 5 11) 0583 1 1 2 12) 0224 1 2 13) 0757 1 1 14) 1201 1 4 15) 0586 1 6 16) 1742 1 2 1 17) 0593 1 4 18) 4252 1 3 19) 1206 1 2 20) 0707 1 1 21) 0992 1 3 22) 0741 4 23) 0084 3 24) 1522 3 25) 1906 3 T o t a l no. of males 1 3 6 6 2 80 - 77 -Table XIX (cont'd) B. SQ v e r s u s IQ IQ L e v e l s Normal SQ I l e v e l s I I I I I IV B o r d e r l i n e 1 1 M i l d 1 1 Moderate 1 3 3 Severe 2 2 2 Pro f o u n d 1 - 78 -Table XX, Aspects of Behavior A s s o c i a t e d with X - l i n k e d MR Number of males S p e c i f i c b e h a v i o r a l d i s o r d e r * r H c 0 >i (0 • H 4-> S-l 4-) • H > l QJ o o r H rrj > 4-> O QJ QJ • H 4-> • H fO £ • H • H i—1 C QJ 10 to • H • H S-l C > U s- i u s-l S-l 4-> QJ r H fO fO > S-l • H i—1 S-l - H LO 4 H 4-> QJ to QJ 0 QJ 0 4-1 0 O S-l fO C X! • H 0 CO (0 O c • H - H • H ffl E x • H T3 MH C " H fO D C O S-4 C/2 - H 0 T D - H fO CJ CO o - H S-l Family QJ S-l > S-l c 10 > S-4 4-> O - H D D > X - H > £ QJ 0 QJ X - H study X! 0 fO o • H • H tO QJ fO CO 4-) 4-> r H fO o u to 0 Qu S-l Cu U fO to X CO > X Cu E s-i O W O X > i - H X S-l co a CO > i Q J n n n i h p r 0 - r H QJ - H 0 QJ QJ >1 E QJ E - H QJ QJ CO ZS QJ >1 C CO E 2 TJ PQ 2 -Q XI r H - COX! 0< CO x! CM & c p Qj-H 1) 0631 1 2 1 2 2) 0534 3 1 3) 0122 1 1 4) 1671 1 2 1 1 5) 6) 2135 1274 1 1 6 2 1 1 7) 8) 1067 3788 2 5 3 9) 2050 2 2 1 1 10) 1007 1 4 1 1 11) 0583 1 1 2 1 12) 0224 2 1 13) 0757 1 1 1 1 14) 1201 2 3 15) 0586 2 3 2 3 1 16) 1742 1 3 1 2 1 17) 0593 1 2 2 1 1 18) 4252 1 3 1 19) 1206 1 1 1 1 20) 0707 1 1 1 21) 0992 2 1 1 1 22) 0741 3 1 2 1 23) 0084 1 1 1 1 24) 1522 1 2 1 25) 1906 3 T o t a l no. of males 22 28 48 10 9 3 .2 2 1 2 1 1 1 * some males have more than one b e h a v i o r a l d i s o r d e r - 79 -4. B i r t h H i s t o r y I n f o r m a t i o n on the b i r t h h i s t o r y r e c o r d e d i n the m e d i c a l f i l e s of 51 a f f e c t e d males i s summarized i n Ta b l e XXI. S i x of these males weighed l e s s than 2500 g a t b i r t h . A l t h o u g h these s i x are d e s c r i b e d as premature t h e r e i s i n s u f f i c i e n t i n f o r m a t i o n t o d i s c e r n between a premature and a s m a l l - f o r -d a t e s baby. The b i r t h w e i g h t of the r e m a i n i n g 45 males f a l l s between 2500 g and 4500 g. None has a b i r t h w e i g h t over 4500g. S i x o f the 51 males-are from t w i n b i r t h s , w h i l e the r e m a i n - -i n g 45 are s i n g l e t o n s . Among those males w i t h a b i r t h w e i g h t of 2500 g or o v e r , 37 appeared normal a t b i r t h a f t e r a f u l l - t e r m pregnancy and a normal d e l i v e r y . E i g h t o f the males had a b i r t h d e s c r i b e d as " d i f f i c u l t " and/or may have e x p e r i e n c e d trauma a t b i r t h . Two of these males, one i n f a m i l y 21)0992 and one i n 22)07441, were d e s c r i b e d as a n o x i c a t b i r t h . Another i n t h i s group, a male i n f a m i l y 13)0757, had h a e m o l y t i c d i s e a s e o f the newborn due t o Rh i n c o m p a t i b i l i t y and r e c e i v e d a b l o o d t r a n s f u s i o n a t b i r t h . A l t h o u g h the mother i n 5)2135 i s d e s c r i b e d as d i a b e t i c , t h e r e a r e no o t h e r u n u s u a l o c c u r r e n c e s , which may have c o n -t r i b u t e d t o the MR, noted i n the mothers or the b a b i e s . - 80 -T a b l e X X I B i r t h H i s t o r y o f M a l e s w i t h X - l i n k e d MR Number o f m a l e s i n e a c h - b i r t h w e i g h t g r o u p . 2 5 0 0 - 3 2 0 1 - 3 9 0 1 -F a m i l y <2500g 3200g 3 9 0 0 g 4 5 0 0 g >4500g No b i r t h s t u d y (<3 ( 3 - 2 5 ( 2 6 - 7 5 ( 7 6 - 9 7 (>97 i n f o r -number % i l e ) % i l e ) % i l e ) % i l e ) % i l e ) m a t i o n 1) 0631 1 3 2) 0534 2 2 3) 0122 2 4) 1671 I t * 1 1 5) 2135 I t 6 6) 1274 2 1 7) 1067 2 5 8) 3788 1 2 9) 2050 1* 3 10) 1007 5 11) 0583 4 12) 0224 1 1 ,1* 13) 0 757 l * . , l t 14) 1201 2 3 15) 0586 I t 3 1 2 16) 1742 3 1 17) 0593 I t , I t 1 2 18) 4252 1* ,2 1 19) 1206 1 2 20) 0707 1 1 21) 0992 1 2 1* 22) 0741 1* 1* 2 23) 0084 2 1 24) 1522 1 2 25) 1906 2 1 T o t a l n o . o f m a l e s 6 12 28 5 0 47 t - f r o m t w i n b i r t h * _ " d i f f i c u l t " b i r t h a n d / o r t r a u m a a t b i r t h - 81 -5. N e u r o l o g i c a l C h a r a c t e r i s t i c s a. s e i z u r e s T w e n t y - f i v e (42%) o f 60 X - l i n k e d m e n t a l l y r e t a r d e d males have a h i s t o r y of a t l e a s t one s e i z u r e (Table X X I I ) . The a s s o c i a t i o n o f s e i z u r e s w i t h t h i s type o f MR i s not n e c e s s a r i l y c o n s i s t e n t w i t h i n a f a m i l y . A l t h o u g h i n f i v e f a m i l i e s a l l o f the m e n t a l l y r e t a r d e d males, f o r which t h e r e are adequate r e c o r d s , have had s e i z u r e s , e i g h t f a m i l i e s have a t l e a s t one m e n t a l l y r e t a r d e d male who has e x p e r i e n c e d s e i z u r e s and one who has n o t . In t w e l v e f a m i l i e s t h e r e are no h i s t o r i e s o f s e i z u r e s among the males w i t h X - l i n k e d MR. In no case does a m i l d l y a f f e c t e d or slow female i n these f a m i l i e s have a h i s t o r y o f e p i l e p s y . b. motor c o n t r o l Motor c o n t r o l i s d e s c r i b e d as normal i n 47 o f 57 a f f e c t e d males. The r e m a i n i n g t e n , whose n e u r o l o g i c a l d i s o r d e r s are l i s t e d i n Table X X I I / have a v a r i e t y o f a s p e c t s of poor motor c o n t r o l which range from c e r e b r a l p a l s y t o s i m p l y poor c o o r d i -n a t i o n . A g a i n , t h e r e i s a v a r i a t i o n w i t h i n f a m i l i e s s i n c e each of these ten a f f e c t e d males are from a d i f f e r e n t f a m i l y . A l s o , e i g h t of those f a m i l i e s have m e n t a l l y r e t a r d e d males w i t h good motor c o n t r o l . - 82 -Table X X I I N e u r o l o g i c a l F e a t u r e s i n Males w i t h X - l i n k e d MR Number of males H i s t o r y o f E p i l e p s y A s p e c t s of motor c o n t r o l c (0 c o c o •H CO •H VI o •H co ro CO •p 0 •H co co - p rH CD •H o >i VI CO -p -p CD CD CO tO o S-I c S-I 4 J CO c O rH to F a m i l y vi D V i D e VI VI X ! > i -H •p (0 0 •p cn S-I •H -H > rH •H 'O e o VI e VI study N N O CD CO CO •H 0 vi O •H D 4-> VI VI TD -P O •r-t •H CM S-I rH ro e a 0 -P -P O "H 0 O o c M-l number CD 0 CD 0 C CD fC Cu CD O O O CD tO O 0 o 0 0 c CO S CO 2 -H u CM CO in CM a fO CM CT> CM O O O 2 -H 1) 0631 2 2 1 3 2) 0534 3 1 4 3) 0122 1 1 1 1 4) 1671 2 1 1 2 5) 2135 1 6 7 6) 1274 1 2 1 2 7) 1067 2 5 2 5 8) 3788 1 2 3 9) 2050 1 3 1 2 1 10) 1007 2 1 2 . 3 2 11) 0583 2 2 3 1 12) 0224 2 1 1 1 1 13) 0757 1 1 1 1 14) 1201 2 3 2 3 15) 0586 5 2 5 2 16) 1742 4 4 17) 0593 2 1 • 2 3 2 18) 4252 4 1 2 1 19) 1206 1 1 1 1 1 1 20) 0707 1 1 1 1 21) 0992 4 1 3 22) 0741 2 2 3 1 23.) 0084 2 1 1 1 1 24) 1522 2 1 1 2 25) 1906 2 1 2 1 T o t a l : ho. of males 25 35 38 3 2 1 1 2 1 47 41 - 83 -6. P h y s i c a l C h a r a c t e r i s t i c s a. h e i g h t The range of h e i g h t of 31 males i s p r e s e n t e d i n Table X X I I I . Only 3 o f the 31 males have a s i g n i f i c a n t l y subaverage (< 3rd p e r c e n t i l e ) h e i g h t . b. head c i r c u m f e r e n c e Measurements o f head c i r c u m f e r e n c e are a v a i l a b l e on 40 males w i t h X - l i n k e d MR. As shown i n Table XXIV, f i v e males i n f o u r f a m i l i e s are m i c r o c e p h a l i c s i n c e the head c i r c u m f e r e n c e i s l e s s than the 3rd p e r c e n t i l e . * The r a t i o of 5/40 i s s l i g h t l y more, though not s i g n i f i c a n t l y more, than what might be e x p e c t e d i n the g e n e r a l p o p u l a t i o n . In one of these f o u r f a m i l i e s , 9)2050, t h e r e are a l s o males w i t h a normal head s i z e . Three males, each i n d i f -f e r e n t f a m i l i e s , have a head c i r c u m f e r e n c e between the 3rd •and 24th p e r c e n t i l e . Two of. these t h r e e f a m i l i e s have m e n t a l l y r e t a r d e d males w i t h a head c i r c u m f e r e n c e around the 50th p e r c e n t i l e . Only one male has a head c i r c u m f e r e n c e g r e a t e r than the 97th p e r c e n t i l e . In t h a t c a s e , the p o s s i b i l i t y o f h y d r o c e p h a l u s was i n v e s t i g a t e d but was e v e n t u a l l y r u l e d o u t . c. u n u s u a l p h y s i c a l f e a t u r e s A l l u n u s u a l or abnormal p h y s i c a l f e a t u r e s d e s c r i b e d i n these males are l i s t e d i n T a b l e XXV. In 26 (45%) of 58 males Less than the 3rd p e r c e n t i l e i s regar d e d as s i g n i f i c a n t l y subaverage, i . e . the head c i r c u m f e r e n c e i s l e s s than 2 s t a n d a r d d e v i a t i o n s below the mean. F a m i l y s t u d y number Table XXIII Height o f Males w i t h . X - l i n k e d MR Number o f males H e i g h t p e r c e n t i l e groups < 3 % i l e 3 - 2 5 % i l e 2 6 - 7 5 % i l e 7 6 - 9 7 % i l e > 9 7 % i l e No i n f o r m a t i o n 1) 0631 2) 0534 3) 0122 4) 1671 5) 2135 6) 1274 7) 1067 8) 3788 9) 2050 10) 1007 11) 0583 12) 0224 13) 0757 14) 1201 15) 0586 16) 1742 17) 0593 18) 4252 19) 1206 20) 0707 21) 0992 22) 0741 23) 0084 24) 1522 25) 1906 T o t a l no. 6'f males 1 1 1 1 2 3 1 2 2 1 1 3 2 1 1 1 13 14 3 1 2 2 6 2 7 3 3 5 2 1 1 4 2 1 3 2 1 1 2 4 3 3 3 67 F a m i l y s t u d y number Table XXIV,, Head C i r c u m f e r e n c e o f Ma l e s w i t h X - l i n k e d MR Number of males . Head c i r c u m f e r e n c e p e r c e n t i l e groups < 3 % i l e 3 - 2 5 % i l e 2 6 - 7 5 % i l e 7 6 - 9 7 % i l e > 9 7 % i l e No i n f o r m a t i o n 1) 0631 2) 0534 3) 0122 4) 1671 5) 2135 6) 1274 7) 1067 8) 3788 9) 2050 10) 1007 11) 0583 12) 0224 13) 0757 14) 1201 15) 0586 16) 1742 17) 0593 18) 4252 19) 1206 20) 0707 21) 0992 22) 0741 23) 0084 24) 1522 25] 1906 T o t a l no. of males 1 1 3 1 1 2 2 1 1 3 3 1 1 3 28 6 2 5 3 1 5 2 1 1 4 3 3 2 2 1 4 3 3 2 58 TABLE XXV P h y s i c a l C h a r a c t e r i s t i c s Associated with X-linked MR S p e c i f i c p h y s i c a l character i s t i c s * i m o 0 ] 01 • H 1 c o • H u 01 o u] u 0 <0 JJ ( 0 u • H E - H >1 fl) • H m Ul O J 0 ) 01 (fl 0) flj 01 JJ 01 X i X . 4 J JJ 3 O M •r—t T J JJ JJ cn 01 O O •rl (0 >i a u CkO ( 0 o o) - E rH rH o. (0 0 ) (fl H C e •rl - H rH CU o T 3 X) X ! U o a E • H 3 ( 0 cn rH ( 0 ( 0 0 01 JJ X ! rH cn • H 1 01 rH rH ( 0 <4H 0 ) •rl rH ( 0 • H -rl E O J O ul rH U I-I E - H ( 0 10 4J E rH c CJ ( 0 H MH (fl *rl rH O •rl 0 ) c JJ ( 0 •rl x : •o •ri O E fl) rH (0 (fl 0 JJ 01 O j - U IH > 1 •rl O rH > JJ fl) IH Q J ' d >i u 73 O O JJ T3 01 01 U 01 rH 0 ( 0 rH U Family 01 M nj e x : oi >u OJ H O W 01 - C C C ( 0 - U M 0) c 10 4 ) H > 1 ( 0 -rl O 01 C • H > 1 > 1 0 ) <0 ( 0 0 O J JJ >i 3 3 u O O c E X i M >i JJ O J 0 ) <0 01 - H 0 Ul • H JJ JJ - ( 0 X I O j O *rl 0 0> JJ O 0 ) JJ - H 01 JJ J J 01 I-I I-I study T3 J J 01 0 - H • H 6 ( 0 J J C 10 O cn c o E XI (0 14H XI E XI O u J J i X ! Cn M >( c (fl C O V H Qj O 4 ) fl) 10 3 C rH 4J >i i-i O rH U C 0 J S-j ( 0 cn 3 0 cn rH 0 ) E O 3 Qj >i u o. C (0 0 ) rH t J rH M U C >I O J * O J number 0 <u C X I ( 0 Ul 0 JJ Ul I-I H JJ O >i o a •rl 0 u • H nj rH ri C JJ N X ! O >i O 0 ) C O - H • H 0 ) (fl fl) >-t >1 O >i Z MH D (0 O SB < U l 4 ) O CQ 10 u OJ O O m i j ft K O J U i j (0 U l S B J J E-i u x ; o O J ca x ; i J cn u E C i-3 X i 1) 0631 1 3 1 2) 0534 1 3 1 1 1 1 1 3) 0122 1 1 1 1 4) 1671 3 5) 2135 1 6 1 1 6) 1274 1 2 1 7) 1067 2 5 8) 3788 3 9) 2050 2 1 1 1 10) 1007 1 2 2 1 1 11) 0583 2 1 1 1 1 12) 0224 1 1 1 1 1 1 13) 0757 1 1 1 14) 1201 1 1 3 1 15) 0586 1 4 2 1 1 3 1 1 1 1 16) 1742 2 2 1 1 1 1 17) 0593 2 1 2 1 1 1 18) 4252 1 2 1 1 1 1 2 1 19) 1206 1 1 1 1 20) 0707 2 21) 0992 4 22) 0741 3 1 23) 0084 1 1 1 1 24) 1522 1 2 1 25) 1906 2 1 To t a l no. of males 32 26 40 2 3 1 1 1 7 1 3 6 1 3 2 1 1 1 1 1 1 1 5 2 1 1 * some males have more than one p h y s i c a l anomaly - 87 -a v a r i e t y o f f e a t u r e s are noted - the most common be i n g b i g or l o p e a r s , h i g h arched p a l a t e , and l a r g e g e n i t a l i a . No spe-c i f i c anomaly i s l i s t e d f o r more than 12% of a l l males w i t h X - l i n k e d MR, or even i n a l l m e n t a l l y r e t a r d e d males w i t h i n one f a m i l y . The r e m a i n i n g 32 males are d e s c r i b e d as h a v i n g no d y s -morphic f e a t u r e s . Only one of those males, one i n f a m i l y no. 25)1906, i s d e s c r i b e d as h a v i n g poor h e a r i n g . I t must be noted t h a t many of the c h a r a c t e r i s t i c s such as b i g e a r s or l a r g e g e n i t a l i a may be c o n s i d e r e d o n l y minor anoma-l i e s found a l s o i n the normal p o p u l a t i o n . These anomalies may not have been u n u s u a l enough t o e l i c i t comments i n the m e d i c a l • f i l e . T h e r e f o r e , i t i s d i f f i c u l t t o p l a c e any s i g n i f i c a n c e on the presence or absence of these anomalies a s s o c i a t e d w i t h X - l i n k e d MR. 7. Summary of C l i n i c a l F e a t u r e s Because m e d i c a l f i l e s were not a v a i l a b l e on a l l m e n t a l l y r e t a r d e d males i n X - l i n k e d f a m i l i e s , and because the ones t h a t were a v a i l a b l e v a r i e d c o n s i d e r a b l y i n the c l i n i c a l i n f o r m a t i o n r e c o r d e d , i t i s d i f f i c u l t t o draw any s p e c i f i c c o n c l u s i o n s and i d e n t i f y any sub-types of n o n - s p e c i f i c X - l i n k e d MR. However, t h e r e i s s u f f i c i e n t e v i d e n c e t o make a few g e n e r a l s t a t ements c o n c e r n i n g the c l i n i c a l f e a t u r e s of X - l i n k e d MR. One s t r i k i n g a s p e c t of t h i s type of MR seems t o be the extreme v a r i a b i l i t y i n e x p r e s s i o n of the c l i n i c a l f e a t u r e s . There i s - 88 -a broad range o f MR not o n l y among f a m i l i e s , but a l s o w i t h i n f a m i l i e s . S p e c i f i c IQ s t r e n g t h s and weaknesses v a r y as do the presence or absence o f s p e c i f i c v e r b a l d e f e c t s . D e v i a n t be-h a v i o r and h y p e r a c t i v i t y are not uncommon.among a f f e c t e d males. A h i s t o r y o f s e i z u r e s and v a r i o u s abnormal a s p e c t s o f motor c o n t r o l may be p r e s e n t . Most a f f e c t e d males are w i t h i n the normal range f o r h e i g h t and head c i r c u m f e r e n c e a l t h o u g h s l i g h t l y more than might be ex p e c t e d are m i c r o c e p h a l i c . A v a r i e t y o f u n u s u a l dysmorphic f e a t u r e s have been d e s c r i b e d i n 45% o f the males - the most common b e i n g b i g e a r s , h i g h a r c h e d p a l a t e and l a r g e g e n i t a l i a . However, none i s c o n s i s t e n t l y noted i n men-t a l l y r e t a r d e d males even from any one f a m i l y . In c o n c l u s i o n , t h e r e i s no d e f i n e d unique p h e n o t y p i c s y n -drome a s s o c i a t e d w i t h X - l i n k e d MR, and, p r i m a r i l y because o f w i t h i n - f a m i l y v a r i a t i o n , no s p e c i f i c s u b - t y p e s have been i d e n -t i f i e d . There s t i l l e x i s t s a r a t h e r heterogeneous group o f males w i t h n o n - s p e c i f i c MR whose main s i m i l a r i t y seems t o be the X-l i n k e d p a t t e r n o f i n h e r i t a n c e . - 89 -CHAPTER IV DISCUSSION A. MR IN BRITISH COLUMBIA The h y p o t h e s i s t h a t X - l i n k e d genes may c o n t r i b u t e t o MR i s not new. I t arose i n or d e r t o account f o r the exce s s of m e n t a l l y r e t a r d e d males found i n v i r t u a l l y a l l MR s t u d i e s . Data on MR i n B r i t i s h Columbia suggest t h a t X - l i n k e d genes are a p l a u s i b l e e t i o l o g y f o r a s i g n i f i c a n t p o r t i o n o f MR. The p r e s e n t s t u d y i n d i c a t e s t h a t t h e r e i s an o v e r a l l 28.2% e x c e s s of m e n t a l l y r e t a r d e d males i n B r i t i s h C olumbia. T h i s s i g n i f i -c a n t e x c e s s seems t o be a t t r i b u t a b l e m a i n l y t o c a s e s of non-s p e c i f i c MR s i n c e i t i s not seen i n most c a t e g o r i e s of MR w i t h a s p e c i f i c e t i o l o g y . A s i g n i f i c a n t e x c e s s of males i s seen a t a l l l e v e l s of n o n - s p e c i f i c MR w i t h one e x c e p t i o n - the prof o u n d l e v e l . The d i s t r i b u t i o n o f a f f e c t e d males and o f a f f e c t e d females among the MR l e v e l s does n ot d i f f e r s i g n i f i c a n t l y . T h e r e f o r e , what-ever the e t i o l o g y o f MR f o r the exce s s of males happens t o be, i t must a f f e c t m a i n l y m i l d , moderate, and severe MR. I t must be noted t h a t t h e r e i s a s i z a b l e p o r t i o n of c a s e s of n o n - s p e c i f i c MR where the l e v e l of MR i s u n s p e c i f i e d - 28.8% of the m e n t a l l y r e t a r d e d males and 30.6% o f the m e n t a l l y r e -t a r d e d f e m a l e s . There has been no f o l l o w - u p o f these c a s e s , but - 90 -there i s no reason to b e l i e v e t h a t the d i s t r i b u t i o n of the un-s p e c i f i e d MR cases among the MR l e v e l s would change the observed d i s t r i b u t i o n s . I t i s very d i f f i c u l t , and i n many cases u n r e l i a b l e , to compare the B.C. MR data with other e p i d e m i o l o g i c a l s t u d i e s . Not only do the means of ascertainment d i f f e r , but the d e f i n i -t i o n and c l a s s i f i c a t i o n of MR vary from one country to another and even vary with time w i t h i n a country. Although the WHO has r e c e n t l y s t a n d a r d i z e d the d e f i n i t i o n and nomenclature a s s o c i a t e d with MR, i t s recommendations are s t i l l not u n i v e r -s a l l y accepted. In a d d i t i o n , because of the d i f f i c u l t y i n i d e n t i f y i n g and a s c e r t a i n i n g the cases of mil d MR, many popula-t i o n s t u d i e s are l i m i t e d to cases of severe and profound MR. S i m i l a r problems e x i s t i n i d e n t i f y i n g and a s c e r t a i n i n g m entally retarded a d u l t s . T h e r e f o r e , prevalence s t u d i e s are o f t e n l i m i t e d to c h i l d r e n i n a s p e c i f i e d age group. The R e g i s t r y p r o v i d e s r e l i a b l e data on the mentally r e -tarded i n B r i t i s h Columbia because of i t s means of ascertainment and i t s o r g a n i z a t i o n . Somewhat s i m i l a r d i s t r i b u t i o n s of males and females among the MR l e v e l s were found i n other s t u d i e s based on community ascertainment such as those i n Edinburgh ( D r i l l i e n , e t a l . , 1966), n o r t h - e a s t Scotland (Innes, e t a l . , 1968) and northern I r e l a n d (MacKay, 1971). Some s t u d i e s t h a t attempted to a s c e r t a i n the mild cases of MR ( D r i l l i e n , e t a l . , 1966; Henderson, e t a l . , 1972 and Rayner, 1964) reported the - 91 -g r e a t e s t number of both males and females i n the m i l d c a t e g o r y . D r i l l i e n , e t a l . (1966) a l s o found t h a t MR ca s e s w i t h no a s s o c i -a t e d a b n o r m a l i t i e s were l i k e l y t o be i n the m i l d MR l e v e l . Those cases due t o Down Syndrome or those a s s o c i a t e d w i t h c e r e b r a l p a l s y due t o b i r t h trauma were l i k e l y t o be more s e v e r e l y a f -f e c t e d . I t i s d i f f i c u l t t o c o n c l u d e whether the d i s t r i b u t i o n s r e p r e s e n t e d i n Table VI are the " t r u e " d i s t r i b u t i o n s i n the p o p u l a t i o n or whether t h e r e are many c a s e s of m i l d MR t h a t have not been a s c e r t a i n e d . MacKay (1971) and Innes and c o l l e a g u e s (1968) both a s c e r t a i n e d more m e n t a l l y r e t a r d e d persons a t the moderate l e v e l than a t the m i l d l e v e l - a f i n d i n g s i m i l a r t o t h a t made i n the p r e s e n t s t u d y . However, both r e p o r t s s t a t e d t h a t such a f i n d i n g may be due t o poor a s c e r t a i n m e n t of m i l d MR c a s e s . In most o t h e r s t u d i e s s i g n i f i c a n t l y more males than f e -males were found a t a l l MR l e v e l s i n v e s t i g a t e d e x c e p t i n the profo u n d c a t e g o r y where a 1:1 sex r a t i o e x i s t e d (New York S t a t e Department of M e n t a l Hygiene, 1955; D r i l l i e n , e t a l . , 1966; Henderson, e t a l . , 1972). These f i n d i n g s are s i m i l a r t o those i n the p r e s e n t s t u d y . Some e x c e p t i o n s appear i n r e p o r t s based on i n s t i t u t i o n a l d a t a which may show an ex c e s s o f females i n the m i l d c a t e g o r y and an excess of males i n the severe and prof o u n d l e v e l s (Pen-r o s e , 1938 ; Reed and Reed, 1965). However, the use of i n s t i t u t i o n a l - 92 -d a t a f o r sex r a t i o s of MR i s u n r e l i a b l e because of o b v i o u s b i a s e s . The number of cases i n s t i t u t i o n a l i z e d i s dependent on the number of a v a i l a b l e beds. The sex r a t i o among i n p a t i e n t s i s based on the s i z e of the male and female d o r m i t o r i e s r a t h e r than on the sex r a t i o among the m e n t a l l y r e t a r d e d i n the com-munity. A t t i t u d e s w i t h r e s p e c t t o who s h o u l d be i n s t i t u t i o n -a l i z e d v a r y c o n s i d e r a b l y from c o u n t r y t o c o u n t r y and w i t h t i m e . In the p a s t m i l d l y a f f e c t e d females were l i k e l y t o be i n s t i t u -t i o n a l i z e d f o r p r o t e c t i o n ( i . e . t o a v o i d pregnancy) (Penrose, 1972, p. 3 1 ) . P a r e n t s of a m i l d l y a f f e c t e d male might i n s t e a d be t o l d , "Why not g e t a w i f e t o look a f t e r him?" (Pearson, 1931). Recent t r e n d s i n Canada are towards d e i n s t i t u t i o n a l i z -i n g m e n t a l l y r e t a r d e d persons and i n t e g r a t i n g them i n t o the community. Only those MR c a s e s w i t h o t h e r d i s a b i l i t i e s r e q u i r -i n g m e d i c a l a t t e n t i o n are now commonly found i n an i n s t i t u t i o n or s c h o o l f o r the m e n t a l l y r e t a r d e d . I t i s of i n t e r e s t t o note t h a t some community s t u d i e s i n western Sweden w i t h m u l t i p l e s o u r c e s of a s c e r t a i n m e n t d i d not show a s i g n i f i c a n t e x c e s s o f males i n the moderate, severe or o profound l e v e l s (Akesson, 1961, 1967, 1968). However, a g r e a t excess of males was observed i n the m i l d c a t e g o r y i n one s t u d y (Rayner, 1964). I t may be t h a t t h e r e are fewer e t i o l o g i c a l f a c t o r s t h a t r e s u l t i n moderate or severe MR i n males o n l y i n western Sweden compared t o p o p u l a t i o n s elsewhere i n Sweden ( W a l l n e r , 1974), i n the U.S. (New York S t a t e Department of - 93 -M e n t a l Hygiene, 1955), Great B r i t a i n ( D r i l l i e n , e t a l . , 1966), Canada (McDonald, 1973) and A u s t r a l i a (Henderson, e t a l . , 1972). S i n c e c a s e s of severe or pro f o u n d MR are more l i k e l y t o be a s c e r t a i n e d by community s e r v i c e s than are c a s e s of m i l d MR, the 1:1 sex r a t i o i n the pro f o u n d l e v e l i s l i k e l y t o be a c c u r a t e . Other i n v e s t i g a t o r s u s i n g m u l t i p l e community a s c e r -tainment observed a s i m i l a r 1:1 sex r a t i o i n the p r o f o u n d c a t e -gory ( D r i l l i e n , e t . a l • , 1966; Henderson, e t . a l . , 1972). T h e r e f o r e , i t seems r e a s o n a b l e t o c o n c l u d e t h a t e t i o l o g i c a l f a c t o r s r e s p o n s i b l e f o r pro f o u n d MR a f f e c t males and females e q u a l l y . To summarize the p o p u l a t i o n d a t a : the s i g n i f i c a n t e x c e s s of m i l d l y , m o d e r a t e l y and s e v e r e l y a f f e c t e d males i s an a c c u r -ate assessment of the sex r a t i o s among the m e n t a l l y r e t a r d e d i n B r i t i s h C o lumbia. The o v e r a l l e x c e s s i s m a i n l y due t o non-s p e c i f i c MR. In g e n e r a l , c ases of MR w i t h s p e c i f i c causes do not c o n t r i b u t e t o the exc e s s o f a f f e c t e d males. T h e r e f o r e , i t can be r e a s o n a b l y h y p o t h e s i z e d t h a t d e f e c t s on the X chromosome may account f o r the e x c e s s o f males w i t h n o n - s p e c i f i c MR a t the m i l d , moderate and severe l e v e l s . I f t h i s h y p o t h e s i s i s c o r -r e c t , then X - l i n k e d genes or d e f e c t s c o u l d account f o r the ex-ce s s of a f f e c t e d males found i n the o v e r a l l m e n t a l l y r e t a r d e d p o p u l a t i o n . - 94 -B. FAMILY STUDIES Two or more n o n - s p e c i f i c m e n t a l l y r e t a r d e d s i b s i n a f a m i l y s t r o n g l y suggest a g e n e t i c component t o the e t i o l o g y . B r i t i s h Columbia d a t a on m u l t i p l y a f f e c t e d s i b s h i p s f o r the 1950 to 1969 b i r t h c o h o r t show t h e r e are 107 s i b s h i p s w i t h two or more a f f e c t e d males and 35 s i b s h i p s w i t h two or more a f f e c t e d females - a r a t i o o f 3.1:1. T h e r e f o r e , t h e r e i s an e x c e s s o f 72 male a f f e c t e d s i b s h i p s which may be accounted f o r by X-l i n k e d genes. Even s i b s h i p s t u d i e s based on i n s t i t u t i o n a l a s c e r t a i n -ment, which i n c l u d e d c a s e s of MR of known and unknown e t i o -l o g i e s , r e p o r t e d a g r e a t preponderance of male a f f e c t e d s i b -s h i p s (Wright, e t a l . , 1959 ; P r i e s t , e t a l . , 1961; W o r t i s , e t a l . , 1966). At l e a s t a 2:1 male a f f e c t e d t o female a f -f e c t e d s i b s h i p r a t i o was o b s e r v e d . P r i e s t and c o l l e a g u e s r e -p o r t e d t h a t 90% of the f a m i l i a l MR c a ses were of unknown e t i o -l o g y . S i n c e they found no e v i d e n c e t h a t the tendency f o r i n s t i t u t i o n a l i z a t i o n of r e t a r d e d i n d i v i d u a l s v a r i e d w i t h sex, they s p e c u l a t e d on the i n f l u e n c e of s e x - l i n k e d f a c t o r s t o account f o r the e x c e s s of f a m i l i e s w i t h o n l y males a f f e c t e d . Among the 141 s i b s h i p s w i t h two or more s e v e r e l y a f f e c t e d s i b s whose MR was of unknown e t i o l o g y a s c e r t a i n e d by D a v i son (1973), 50 s i b s h i p s had o n l y a f f e c t e d males w h i l e 21 s i b s h i p s had o n l y a f f e c t e d females - a r a t i o of 2.4:1. Turner and Turner (1974) r e p o r t e d a s i m i l a r r a t i o o f 58:22 (2.6:1) of - 95 -male a f f e c t e d s i b s h i p s t o female a f f e c t e d s i b s h i p s among a ten year b i r t h c o h o r t of c h i l d r e n w i t h moderate MR i n which o n l y Down Syndrome c a s e s were e x c l u d e d . The r a t i o o f 3.1:1 o f s i b -s h i p s w i t h a f f e c t e d males t o s i b s h i p s w i t h a f f e c t e d females r e p o r t e d i n t h i s s t u d y i s s l i g h t l y h i g h e r than the 2.4:1 and 2.6:1 r a t i o s . The p r e s e n t s t u d y i n c l u d e s a l l l e v e l s o f MR. N e i t h e r Davison nor Turner and Turner a s c e r t a i n e d m i l d c ases o f MR. In the 1950 t o 1969 b i r t h c o h o r t t h e r e i s a s l i g h t , though i n s i g n i f i c a n t , i n c r e a s e of f a m i l i a l c a s e s of m i l d l y a f f e c t e d males compared t o m i l d l y a f f e c t e d f e m a l e s . T h i s t r e n d i s e v i -dent i n Table IX. T h i s s l i g h t i n c r e a s e may c o n t r i b u t e t o the h i g h e r 3.1:1 r a t i o . T h i s r a t i o i s l i k e l y t o be more a c c u r a t e than those p r e -v i o u s l y r e p o r t e d f o r f a m i l i e s w i t h two or more s i b s o f the same sex a f f e c t e d w i t h n o n - s p e c i f i c MR. A l l c ases o f MR w i t h a s p e c i f i c e t i o l o g y were o m i t t e d i n i t i a l l y so o n l y f a m i l i e s w i t h n o n - s p e c i f i c MR i n two or more s i b s were s u r v e y e d . S i n c e the R e g i s t r y has had ongoing a s c e r t a i n m e n t from m u l t i p l e s o u r c e s s i n c e 1952, c a s e s o f MR, whether l i v i n g or dead a t the time of the p r e s e n t study,.were o b t a i n e d from t h i s s o u r c e . Because the R e g i s t r y n o r m a l l y n o t e s whether or not o t h e r f a m i l y members are r e g i s t e r e d and v e r i f i e s the r e l a t i o n s h i p , the d a t a of f a m i l i a l c a s e s of n o n - s p e c i f i c MR born between 1950 and 1969 are l i k e l y ' t o be a c c u r a t e . I t i s u n l i k e l y t h a t the e x c e s s o f male a f f e c t e d s i b s h i p s i s due l a r g e l y t o MR of m u l t i f a c t o r i a l o r i g i n w i t h d i f f e r e n t - 96 -male and female t h r e s h o l d s . I f t h a t were t r u e more males than females s h o u l d be m e n t a l l y r e t a r d e d among the s i b s h i p s t h a t have both male and female a f f e c t e d s i b s . But among those s i b -s h i p s , the sex r a t i o does not d e v i a t e s i g n i f i c a n t l y from 1:1. A c c o r d i n g t o a m u l t i f a c t o r i a l h y p o t h e s i s w i t h d i f f e r e n t i a l sex t h r e s h o l d s , i t might be p r e d i c t e d t h a t males would be more s e v e r e l y a f f e c t e d . However, e v i d e n c e from p o p u l a t i o n d a t a and from m u l t i p l y a f f e c t e d s i b s h i p s does not c o n f i r m t h i s p r e d i c -t i o n . The d i s t r i b u t i o n of males and t h a t o f females among the MR l e v e l s are v e r y s i m i l a r . In the s i b s h i p s w i t h both a men-t a l l y r e t a r d e d male and femal e , one sex i s j u s t as l i k e l y as the ot h e r t o be the more s e v e r e l y a f f e c t e d s i b . T h e r e f o r e , i t i s more r e a s o n a b l e t o h y p o t h e s i z e t h a t X - l i n k e d genes, r a t h e r than m u l t i f a c t o r i a l i n h e r i t a n c e , may account f o r the exce s s of male a f f e c t e d s i b s h i p s . The f a m i l y h i s t o r y i n f o r m a t i o n on the s i b s h i p s w i t h two or more a f f e c t e d males p r o v i d e s e v i d e n c e f o r the X - l i n k e d i n h e r i -tance h y p o t h e s i s . Among the s i b s born a f t e r the b i r t h of the second inde x m e n t a l l y r e t a r d e d male, t h e r e are e q u a l numbers of normal and n o n - s p e c i f i c m e n t a l l y r e t a r d e d males. Such a f i n d -i n g i s expected i f the m a j o r i t y of the MR cases i n the s e s i b -s h i p s i s due t o r e c e s s i v e genes - e i t h e r X - l i n k e d or autosomal. Among the s i b s of the f a t h e r s t h e r e are o n l y two MR c a s e s -one male and one fema l e . A few s p o r a d i c c a s e s of MR are not un u s u a l i n any sampling of f a m i l y h i s t o r i e s . Among the m a t e r n a l - 97 -s i b s t h e r e are two m e n t a l l y r e t a r d e d females as might be ex-p e c t e d ; however, e l e v e n males w i t h MR are r e p o r t e d . These d a t a r e a s o n a b l y f i t the h y p o t h e s i s t h a t X - l i n k e d genes do account f o r the n o n - s p e c i f i c MR i n the exc e s s of s i b s h i p s w i t h two or more a f f e c t e d males. C. FREQUENCY OF X-LINKED MR S i n c e the f a m i l y d a t a p r o v i d e e v i d e n c e f o r t h i s h y p o t h e s i s , the e x c e s s number of male a f f e c t e d s i b s h i p s i n t t h e 1950 t o 1969 b i r t h c o h o r t was used t o c a l c u l a t e the minimum f r e q u e n c y of X - l i n k e d MR. The c a l c u l a t e d minimum f r e q u e n c y o f 1.83 per 1000 males i n the B r i t i s h Columbia p o p u l a t i o n f o r n o n - s p e c i f i c MR caused by X - l i n k e d genes not o n l y a c c o u n t s f o r the e x c e s s of n o n - s p e c i f i c m e n t a l l y r e t a r d e d males i n m u l t i p l y a f f e c t e d s i b -s h i p s , but a l s o can account f o r the exc e s s of males w i t h non-s p e c i f i c MR found i n the p o p u l a t i o n . The minimum f r e q u e n c y o f 2.44 per 1000 females i n the B r i t i s h Columbia p o p u l a t i o n f o r c a r r i e r females of X - l i n k e d genes c a u s i n g MR i s h i g h e r than i s the c a l c u l a t e d p r e v a l e n c e r a t e of 0.74 per 1000 females i n the New South Wales p o p u l a t i o n (Turner and T u r n e r , 1974). Such a d i f f e r e n c e i n r a t e s i s l i k e l y due t o a c o m b i n a t i o n of f a c t o r s . Turner and Turner reviewed the s i b s h i p d a t a on o n l y the m o d e r a t e l y r e t a r d e d c h i l d r e n i n a 10 year b i r t h c o h o r t l i v i n g a t the time of the s u r v e y . The p r e s e n t s t u d y / u t i l i z e d n o t o n l y the r e c o r d s of cases a t a l l - 98 -l e v e l s o f MR, but a l s o a s c e r t a i n e d c a s e s both l i v i n g and dead a t the time o f the s t u d y who had been di a g n o s e d and r e g i s t e r e d as m e n t a l l y r e t a r d e d i n the R e g i s t r y . I t i s assumed t h e r e are l i k e l y n o n - s p e c i f i c MR ca s e s who have d i e d b e f o r e a d i a g n o s a b l e age wh i c h , i f a s c e r t a i n e d , might i n c r e a s e the c a l c u l a t e d f r e q u e n c y of X - l i n k e d MR. However, s i n c e a b i r t h c o h o r t of r e g i s t e r e d MR c a s e s , whether l i v i n g or dead a t the time o f the s t u d y , was u t i l i z e d , the f r e q u e n c y of 1.83 per 1000 males may be c o n s i d e r e d a minimum i n c i d e n c e f o r n o n - s p e c i f i c X - l i n k e d MR i n the B r i t i s h Columbia p o p u l a t i o n . D. X-LINKED GENES I f the c a l c u l a t e d f r e q u e n c y o f X - l i n k e d MR i s c o n s i d e r e d the minimum i n c i d e n c e r a t e , i t i s tem p t i n g t o s p e c u l a t e on how many genes on the X chromosome may cause n o n - s p e c i f i c MR. The number o f genes can be e s t i m a t e d i n d i r e c t l y by u t i l i z i n g the e q u a t i o n , u = — — —r which c o r r e l a t e s the f r e q u e n c y o f a d i s e a s e due t o an X - l i n k e d r e c e s s i v e gene and the m u t a t i o n r a t e i n a p o p u l a t i o n a t e q u i l i b r i u m (y = m u t a t i o n r a t e , f = f i t n e s s of the X - l i n k e d gene, and q = f r e q u e n c y of the gene which i s a l s o the f r e q u e n c y of a f f e c t e d males) (Haldane, 1935). S i n c e m e n t a l l y r e t a r d e d males do not n o r m a l l y r e p r o d u c e , the f i t n e s s i n t h i s case approaches z e r o . The o v e r a l l m u t a t i o n r a t e f o r X - l i n k e d genes c a u s i n g n o n - s p e c i f i c MR would then be: 1.83 x 1 0 ~ 3 , , i n-4 y = 2 = 6.1 x 10 - 99 -M u t a t i o n r a t e s have been e s t i m a t e d by Haldane's i n d i r e c t method f o r X - l i n k e d d i s o r d e r s which are r e l a t i v e l y f r e q u e n t i n a p o p u l a t i o n . V o g e l and Rathenberg (1975) r e g a r d e d e s t i -_5 mates of 9.2 x 10 f o r Duchenne muscular d y s t r o p h y (Morton and Chung, 1959) and 3.2 x 1 0 ~ 5 f o r H e m o p h i l i a A ( I k k a l a , 1960) as r e l i a b l e , a l t h o u g h r a r e r c o n d i t i o n s , such as n e p h r o g e n i c _7 d i a b e t e s i n s i p i d u s , may have..mutation r a t e s l e s s than 1 x 10 (Stevenson and K e r r , 1967). An average m u t a t i o n r a t e of 1 x 10 ^ per gamete f o r s i n g l e l o c i on the X chromosome i s g e n e r a l -l y a c c e p t e d (Vogel and Rathenberg, 1975). I f the m u t a t i o n r a t e a t a s i n g l e l o c u s c a u s i n g X - l i n k e d MR i s 1 x 10 ^, then t h e r e would be 610 genes c a u s i n g X - l i n k e d MR. However, i f the muta-t i o n r a t e f o r s i n g l e l o c i c a u s i n g MR i s i n the same o r d e r o f magnitude as those r a t e s f o r Duchenne muscular d y s t r o p h y or H e m o p h i l i a A, which may not be u n r e a l i s t i c , then the number of X - l i n k e d genes c a u s i n g MR would range from 7 t o 19. In c o m p a r i s o n , Morton and h i s c o l l e a g u e s (1977) r e a n a l y z e d the d a t a from the 1938 C o l c h e s t e r s u r v e y by P e n r o s e , which was based on c l i n i c a l and f a m i l y i n f o r m a t i o n o f i n s t i t u t i o n a l c a s e s . T h e i r s t u d y was i n c o n c l u s i v e r e g a r d i n g the a c t u a l c o n -t r i b u t i o n of X - l i n k e d genes t o MR. However, on the b a s i s of a complex s e g r e g a t i o n a n a l y s i s , they e s t i m a t e d t h a t t h e r e may be 351 autosomal l o c i t h a t c o u l d cause a mental d e f e c t . I f the l o c i t h a t produce MR were randomly d i s t r i b u t e d among a l l chromo-somes, then the X chromosome would c a r r y a p r o p o r t i o n a t e number - 100 -o f r e c e s s i v e genes. An e s t i m a t e o f 18 X - l i n k e d l o c i was thus -5 c a l c u l a t e d . I f the m u t a t i o n r a t e were 3.2 x 10 per l o c u s , t h ey e s t i m a t e d a p o s s i b l e i n c i d e n c e o f X - l i n k e d MR t o be 1.74 per 1000 male b i r t h s - a r a t e s i m i l a r t o the e s t i m a t e d minimum i n c i d e n c e of 1.83 per 1000 male b i r t h s i n the p r e s e n t s t u d y . Thus, an e s t i m a t e o f 7 t o 19 X - l i n k e d l o c i c a u s i n g n o n - s p e c i f i c -5 MR w i t h a m u t a t i o n r a t e o f 3-9 x 10 per l o c u s may be p l a u s i b l e . I t i s v e r y d i f f i c u l t t o say whether any of these X - l i n k e d l o c i , which have a l l e l e s t h a t cause n o n - s p e c i f i c MR, a l s o have a l l e l e s t h a t c o n t r i b u t e t o s u p e r i o r i n t e l l i g e n c e as Lehrke had suggested (1972, 1974, 1978). As A n a s t a s i (1972) p o i n t e d o u t , d a t a on the excess of m e n t a l l y r e t a r d e d males i n a p o p u l a t i o n i s i r r e l e v a n t w i t h r e s p e c t t o an h y p o t h e s i s of X - l i n k a g e f o r major i n t e l l e c t u a l t r a i t s . A l o c u s whose d e f e c t i v e a l l e l e u l -t i m a t e l y causes MR does not n e c e s s a r i l y have another a l l e l e t h a t codes f o r a n y t h i n g o t h e r than normal m e t a b o l i c f u n c t i o n i n g . The p r e s e n t s t u d y has c o n t i n u a l l y r e f e r r e d t o X - l i n k e d MR being due t o genes on the X chromosome. But the p o s s i b i l i t y t h a t t h i s type of MR may be caused by autosomal r e c e s s i v e genes w i t h s e x - l i m i t e d e x p r e s s i o n cannot be d i s c o u n t e d . E vidence t o d i s t i n g u i s h between the two modes of i n h e r i t a n c e i s u s u a l l y d e r i v e d from male t o male t r a n s m i s s i o n but m e n t a l l y r e t a r d e d males do not n o r m a l l y r e p r o d u c e . Hence, d i f f e r e n t i a t i o n i s v e r y d i f f i c u l t f o r a m ental d e f e c t and i s not d i s c e r n a b l e i n the p r e s e n t s t u d y . - 101 -Markers on the X chromosome may h e l p t o d etermine the l o c a t i o n o f genes c a u s i n g n o n - s p e c i f i c MR. Xg l i n k a g e i n v e s -t i g a t i o n s were n o n - i n f o r m a t i v e i n most r e p o r t s . Only one i n -v e s t i g a t i o n o f a f a m i l y w i t h X - l i n k e d MR r e p o r t e d no l i n k a g e w i t h the X g a l o c u s ( W o l f f , e t a l . , 1978), a l t h o u g h l i n k a g e was r e p o r t e d f o r MR w i t h or w i t h o u t h y d r o c e p h a l u s ( F r i e d and Sanger, 1973). The f r a g i l e s i t e on the l o n g arm of the X chromosome may a c t as a marker i n those f a m i l i e s where i t can be demonstrated. However, the a s s o c i a t i o n of X - l i n k e d MR and the f r a g i l e s i t e i s not w e l l u n d e r s t o o d . There i s no e v i d e n c e t h a t a d e f e c t i v e gene c a u s i n g MR l i e s a t or near the f r a g i l e s i t e . I t might be s p e c u l a t e d t h a t autosomal genes e x i s t t h a t a f f e c t e i t h e r or both the c y t o l o g i c a l and p h e n o t y p i c e x p r e s -s i o n o f the f r a g i l e s i t e whether or not t h e r e i s a c a u s a l a s s o c i a t i o n between i t and MR. I t may be t h a t n o n - s p e c i f i c MR i s caused e i t h e r by X - l i n k e d genes or by autosomal genes w i t h s e x - l i m i t e d e x p r e s s i o n . E. A MARKER X CHROMOSOME The f r e q u e n c y of i n d i v i d u a l s i n the p o p u l a t i o n i n whose lymphocytes the f r a g i l e s i t e , or marker, on the X chromosome can be demonstrated i s not y e t known. I t i s u n f o r t u n a t e t h a t the p r e s e n t s t u d y d i d not i n c l u d e c y t o g e n e t i c i n v e s t i g a t i o n s of the f r a g i l e s i t e on the X chromosome. The s t u d y was p r a c -t i c a l l y complete b e f o r e S u t h e r l a n d (1977a) r e p o r t e d the - 102 -dependency of e x p r e s s i o n o f f r a g i l e s i t e s on the type of c u l t u r e medium making a s u r v e y f e a s i b l e . T u r n e r , e t a l . (1978) demon-s t r a t e d the marker i n a f f e c t e d males i n s i x of s i x t e e n f a m i l i e s w i t h X - l i n k e d MR. Howard-Peebles and c o l l e a g u e s (1979) r e -p o r t e d f i n d i n g i t i n a f f e c t e d males i n o n l y one of f o u r f a m i l i e s w i t h X - l i n k e d MR (from Howard-Peebles, p e r s . comm., 1979, the number i s now t h r e e o f s i x f a m i l i e s ) . In another r e p o r t , the marker has been demonstrated i n t h r e e of s i x f a m i l i e s ( J a c o b s , e t a l . , 1979). A Saskatchewan s t u d y has found the marker i n a f f e c t e d males i n s i x of seven f a m i l i e s (Fox, 1979, p e r s . comm.). From these f o u r s u r v e y s , i t can be e s t i m a t e d t h a t a p p r o x i m a t e l y 18 of 35, or 50%, o f a l l c a s e s of X - l i n k e d MR are a s s o c i a t e d w i t h the f r a g i l e s i t e on the X chromosome. T h e r e f o r e , i f X-l i n k e d n o n - s p e c i f i c MR o c c u r s i n 1.83 per 1000 male b i r t h s , an i n c i d e n c e of the: marker X chromosome may be a p p r o x i m a t e l y 0.92 per 1000 male b i r t h s . The f r e q u e n c y i n the p o p u l a t i o n o f a l l a utosomal f r a g i l e s i t e s has been r o u g h l y e s t i m a t e d t o be about 1 i n 444 or 0.2% (Hecht and Kaiser-McCaw, 1979). S i n c e a t l e a s t s i x d i f f e r e n t autosomal f r a g i l e s i t e s have been r e p o r t e d , the p o p u l a t i o n f r e q u e n c y of each autosomal f r a g i l e s i t e may be around 0.3 per 1000. Hence, the f r a g i l e s i t e on the X chromosome appears t o be the most common f r a g i l e s i t e . I t i s a l s o the o n l y one a s -s o c i a t e d w i t h a s p e c i f i c abnormal t r a i t ; the o t h e r s seem t o be innocuous p h e n o t y p i c a l l y . - 103 -I f the e s t i m a t e of 0.92 per 1000 males f o r the i n c i d e n c e of the marker X i s c o r r e c t , the marker X chromosome would be the second most common chromosome a b n o r m a l i t y a f t e r Trisomy 21 a s s o c i a t e d w i t h MR. I t w i l l be of i n t e r e s t t o see i f any f u t u r e s t u d i e s d e s i g n e d t o o b t a i n an e s t i m a t e of the marker X chromo-some i n the p o p u l a t i o n w i l l f i n d such a f r e q u e n c y . A l t h o u g h X - l i n k e d MR a s s o c i a t e d w i t h the marker X chromo-some i s sometimes r e f e r r e d t o as "Renpenning Syndrome" (Turner, e t - a l . , 1978), i t i s of i n t e r e s t t o note t h a t the a f f e c t e d males i n the f a m i l y o r i g i n a l l y d e s c r i b e d by Renpenning, e t a l . (1962) do not e x p r e s s the f r a g i l e s i t e on the X chromosome (Fox, 1979, p e r s . comm.). P o s s i b l y the term, Renpenning Syn-drome, i f i t i s t o be used a t a l l , s h o u l d r e f e r t o the X - l i n k e d n o n - s p e c i f i c MR not a s s o c i a t e d w i t h the X chromosome a b n o r m a l i t y . F. CLINICAL FEATURES OF X-LINKED MR A l t h o u g h t h i s s t u d y d i d not d i f f e r e n t i a t e c l i n i c a l sub-t y p e s of X - l i n k e d MR, s e v e r a l c o n c l u s i o n s can be drawn c o n c e r n -i n g the MR and a s s o c i a t e d c h a r a c t e r i s t i c s . V a r i a b i l i t y e x i s t s i n the l e v e l of MR i n a f f e c t e d males not o n l y among but a l s o w i t h i n f a m i l i e s . Among the female c a r r i e r s i n these f a m i l i e s , 21% o f them may e x p r e s s the gene p a r t i a l l y and thus have b o r -d e r l i n e or m i l d MR. - 104 -Lehrke (1974) and o t h e r s (Deroover, e t a l . , 1977) hypo-t h e s i z e d t h a t a f f e c t e d males from these f a m i l i e s may have a lower v e r b a l than performance IQ. E l e v e n a f f e c t e d males d i d p e r f o r m b e s t i n n o n - v e r b a l a r e a s , but f o u r males had a h i g h e r v e r b a l IQ w h i l e another f o u r males showed no IQ s t r e n g t h s or weaknesses. Howard-Peebles, e t a l . (1979) r e p o r t e d t h a t i n t h r e e of f o u r f a m i l i e s , males showed a g e n e r a l i z e d r a t h e r than s p e c i f i c language weakness w i t h more s t r e n g t h s o c c u r r i n g i n non-v e r b a l a r e a s such as manual e x p r e s s i o n . In one f a m i l y (the o n l y one e x p r e s s i n g the marker X chromosome) the males demonstrated n e i t h e r a weakness i n v e r b a l f u n c t i o n nor a s t r e n g t h i n manual e x p r e s s i o n . Among the f a m i l i e s i n the p r e s e n t s t u d y , a marker X chromosome has been found by o t h e r r e s e a r c h e r s i n some a f -f e c t e d males, i n two f a m i l i e s , 14)1201 • (Ferguson-Smith, 1974, p e r s . comm.) and 15)0586 ( J a c o b s , e t a l . , 1979). I n f o r m a t i o n on IQ s t r e n g t h s and weaknesses was a v a i l a b l e on o n l y one a f -f e c t e d male i n each of these f a m i l i e s . In f a m i l y 14)1201 the male had poor e x p r e s s i v e speech, w h i l e the male i n f a m i l y 15)0586 showed no IQ s t r e n g t h s or weaknesses. T h e r e f o r e , t h e r e seems t o be no c o n c l u s i v e a s s o c i a t i o n w i t h language a b i l i t y and the f r a g i l e s i t e on the X chromosome. Lehrke (1974) a l s o suggested t h a t s p e c i f i c speech d e f e c t s may be a s s o c i a t e d w i t h X - l i n k e d MR. I n f o r m a t i o n on s p e c i f i c v e r b a l d e f e c t s i n 38 a f f e c t e d males r e v e a l e d 17 w i t h no v e r b a l d i s a b i l i t y and among the r e m a i n i n g 21, poor a r t i c u l a t i o n , which - 105 -was o f t e n outgrown, was the most common speech problem. Howard-P e e b l e s , e t a l . (1979) a l s o found a r t i c u l a t i o n e r r o r s t o be the most common d e f e c t i n speech p r o d u c t i o n of males w i t h X-l i n k e d MR. S i n c e the a r t i c u l a t i o n e r r o r s were s i m i l a r t o the most f r e q u e n t m i s a r t i c u l a t i o n s e x h i b i t e d by i n t e l l e c t u a l l y n o r -mal c h i l d r e n and by a d e f i n e d r e t a r d e d p o p u l a t i o n (Down Syn-drome) , they c o n c l u d e d t h a t poor a r t i c u l a t i o n was the r e s u l t o f d e l a y e d development and d i d not demonstrate a d i s t i n c t i v e p a t t e r n . T h e r e f o r e , a l t h o u g h the i n c i d e n c e o f speech d e f e c t s i s h i g h e r i n p o p u l a t i o n s o f the m e n t a l l y r e t a r d e d than i n the g e n e r a l p o p u l a t i o n (Matthews, 1974), t h e r e i s no b a s i s t o the a l l e g a t i o n t h a t s p e c i f i c speech d e f e c t s are a s s o c i a t e d w i t h X - l i n k e d MR. Neuhauser, e t - a l . (1969) suggested t h a t males w i t h X-l i n k e d MR may show b e t t e r than e x p e c t e d a d a p t i v e b e h a v i o r f o r t h e i r degree of r e t a r d a t i o n . They f e l t t h a t t h i s was one reason why so few f a m i l i e s w i t h X - l i n k e d MR had been i d e n t i f i e d . How-e v e r , r e s u l t s i n the p r e s e n t s t u d y show t h a t the l e v e l o f s o c i a l a d a p t a b i l i t y i s p r o p o r t i o n a l t o the l e v e l o f MR - the h i g h e r the IQ, the h i g h e r the SQ; the lower the IQ, the lower the SQ. B e h a v i o r a l d i s o r d e r s are not o n l y more common among males than among females (Kauf fman, 1977, pp. 39-40) but are a l s o more com-mon among the m e n t a l l y r e t a r d e d ( B e i e r , 1964). T h e r e f o r e , the f i n d -i n g t h a t s l i g h t l y more than h a l f o f the a f f e c t e d males i n t h i s s t u d y e x h i b i t b e h a v i o r a l d i s o r d e r s - m a i n l y d e v i a n t b e h a v i o r and h y p e r a c t i v i t y - may not be p e c u l i a r t o X - l i n k e d MR. A number - 106 -of d i f f i c u l t i e s a r i s e in comparing t h i s sample with other s t u d i e s . The d e f i n i t i o n of a b e h a v i o r a l d i s o r d e r i s vague and v a r i e s c o n s i d e r a b l y from study to study. Ascertainment i n the present study i s from s e v e r a l sources, so the d e f i n i t i o n i s not uniform even w i t h i n t h i s group. A l s o , the nature of the a s s o c i -a t i o n between b e h a v i o r a l d i s t u r b a n c e and MR i s u n c l e a r (Benton, 1964). T h e r e f o r e , i t i s d i f f i c u l t t o draw any c o n c l u s i o n s r e -garding behavior and X - l i n k e d MR. B i r t h w e i g h t s of the X - l i n k e d MR i n d i v i d u a l s i n the present study were w i t h i n the normal range f o r the g e n e r a l p o p u l a t i o n . Turner, e t a l . ('1980) noted an i n c r e a s e i n b i r t h w e i g h t s i n a f f e c t e d males with a marker X chromosome. However, such an i n c r e a s e i s not apparent i n the present sample. I f anything, there i s a s l i g h t , though i n s i g n i f i c a n t , excess of males with low b i r t h w e i g h t s . Although b i r t h trauma may c o n t r i b u t e to the MR i n some cases, i t i s not a common f a c t o r i n the m a j o r i t y of b i r t h s of X - l i n k e d mentally r e t a r d e d males. I t i s i n t e r e s t i n g t h a t a h i s t o r y of e p i l e p s y i s r e p o r t e d in 40% of the males with X - l i n k e d MR. The presence of e p i l e p s y a s s o c i a t e d with MR i s o f t e n used as one c r i t e r i o n to e l i m i n a t e probands from a MR f a m i l i a l study (Penrose, 1938; Reed and Reed, 1965 ;. Turner, e t a l . , 1971). I t i s f e l t t h a t f r e -quent s e i z u r e s may cause or c o n t r i b u t e to the MR. D i s t i n g u i s h -ing between MR caused by s e i z u r e s and MR with e p i l e p s y caused by a s i m i l a r u n d e r l y i n g d e f e c t i s very d i f f i c u l t . By - 107 -e l i m i n a t i n g such probands, r e s e a r c h e r s may be a r t i f i c i a l l y reducing the number of f a m i l i e s with X - l i n k e d MR i n any given study. Bundey and C a r t e r (1974) r e p o r t e d a high recurrence r i s k (10%) f o r b r o t h e r s of male probands with e p i l e p s y and an IQ l e s s than 50. No s i s t e r s of the probands were a f f e c t e d . A l s o , no s i b s of female probands with severe MR and e p i l e p s y were a f f e c t e d . Although no p a t t e r n of X-linkage was apparent i n the f a m i l i e s of male probands, X - l i n k e d MR with or without e p i l e p s y may c o n t r i b u t e to 'the high recurrence r i s k f o r male s i b s among the male probands. Good motor c o n t r o l i s reported f o r most males with X - l i n k e d MR, although poor neuromuscular c o o r d i n a t i o n i s not uncommon. In 18% of the a f f e c t e d males in the present study a v a r i e t y of aspects of poor motor c o n t r o l from c e r e b r a l p a l s y to a p e c u l i a r g a i t i s r e p o r t e d . C h a r a c t e r i s t i c s measured q u a n t i t a t i v e l y such as height and head circumference do not vary s i g n i f i c a n t l y from a normal p o p u l a t i o n d i s t r i b u t i o n . However, there are s l i g h t l y more males than expected who are s h o r t . There are a l s o a few more males than expected who are m i c r o c e p h a l i c , although microcephaly i s not a f e a t u r e found i n a l l mentally r e t a r d e d males i n any one f a m i l y . I t , too, i s a v a r i a b l e f e a t u r e . No dysmorphic f e a t u r e s were repo r t e d f o r the m a j o r i t y of males with X - l i n k e d MR. In 40% of the males, a v a r i e t y of - 108 -u n u s u a l or abnormal p h y s i c a l c h a r a c t e r i s t i c s were n o t e d . The most common s p e c i f i c p h y s i c a l f e a t u r e s were b i g e a r s , h i g h arched p a l a t e , and l a r g e g e n i t a l i a . B i g e a r s i s a v a r i a b l e f e a t u r e observed i n some, but not a l l , a f f e c t e d males i n f a m i -l i e s w i t h X - l i n k e d MR (Renpenning, e t a l . , 1962; Dunn, e t  a l . , 1963 ; Lubs, 1969; S t e e l e and C horazy, 1974 ; Harvey, e t  a l . , 1977). A h i g h arched p a l a t e , which may be a s s o c i a t e d w i t h m a c r o g n a t h i a or a prominent jaw, i s another c h a r a c t e r i s t i c t h a t has been d e s c r i b e d p r e v i o u s l y i n some a f f e c t e d males (Dav i s o n , 1973; Harvey, e t a l . , 1977; Derobver, e t a l . , 1977). M a c r o - o r c h i d i s m a s s o c i a t e d w i t h X - l i n k e d MR has been r e -p o r t e d i n some f a m i l i e s ( E s c a l a n t e , e t - a l . , 1971; T u r n e r , e t a l . , 1975; Biederman, e t a l . , 1976). I t seems t o be p r e -s e n t i n a l l a f f e c t e d males w i t h i n these f a m i l i e s , a l t h o u g h p r e -c i s e measurements of the t e s t e s i s e s s e n t i a l i n o r d e r t o r e a c h a d e f i n i t e c o n c l u s i o n (Howard-Peebles, 1979, p e r s . comm.). The a c t u a l l e n g t h , w i d t h , and volume of the t e s t e s may v a r y con-s i d e r a b l y i n these males even w i t h i n one f a m i l y , but the t e s -t i c u l a r volume does seem t o be above the 90th p e r c e n t i l e i n most c a s e s ( S u t h e r l a n d and A s h f o r t h , 1979; Howard-Peebles, 1979, p e r s . comm.). R e c e n t l y , the marker X chromosome has been demonstrated i n lymphocytes from males w i t h m a c r o - o r c h i d i s m , and X - l i n k e d MR ( T u r n e r , e t , a l . , 1978; S u t h e r l a n d and A s h f o r t h , 1979). T h i s a s s o c i a t i o n l e d t o the c o n c l u s i o n t h a t t h e r e may be two c l i n i c a l - 109 -e n t i t i e s - X - l i n k e d MR w i t h a marker X chromosome and macro-o r c h i d i s m i n a f f e c t e d males and n o n - s p e c i f i c X - l i n k e d MR w i t h -out the X chromosome a b n o r m a l i t y and w i t h o u t l a r g e t e s t e s . Such a c o n c l u s i o n i s s t i l l c o n t r o v e r s i a l because o f the c y t o g e n e t i c and c l i n i c a l o b s e r v a t i o n s on s i x f a m i l i e s r e p o r t e d by J a c o b s , e t a l . (1979). In t h r e e f a m i l i e s , a f f e c t e d males e x p r e s s e d the marker X chromosome but d i d not have m a c r o - o r c h i d i s m . In the rem a i n i n g t h r e e f a m i l i e s , i n c l u d i n g one w i t h m a r c o - o r c h i d i s m , a marker X chromosome was not demo n s t r a t e d . G. GENETIC COUNSELLING IMPLICATIONS T h i s s t u d y has a number of i m p l i c a t i o n s f o r g e n e t i c c o u n s e l l i n g . A f r e q u e n c y o f 1.83 per 1000 males f o r X - l i n k e d MR makes t h i s type of MR as common as Down Syndrome f o r males i n the B r i t i s h Columbia p o p u l a t i o n . However, the r e c u r r e n c e r i s k f o r MR caused by an X - l i n k e d d e f e c t i s much g r e a t e r than the r e -c u r r e n c e r i s k f o r Down Syndrome - 25% compared t o 1-2% ( P f e i f f e r , e t a l . , 1973). P a r e n t s and s i b s o f m e n t a l l y r e t a r d e d p ersons are c o n -cerned about the d i s a b i l i t y r e c u r r i n g i n o t h e r o f f s p r i n g . The m e d i c a l p r o f e s s i o n i s o b l i g a t e d t o p r o v i d e a c c u r a t e r e c u r r e n c e r i s k s f o r those c ases o f MR caused by p o t e n t i a l l y r e c u r r i n g f a c t o r s . I f no s p e c i f i c e n v i r o n m e n t a l , b i o c h e m i c a l , or c y t o -l o g i c a l cause for' the MR i s known, r e c u r r e n c e r i s k s may be as h i g h as 25% or may be i n the low range of 2-10%. - 110 -With r e s p e c t t o n o n - s p e c i f i c MR i n males, the main prob-lem i s d i s t i n g u i s h i n g X - l i n k e d MR from MR due t o o t h e r e t i o l o -g i e s i n s p o r a d i c c a s e s where no p a t t e r n o f i n h e r i t a n c e i s apparent i n the f a m i l y h i s t o r y . A s s o c i a t e d f e a t u r e s such as language d e f i c i t , h y p e r a c t i v i t y , s e i z u r e s , m a c r o - o r c h i d i s m or b i g e a r s may or may not h e l p i n the d i a g n o s i s o f X - l i n k e d MR. C y t o g e n e t i c i n v e s t i g a t i o n f o r a marker X chromosome might a l s o prove u s e f u l and, t h u s , i s recommended as a d i a g n o s t i c p r o c e d u r e . In 33% o f f a m i l i e s w i t h two or more males i n one s i b s h i p a f f e c t e d w i t h n o n - s p e c i f i c MR, the MR i s l i k e l y due t o f a c t o r s a f f e c t i n g both males and females e q u a l l y . In 67% of these f a m i l i e s the MR may be due t o X - l i n k e d genes. A f a m i l y h i s t o r y of n o n - s p e c i f i c MR i n h e r i t e d i n an X - l i n k e d p a t t e r n i s e x p e c t e d t o be found i n h a l f of those s i b s h i p s . A g a i n , a c l i n i c a l and c y t o g e n e t i c i n v e s t i g a t i o n o f the a f f e c t e d males may be u s e f u l i n d i a g n o s i n g X - l i n k e d MR, e s p e c i a l l y i f the f a m i l y h i s t o r y p r o v i d e s no e v i d e n c e f o r X-rlinked i n h e r i t a n c e . W i th two n o n - s p e c i f i c m e n t a l l y r e t a r d e d males i n one s i b -s h i p , a 25% r e c u r r e n c e r i s k f o r s i b s (50% r e c u r r e n c e r i s k f o r b r o t h e r s ) i s a p o s s i b i l i t y . I f o n l y one male i s a f f e c t e d and no p r e c i s e e t i o l o g y i s s u s p e c t e d , r e c u r r e n c e r i s k s are more o b s c u r e . T u r n e r , e t a l . ( 1 9 7 1 a ) r e p o r t r e c u r r e n c e r i s k s f o r s i b s o f males w i t h undiagnosed MR as 8% f o r m i l d MR, 9% f o r moderate MR, 2% f o r severe MR, and 6% f o r p r o f o u n d MR. Bundey and C a r t e r (1974) r e p o r t a 9% r e c u r r e n c e r i s k f o r s i b s o f males - I l l -with an IQ l e s s than 50 and no a s s o c i a t e d p h y s i c a l or n e u r o l o -g i c a l a b n o r m a l i t i e s . C e r t a i n l y , a good c l i n i c a l , b i o c h e m i c a l and c y t o g e n e t i c i n v e s t i g a t i o n i s important i n order to i d e n t i f y a p r e c i s e cause of MR which may s i g n i f i c a n t l y i n c r e a s e or de-crease t h a t recurrence risk.. H. SUMMARY Th i s study presents evidence t h a t X - l i n k e d ;MR, does cause a s i g n i f i c a n t p o r t i o n of n o n - s p e c i f i c MR. A minimum i n c i d e n c e of 1.83 per 1000 male b i r t h s f o r X - l i n k e d MR i s c a l c u l a t e d . With such a frequency 27% of a l l n o n - s p e c i f i c m e n t a l l y r e t a r d e d males may have an X - l i n k e d form of MR. T h i s p r o p o r t i o n accounts for the excess of mentally r e t a r d e d males compared to females who are m e n t a l l y r e t a r d e d . Although t h i s study i s not s u c c e s s f u l i n d i s t i n g u i s h i n g d i f f e r e n t c l i n i c a l forms of X - l i n k e d MR, i t does p o i n t out the v a r i a b i l i t y of a s s o c i a t e d f e a t u r e s i n a f f e c t e d males w i t h i n f a m i l i e s . There may be 7 to 19 l o c i where a d e f e c t i v e a l l e l e c o u l d r e s u l t i n MR i n the male. These l o c i may be on the X chromosome or on an autosome with the d e f e c t i v e a l l e l e being dominant with s e x - l i m i t e d e x p r e s s i o n . 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K e r r , 1967, On the d i s t r i b u t i o n o f f r e q u e n c i e s of m u t a t i o n t o genes d e t e r m i n i n g h a r m f u l t r a i t s i n man, Mutat. Res. 4:339-352. S t o l l e r , A., 1965, E p i d e m i o l o g y of mental d e f i c i e n c y i n V i c t o r i a , i n P r o c e e d i n g s of the F o u r t h I n t e r s t a t e Conference on  M e n t a l D e f i c i e n c y , J.D. Van P e l t , ed., A u s t r a l i a n Group f o r the S c i e n t i f i c Study of M e n t a l D e f i c i e n c y , Melbourne, pp. 18-28. S u t h e r l a n d , G.R., 1977a, F r a g i l e s i t e s on human chromosomes: d e m o n s t r a t i o n of t h e i r dependence on the type of t i s s u e c u l t u r e medium, S c i e n c e 197:265-266. S u t h e r l a n d , G.R., 1977b, Marker X chromosomes and men t a l r e t a r d a t i o n ( l e t t e r ) , N. E n g l . J . Med. 296:1415. S u t h e r l a n d , G.R. and P.L.C. A s h f o r t h , 1979, X - l i n k e d mental r e t a r d a t i o n w i t h m a c r o - o r c h i d i s m and the f r a g i l e s i t e a t Xq 27 or 28, Hum. Genet. 48:117-128. Thomson, G.H., 1953, S o c i a l I m p l i c a t i o n s of the 1947 S c o t t i s h  Method Survey, U n i v e r s i t y London P r e s s , London. T r e d g o l d , A.F., 1914, M e n t a l D e f i c i e n c y , M a c m i l l a n Co. of Canada, L t d . , T o r o n t o , p. 18. - 119 -T r i m b l e , B.K., 1976, Record l i n k a g e and g e n e t i c r e g i s t e r s , i n R e g i s t e r s f o r the D e t e c t i o n and P r e v e n t i o n of G e n e t i c  D i s e a s e , A.E.H. Emery, arid J.R. M i l l e r , e d s . , Symposia Speer i a l i s t s , S t r a t t a n I n t e r c o n t i n e n t a l M e d i c a l Book Corp., New York, pp. 87-101. T u r n e r , G., E. C o l l i n s and B. T u r n e r , 1971a, Recurrence r i s k of mental r e t a r d a t i o n i n s i b s , Med. J . A u s t . 1:1165-1166. T u r n e r , G., A. D a n i e l and M. F r o s t , 1980, X - l i n k e d m e n t a l r e t a r d a t i o n , m a c r o - o r c h i d i s m , and the Xq 27 f r a g i l e s i t e , J . P e d i a t . , i n p r e s s . T u r n e r , G., C. Eastman, J . Casey, A. McLeay, P. P r o c o p i s and B. T u r n e r , 1975, X - l i n k e d mental r e t a r d a t i o n a s s o c i a t e d w i t h m a c r o - o r c h i d i s m , J . Med. Genet. 12:367-371. T u r n e r , G., B. E n g i s c h , D.G. L i n d s a y and B. T u r n e r , 1972, X - l i n k e d m e n t a l r e t a r d a t i o n w i t h o u t p h y s i c a l a b n o r m a l i t y (Renpenning 1s Syndrome) i n s i b s i n an i n s t i t u t i o n , J . Med. Genet. 9:324-330. T u r n e r , G., R. T i l l and A. D a n i e l , 1978, Marker X chromosomes, men t a l r e t a r d a t i o n and m a c r o - o r c h i d i s m ( l e t t e r ) , N. E n g l .  J . Med. 299:1472. T u r n e r , G. and B. T u r n e r , 1974, X - l i n k e d mental r e t a r d a t i o n , J . Med. Genet. 11:109-113. T u r n e r , G., B. Turner and E. C o l l i n s , 1970, Renpenning's Syn-drome - X - l i n k e d mental r e t a r d a t i o n , L a n c e t , 11:365-366. T u r n e r , G., B. Turner and E. C o l l i n s , 1971b, X - l i n k e d mental r e t a r d a t i o n w i t h o u t p h y s i c a l a b n o r m a l i t y : Renpenning's Syndrome, Develop. Med. C h i l d . N e u r o l . 13:71-78. U.S. P u b l i c H e a l t h S e r v i c e , 1967, P a t i e n t s i n M e n t a l I n s t i t u - t i o n s , 1965. P a r t 1: P u b l i c I n s t i t u t i o n s f o r the M e n t a l l y  R e t a r d e d , N a t i o n a l I n s t i t u t e of M e n t a l H e a l t h , B u l l e t i n no. 1597. V o g e l , F. and R. Rathenberg, 1975, Spontaneous m u t a t i o n i n man, i n Advances i n Human G e n e t i c s , v o l . 5, H. H a r r i s and K. H i r s c h h o r n , eds., Plenum P r e s s , New Y o r k , pp. 223-318. W a l l n e r , T., 1974, A l t e r s v e r t e i l u n g and G e s c h l e c t s z u g e h o r i g k e i t b e i g e i s t i g B e h i n d e r t e n i n Schweden 1973, R e h a b i l i t a t i o n 13:56-61. - 120 -W o l f f , G., H. Hameister and H-H. Ropers, 1978, X - l i n k e d mental r e t a r d a t i o n : t r a n s m i s s i o n of the t r a i t by an a p p a r e n t l y u n a f f e c t e d male, Am. J . Med. Genet. 2:217-224. W o r t i s , H., M. P o l l a c k and J . W o r t i s , 1966, F a m i l i e s w i t h two or more m e n t a l l y r e t a r d e d or m e n t a l l y d i s t u r b e d s i b l i n g s : the preponderance o f males, Am. J . Ment. D e f i c . 70:745-752. W r i g h t , S.W., G. T a r j a n and L. E y e r , 1959, I n v e s t i g a t i o n o f f a m i l i e s w i t h two or more m e n t a l l y d e f e c t i v e s i b l i n g s , Am. J . P i s . C h i l d . 97:445-463. Wunsch, W.L., 1951, The f i r s t complete t a b u l a t i o n o f the Rhode I s l a n d mental d e f i c i e n c y r e c o r d , Am. J . Ment. P e f i c . 55:293-312. Yarbrough, K.M. and P.N. Howard-Peebles, 1976, X - l i n k e d non-s p e c i f i c mental r e t a r d a t i o n , C l i n . Genet. 9:125-130. Zachmann, M., A P r a d e r , H.P. K i n d , H. H a f l i g e r and H. B u d l i g e r , 1974, T e s t i c u l a r volume d u r i n g a d o l e s c e n c e , c r o s s - s e c t i o n a l and l o n g i t u d i n a l s t u d i e s , H e l v . P a e d i a t . A c t a . 29:61-72. 0 APPENDIX I Published X-linked Mental Retardation Pedigrees as of End of Year, 1978 An attempt has been made to standardize these reports in order to facilitate comparisons. Originally, the mental status of affected persons was reported in a variety of ways, even within one family. The data on the mental status have been reassigned as well as possible to the AAMD recommended levels of mental retardation (American Association of Mental Deficiency, 197.3). Reference 1) Martin and Bell, 1943 Ethnic Background English Number of reported generations Number of affected sibships Number of affected males 11 Mental status of affected males 9 severe MR 2 unspecified MR Mental status of females 2 borderline Comments, assoc-iated anomalies, etc.  2d* psychotic; most are inarticulate; related through 2 normal <f 2) Allan, Herndon, and Dudley, 1944 3) Losowsky, 1961 4) Renpenning, Gerrard, Zaleski and Tabata, 1962 American English Canadian, Dutch-German Mennonite 12 6 7 24 10 20 5) Dunn, Renpenning, Gerrard, Miller, Tabata and, Feder-off, 1963 Canadian, German 10 19 few of 22 severe MR most of 22 profound MR 2 unspecified MR 2 moderate MR 8 severe MR 1 borderline MR 1 moderate MR 8 severe MR 4 profound MR 6 unspecified MR 1 mild MR 6 moderate MR 8 severe MR 4 profound MR normal moderate muscular atrophy, not pro-gressive; marked speech defect; ( inarticulate gibberish. 2 mild MR 1 MR o* related f° through normal male. 1 — 1 I normal somewhat prominent ears; 2o* seizures; lo* blind; lo* diabetes; 1<? bilateral colobomata; lo" cataracts; mean head circumference of 14 MRo* 50.0+1.5 cm. several 9 <f prominent lower jaw; borderline 10^ large ears; 4o" elongated head; 5o* poorly aligned teeth; l<f seizures; 3o* scoliosis; 2<f weak, hypotonic; several retarded speech; 3<y myopia, strabismus, nystagmus. Reference 6) Opitz, Segal, Klove, Mathews, Lehrke, 1965 (also Lehrke, 1974, Family #1) Ethnic background American, French-Canadian Number of reported generations Number of affected sibships Number of affected males 20 7) Lubs, 1969 American 8) Snyder and Robin-son, 1969 American 9) NeuhSuser, Zerbin- A) German RUdin, Pfeiffer and Klar, 1969 (also NeuhSuser and Zerbin-RCldin, 1970) B) Dutch-German 10) Escalante, Grunspun, Brazilian and Frota-Pessoa, 1971 11) Turner, Turner and A) Australian Collins, 1971 Mental status Mental status of affected males of females 5 borderline MR normal 10 mild MR 1 moderate MR 3 severe MR 1 profound MR 2 mild MR normal 1 moderate MR 1 severe MR 3 mild MR 1 moderate MR 5 unspecified MR normal 1 mild MR 2 moderate MR 4 unspecified MR 8 moderate-severe MR 9 severe MR 2 borderline 3 borderline 1 mild MR 3 moderate MR normal Comments, assoc-iated anomalies, etc. 11 d* verbal ability less than performance ability; 2 d* seizures; Id" cerebral palsy; Id* hearing loss; Id" hypotonic; Id" head circumference subnormal. Id" prominent jaw and large low set ears; Id" seizures; Id1 microcephaly, <3rc3 % i l e in height and weight; 2 d" poor gross motor coordination; Xg a typing - not infor-mative; marker X chromosome. no seizures; dermatoglyphics normal; 4d" hypotonic; Id" asymmetric facies; 2d* awkward, clumsy; Xg a typing - not infor-mative . 3d" verbal disability; dermatoglyphics normal; Xg a - not informative. (no further comments) a l l large genitalia; 2d" grand mal seizures. moderate MR -criterion for ascertainment. Number Number Number of of of Ethnic reported affected affected Reference background generations sibships males B) Australian 3 2 3 C) Australian 4 4 5 D) Australian 4 7 10 E) Australian 3 2 4 12) Turner, Engisch, A) Australian 3 2 3 Lindsay and Turner, 1972 B) Australian 2 2 4 C) Australian 4 D) Australian 4 E) Australian 3 F) Australian 3 Comments, assoc-Mental status Mental status iated anomalies, of affected males of females etc. 3 moderate MR normal moderate MR - criterion for ascertainment. 5 moderate MR normal moderate MR - criterion for ascertainment; l<f seizures. 10 moderate MR 4 moderate MR normal normal 3 moderate-profound MR normal 4 moderate-profound MR normal 5 moderate-profound MR 4 borderline 4 moderate-profound MR normal 5 moderate-profound MR 2 borderline moderate MR - criterion for ascertainment. moderate MR - criterion for ascertainment. moderate-profound MR -criterion for ascer-tainment; Id" hyperactive. moderate-profound MR -criterion for ascer-tainment; 3d" large testes; 3d* fine skin, no chest hair. moderate-profound MR -criterion for ascer-tainment. moderate-profound MR -criterion for ascer-tainment; 1<P limited speech. moderate-profound MR -criterion for ascer-tainment. 3 moderate-profound MR 2 borderline 1 moderate-profound MR moderate-profound MR - c r i -terion for ascertainment; MR 9 seizures, microceph-aly, spastic lower limbs; d*s normal head circum-ference . Number Number Number of of of Ethnic reported affected affected Reference background generations sibships males 13) Fried, 1972 Scottish 4 6 6 (also Fried and Sanger, 1973) 14) Davison, 1973 A) English 2 2 3 B) English 4 3 5 C) English 3 2 2 D) English 2 2 5 E) English 3 3 6 Comments, assoc-Mental status Mental status iated anomalies, of affected males of females etc. 2 moderate MR 4 severe MR normal 2o* hydrocephalus; 3d" prominent ears; 3o* clumsy gait; lo" spastic limbs; 4o* kyphosis with scolir osis; 6<f poor muscularity; no seizures; close linkage with Xg locus. 3 moderate to profound MR normal 1 moderate MR normal 3 moderate-profound MR 1 unspecified MR 2 moderate-profound MR normal moderate-profound MR -criterion for ascer-tainment; (Family #42) lo* no speech mcderate-profcund MR -criterion for ascer-tainment; (Family #59) 3o* seizures; lo* high arched palate. moderate-profound MR -criterion for ascer-tainment; (Family #96) 1(T no speech; lo* high arched palate. 5 moderate-profound MR normal 6 moderate-profound MR normal moderate-profound MR -criterion for ascer-tainment; (Family #103) lo* nystagmus mode rate-profound MR - c r i -terion for ascertainment; (Family #108) 3o* no speech; lo" strabismus; 1 o* kyphoscol ios i s; Xg a typing - not infor-mative. Reference Ethnic background F) English Number of reported generations Number of affected sibships Number of affected males G) English H) English 15) Lehrke, 1974 A) American 11 B) American 14 C) American D) American 16) SchOnenberg and German BOttcher, 1974 4 2 5 Mental status of affected males Mental status of females 3 moderate-profound MR normal 4 moderate-profound MR normal 3 mild MR 1 moderate MR 1 moderate MR 5 severe MR 2 profound MR 3 unspecified MR 2 mild MR 4 moderate MR 8 unspecified MR 5 unspecified MR 4 unspecified MR 3 moderate MR 1 severe MR 1 profound MR normal normal normal 1 borderline normal 1 borderline Comments, assoc-iated anomalies, etc.  moderate-profound MR -criterion for ascer-tainment; (Family #161) Id" seizures; Id" high arched palate. moderate-profound MR -criterion for ascer-tainment; (Family #228) 2d" odd facies, high arched palate; Id" spatulate thumbs. moderate-profound MR -criterion for ascer-tainment; (Family #248) 2d* high arched palate; 3d* in turned thumbs; Id" large head; 2<T slightly spastic limbs; Xg a typing - not infor-mative. (Family #2) Id" seizures. (Family #3) no further comments. (Family #4) no further comments. (Family #5) no further comments. 2d" indistinct speech; Id" hypotonia. Reference 17) Steele and Chorazy, 1974 Ethnic background American Number of reported generations Number of affected sibships Number of affected males 18) Turner, Eastman, Casey, McLeay, Procopis, and Turner, 1975 A) Australian B) Australian 19) Biederman, Bower, French- Not Not and Swallow, 1977 Canadian reported reported 20) Ruvalcaba, Myhre, Roosen-Runge and Beckwith, 1977a,b 21) Yarbrough and Howard-Peebles, 1976 A) American B) American American 4 3 11 5 4 19 Mental status of affected males Comments, asscc-Mental status iated anomalies, of females etc. 6 mild-moderate MR 2 moderate MR 2 severe MR 1 unspecified MR 1 mild-moderate MR 1 severe MR 1 unspecified MR 6 unspecified MR 5 unspecified MR 4 unspecified MR 1 mild MR 2 moderate MR 4 severe MR I profound MR II unspecified MR normal 6 o* <5th % i l e in height; head circumference range 47-56 cm; 3o* prominent ears. normal head circumference nor-mal, range 54-58 cm; 4o* large testes, no endocrine disturbances; 2o* l i t t l e body hair. normal 2o" large testes, no endocrine disturbances; 2 a* seizures; 1 o* hyperactive. 1 MR with 6o" macro-orchidism; epilepsy 2 or more o* broad hands and feet, short digits, large ears, seizures. 2 mild MR 4o* megalotestes 1 mild MR 3o* megalotestes normal 7 d" speech impediment; 2 o* poor verbal articu-lation; 5 o" lack of fine motor coordination; 3 o* seizures; 3 o* shuffling gait; 2 o* hyperactive; lo" dolichocephalic; 1 o" rocker-bottom feet; lo* mild dorsal kyphosis Id* deformed hands; dermatoglyphics normal. Reference 22) Harvey, Judge, and Wiener, 1977 Number Number Number of of of Ethnic reported affected affected background generations sibships males A) Australian 4 3 7 B) Australian C) Australian 3 D) Australian 4 23) Deroover, Fryns, Parloir, Van Den Berghe, 1977 Flemish 22 24) Howard-Peebles, Stoddard and Mims, 1978 (also Howard-Peebles, Stoddard & Mims, 1979) A) American Comments, asscc-Mental status Mental status iated anomalies, of affected males of females etc.  1 mild MR 3 moderate MR 1 severe MR 2 unspecified MR 3 moderate MR 1 severe MR normal normal marker X chromosome; 1<? large feet and hands; Id mild pectus excava-tion. marker X chromosome; 2d seizures; Id large ears, strabis-mus, high palate, large hands. 1 mild-moderate MR 1 moderate MR normal Id mild neuromuscular incoordination; marker X chromosome. 3 mild MR 3 unspecified MR borderline MR mild MR moderate MR severe MR profound MR unspecified MR normal 2 borderline 3 mild 2d seizures; marker X chromosome. lid" poorly developed speech; 3 d retarded psycho motor development; 3 d impaired speech; 3 <? pedes plani; I d hydrocephalus; 1 d seizures; 1 d strabismus; 1 <f high arched palate ; Id" mandibular progna-thism; 1 d scoliosis; 1 d" partial syndactyly; Xg a typing - not infor-mative . 3 mild MR 6 unspecified MR normal (Family B) 3 <f delayed language; 3 d articulation errors. Reference Number Number Number of of of Ethnic reported affected affected background generations sibships males B) American 4 8 11 C) American 25) Wolff, Hameister, and Ropers, 1978 German Mental status of affected males Mental status of females 1 borderline MR 1 moderate MR 9 unspecified MR normal 2 moderate MR normal 2 severe MR 1 unspecified MR 5 moderate-profound MR 4 borderline 2 severe MR 1 profound MR / Comments, assoc-iated anomalies, etc. (Family C) 2 <f delayed language; 2o* articulation errors. (Family D) marker X chromosome. 2o" limited speech; Id" ptosis of right eye no close linkage with Xg a locus. - 129 -APPENDIX I I Forms and Q u e s t i o n n a i r e Form l e t t e r s used t o c o n t a c t f a m i l i e s w i t h f a m i l i a l m ental r e t a r d a t i o n . 1. C o v e r i n g l e t t e r from Dr. B. T i s c h l e r , M e d i c a l D i r e c t o r , Woodlands S c h o o l . 2. E x p l a n a t o r y l e t t e r s e n t t o f a m i l i e s r e q u e s t i n g t h e i r p a r t i c i p a t i o n . 3. R e p l y form used t o e x p r e s s t h e i r i n t e r e s t i n p a r t i c i -p a t i o n . Q u e s t i o n n a i r e used f o r i n t e r v i e w a d m i n i s t e r e d ^ . o r a l l y : t o c o - o p e r a t i v e f a m i l i e s . Form used t o summarize c l i n i c a l i n f o r m a t i o n from m e d i c a l f i l e s on males w i t h X - l i n k e d mental r e t a r d a t i o n . .-'130 -D E P A R T M E N T O F H U M A N R E S O U R C E S F I E L D S E R V I C E Dear . . . . . < ' « E n c l o s e d p l e a s e f i n d a l e t t e r by Diana H e r b s t , from the Department o f M e d i c a l Genetics at The U n i v e r s i t y o f B r i t i s h Columbia*. I do f e e l the study may add t o the understanding o f c a u s a t i v e f a c t o r s i n mental r e t a r d a t i o n and might h e l p your f a m i l y , as w e l l as other f a m i l i e s who have m e n t a l l y r e t a r d e d i n d i v i d u a l s . I would suggest t h a t i t would be a d v i s a b l e f o r you t o p a r t i c i p a t e i n t h i s s t u d y . Yours t r u l y , B , T i s c h l e r , M . D . , F . R . C . P . ( C ) M e d i c a l D i r e c t o r BT:ml E n d - 132 -Would you be i n t e r e s t e d i n p a r t i c i p a t i n g i n such a study? Name Address Phone I f you a r e not i n t e r e s t e d , i s t h e r e another member of the f a m i l y whom we s h o u l d c o n t a c t who would be i n t e r e s t e d i n p a r t i c i p a t i n g i n t h e study? _ _ I f s o , t h e i r name ( . t . Address . _ . You w i l l be contacted by phone or through the m a i l t o set up an appointment at a time and p l a c e t h a t i s convenient f o r y o u . Do you have any questions concerning the p r o j e c t ? Return T o : Diana Herbst Dept. of M e d i c a l Genetics U n i v e r s i t y of B . C. Vancouver, B . C. - 133 -(^ UESTIOWiIAIRE FOR. MENTAL RETARDATION STUDY STUDY # DATE Patient's name • Birthdate Birth weight Description of di s a b i l i t i e s (include temperament, response to people, and verbal a b i l i t y ) : When was the retardation f i r s t noticed? Did you notice any events which may have precipitated the retardation (birth Injury, accident, etc.)? Relationship of person giving information Family Information: Patient's brothers and sisters: Name sex age health education Children of brothers and sisters Parent Name sex age health education Father's name Birthdate Occupation Education - 134 -Father's mother's name Birthdate Health Father's father's name Birthdate Health Father's brothers and sisters ( l i s t oldest to youngest): Name sex age health education # of Children ch. health Mother's maiden name Birthdate Occupation Education •  Mother's mother's name ________________________ Birthdate Health Mother's father's name Birthdate Health Mother's brothers and sisters ( l i s t oldest to youngest): Name sex age health education 9oi children ch. health Is anyone In the family color blind? Does anyone have any verbal d i s a b i l i t i e s or problems v/ speech? - 135 -X-LINKED MR STUDY STUDY NO. NAME - BIRTHDATE IQ SCORE -MOTOR -VERBAL -ETIOLOGICAL CODE -BIRTHWEIGHT -GESTATION -OTHER BIRTH INFO -HEIGHT -HEAD CIRCUMFERENCE -SEIZURES -ABNORMAL GENITALIA -GENERAL PHYSICAL CHARACTERISTICS -BEHAVIOURAL DISORDERS -HYPERACTIVE -AUTISTIC -OTHER DISTURBANCE -SPECIFIC VERBAL DISABILITY -BIOCHEMICAL TESTS -KARYOTYPE -APPENDIX III L i v i n g Cases of Mental Retardation in B r i t i s h Columbia Registered in the Health Survei 1977, and Categorized by Degree of Retardation, E t i o l o g y , Age-group, and Sex. Level of MR Borderline Mild ICDA* Sex Aqe Group Code 0-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 310.0 M 0 0 2 4 7 5 0 0 F 0 0 2 3 3 1 0 1 310.1 M 0 0 0 0 1 3 1 0 F 0 0 0 0 1 1 0 0 310.2 M 0 0 0 0 2 1 1 0 F 0 0 0 1 1 3 1 0 310.3 M 0 0 0 0 0 1 0 1 F 0 0 0 0 1 0 0 0 310.4 M 0 1 0 0 8 0 0 0 F 0 1 1 0 2 0 0 0 310.5 M 0 0 3 4 3 2 0 0 F 0 7 1 1 1 0 0 0 310.6 M 0 0 0 1 0 0 0 0 F • 0 0 1 1 0 0 0 0 310.7 M 6 0 0 1 2 0 0 0 F 0 0 0 0 0 0 0 0 310.8 M 0 0 1 3 6 2 0 0 F 0 0 0 3 4 2 0 0 310.9 M 3 25 110 227 750 229 43 . 33 F 0 27 62 121 444 215 26 21 311.0 M . 1 0 1 1 5 7 0 0 F 0 0 1 2 2 2 2 0 311.1 M 0 0 0 1 4 1 0 0 F 0 0 0 1 0 1 0 0 311.2 M • 0 0 1 1 1 3 0 0 F 0 0 0 1 4 2 0 0 311.3 M 0 0 1 0 0 0 0 0 F 0 1 0 0 0 0 0 0 311.4 M 0 1 2 6 2 0 0 0 F 0 2 0 3 8 1 0 1 311.5 M 0 4 5 7 8 4 2 0 F 1 9 9 3 11 2 0 0 * 8th Revision of the I n t e r n a t i o n a l C l a s s i f i c a t i o n of Diseases, Adapted. Refer to Table V for code c l a s s i f i c a t i o n s . Registry at Year-end, Subtotals Tota 60 + <19 >20 0 6 12 18 0 5 5 10 0 0 5 5 0 0 2 2 0 0 4 4 0 1 5 6 0 0 2 2 0 0 1 1 0 1 8 9 0 2 2 4 0 7 5 12 0 9 1 10 0 1 0 1 0 2 0 2 0 1 2 3 0 0 0 0 0 4 8 12 0 3 6 9 14 367 1139 1506 11 208 717 925 0 3 12 15 0 3 6 9 0 1 5 6 0 1 1 2 0 2 4 6 0 1 6 7 0 1 0 1 0 1 0 1 0 9 2 11 0 5 10 15 0 16 14 30 0 22 13 35 Level of MR ICDA Sex  Code 311.6 M F Mild 311.7 M F 311.8 M F 311.9 M F 312.0 M F 312.1 M F 312.2 M F Moderate 312.3 M F 312.4 M F 312.5 M F 312.6 M F 312.7 M F 312.8 M F 312.9 . M F 313.0 M F Severe 313.1 M F 313.2 M F 313.3 M F 313.4 M F 0-4 5-9 10-14 15-19 0 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 4 33 92 165 2 17 65 105 0 0 1 2 0 0 0 0 1 1 1 0 0 0 0 0 0 0 3 1 0 0 0 1 0 0 1 0 0 1 0 0 2 1 6 6 2 3 8 5 81 64 49 58 65 46 52 55 0 1 1 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 2 1 0 0 0 0 1 20 93 142 0 21 60 105 0 1 0 1 0 0 1 1 0 1 1 0 0 0 0 2 0 0 2 1 0 0 1 1 0 0 0 0 0 1 1 0 3 9 11 10 1 8 18 5 20-29 30-39 40-49 50-59 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 2 0 0 0 349 206 45 17 282 191 44 29 5 1 0 0 3 1 0 0 3 0 0 0 1 4 0 0 2 1 0 0 3 2 0 0 0 0 0 0 0 0 0 0 8 1 2 2 9 3 0 1 78 12 10 6 70 21 8 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 267 86 52 26 18 2 79 45 32 5 2 0 0 4 2 2 0 3 1 0 0 0 1 0 0 2 4 0 0 0 0 0 0 1 0 0 0 0 1 0 0 5 4 1 0 8 3 0 1 Subtotals T o t a l s 60+ <19 >20 0 3 0 3 0 0 0 0 0 0 1 1 2 0 3 3 0 2 0 2 0 0 2 2 9 294 626 920 10 189 556 745 0 3 6 9 0 0 4 4 0 3 3 6 0 0 5 5 1 4 4 8 0 1 5 6 0 1 0 1 0 1 0 1 0 15 13 28 0 18 13 31 2 252 108 360 0 218 101 319 0 2 0 2 0 2 0 2 0 0 . 0 0 0 0 0 0 0 3 1 4 0 0 1 1 19 256 450 706 9 186 347 533 0 2 7 9 0 2 8 10 0 2 4 6 0 2 1 3 0 3 6 9 0 2 0 2 0 N 0 1 1 0 2 1 3 0 33 10 43 0 32 12 44 Level of MR ICDA Sex Subtotals T o t a l s Severe Profound 314.2 M 0 0 0 2 2 2 1 1 0 2 6 8 1 -oo C O Unspecified Code 0-4 5-9 10-14 15-19 20-29 30-39 40-49 50-59 60+ <19 >20 313.5 M 1 3 14 21 25 28 8 7 1 39 69 108 F 0 0 3 14 25 19 11 10 1 17 66 83 313.6 M 1 1 1 0 0 0 0 0 0 3 0 3 F 0 0 0 0 0 0 0 0 0 0 0 0 313.7 M 0 0 0 0 0 0 0 0 0 0 0 0 F 0 0 0 0 0 0 0 0 0 0 0 0 313.8 M • 0 0 0 0 0 0 0 0 0 0 0 0 F 0 0 0 0 0 0 0 0 0 0 0 0 313.9 M 7 24 44 66 126 76 35 40 16 141 293 434 F 2 13 23 53 83 66 34 20 19 91 222 313 314.0 M 0 0 2 4 6 0 0 0 0 6 6 12 F 0 1 1 2 7 0 0 0 0 4 7 11 314.1 M 0 0 0 0 3 0 0 0 0 0 3 3 F 0 0 1 1 1 0 0 0 0 2 1 3  0 0 0 0 2 6 8 F 0 0 0 1 3 2 0 0 0 1 5 6 314.3 M 0 1 0 0 0 0 0 0 0 1 0 1 F 0 0 0 0 2 0 « 0 0 0 0 2 2 314.4 M 0 5 11 8 12 2 1 1 1 24 17 41 F 1 10 17 10 10 0 0 1 0 38 11 _ 49 314.5 M 0 0 3 14 14 7 9 2 1 17 33 50 F 0 1 1 10 10 4 9 2 0 12 25 37 314.6 M 0 0 0 0 0 0 0 0 0 0 0 0 F 0 1 0 0 0 1 0 0 0 1 1 2 314.7 M 0 0 0 0 1 0 0 0 0 0 1 •1 F 0 0 0 0 0 0 0 0 0 0 0 0 314 .8 M 0 0 0 0 0 0 0 0 0 0 0 0 F 0 0 0 0 0 0 0 0 0 0 0 0 314.9 M 1 19 30 49 78 43 27 5 6 99 159 258 F 1 17 23 40 66 47 13 7 4 81 137 218 315.0 M 0 0 1 1 3 4 0 1 0 2 8 10 F 0 0 1 0 7 0 0 0 0 1 7 8 315.1 M 0 0 0 0 1 0 0 0 0 0 1 1 F 0 0 0 1 2 0 0 0 0 1 2 3 315.2 M 0 0 2 4 3 1 0 0 0 6 4 10 F 0 2 0 5 2 3 5 1 0 7 11 18 315.3 M 0 1 0 1 0 0 0 0 0 2 0 2 F 1 2 0 1 0 0 0 0 0 4 0 4 Level of MR Unspecified ICDA Sex Code 0-4 5-9 315.4 M 13 16 F 16 22 315.5 M 1 21 F 1 27 315.6 M 0 1 F 0 0 315.7 M 0 0 F 0 0 315.8 M 0 0 F 0 0 315.9 M 21 74 F 25 42 10-14 15-19 20-29 14 12 5 12 4 9 27 24 56 28 25 40 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 87 119 255 65 97 217 30-39 40-49 50-59 1 0 0 0 1 0 38 11 1 22 2 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 141 37 19 119 30 23 Subtotals T o t a l s 60+ <19 >20 0 55 6 61 0 54 10 64 2 73 108 181 2 81 71 152 . 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 14 301 466 767 15 229 404 633 - 140 -A P P E N D I X I V P e d i g r e e s o f K i n d r e d s w i t h X - l i n k e d M e n t a l R e t a r d a t i o n T h e f o l l o w i n g p e d i g r e e s c o n t a i n a l l o f t h e m a t e r n a l f a m i l y members t h a t w e r e a s c e r t a i n e d e x c e p t p e d i g r e e n o . 15) 0586 w h i c h i n c l u d e s o n l y t h e B r i t i s h C o l u m b i a b r a n c h o f a l a r g e f a m i l y o r i g i n a l l y i n v e s t i g a t e d by D u n n , e t a l . ( 1 9 6 3 ) . O n l y members o f t h e B r i t i s h C o l u m b i a b r a n c h o f t h i s f a m i l y w e r e i n c l u d e d i n t h e a n a l y s i s i n o r d e r t o e l i m i n a t e a n y b i a s c o n t r i b u t e d t o t h e o v e r a l l r e s u l t s by o n e v e r y l a r g e k i n d r e d . Pedigree Legend • O male, female, normal intelligence O s e x n°t known, presumed normal intelligence four siblings o miscarriage stillbirth J Z f 0 deceased • # mentally retarded, nonspecific E_ © borderline intelligence DO d> Down syndrome 11 © mentally retarded, postnatal trauma ^ progeny known but not listed |P *J no children ~ propositus - 141 -0- O—rO • I 0 i • • • 1) 0631 <l> A c h - i D - r - O 6 ft 2) 0534 - 142 Q-r-O cJ_)3> i_!_i^3> i__-i3> © D O © 3) 0122 J 2 --a 4 ft J i o A c 4) 1671 I - 14 3 -3L ft 0 ft 5) 2135 • — r O D-r—O JL a m 6 0 6 J J JTJ a 6) 1274 - 144 -0-r-O -5 ] / / If [f H 6 6 _ 0 0 0 0 7) 1067 - o -o IL i 6 cb 6 i _ 6 / 8) 3788 - 145 -572- -O / e f t 9) 2050 J2f-_ 0 / 10) 1007 - 146 -O-T0 H A D-r-i D-r-O ^ 13 11) 0583 J * - 0 -clcioio 12) 0224 - 14 7 -13) 0757 hss-r-ir ri A <J> A / / 14) 1201 - 148 -e f t 15) 0586 0- o -0 m 6 6 A > 6o 6 - 6 .A cVo m / / 6 d 16) 1742 - 149 -0- 4 n r 17) 0593 Q-r-C> Ci) ii) o-T-6 5 J T 3 m [2] 18) 4252 0-T-O L ^ o i i o o / - s 4> 19) 1206 Q-r-O JL i 6 i-i-a 6-rQ ir i m 20) 0707 - 151 0-T-& . c U 6 - . 4> 21) 0992 Q-rA A A J_f j£f J_f A D - r A - t O r - a A L ^ N h <j>£aI 22) 0741 - 152 -D-nrO D-rA k 6 S A A A HI 4 23) 0084 6-m 0 a D 6 ^ > 4><H>4> OTTO, / IT m a 24) 1522 - 153 -m EZ 6 A-HD if A / 25) 1906 

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