L A T E ONSET AUTOSOMAL DOMINANT CEREBELLAR A T A X I A

A FAMILY DESCRIPTION A N D LINKAGE ANALYSIS W I T H T H E H L A SYSTEM

WALTER MOEMA A.

O.

ARRUDA *

M.

LUIZA ***

PETZL-ERLER JURG

** OTT ***

CARDOSO

THOMAS

LEHNER

S U M M A R Y A f a m i l y s u f f e r i n g a n a u t o s o m a l d o m i n a n t f o r m o f late o n s e t h e r e d i t a r y cerebellar ataxia is described. E i g h t affected family m e m b e r s w e r e personally studied, and data from another four were obtained through anamnesis. T h e mean age of onset was 3 7 . 1 5 . 4 y e a r s (27-47 y e a r s ) . T h e clinical picture consisted basically of a pure ataxic cerebellar syndrome. CT-scan disclosed diffuse cerebellar a t r o p h y w i t h relative sparing of t h e b r a i n s t e m (and n o i n v o l v e m e n t o f s u p r a t e n t o r i a l s t r u c t u r e s . N e u r o p h y s i o l o g i c a l studies (nerve conduction, V E P and B A E P ) w e r e normal. T w e n t y - s i x individuals were typed for H L A histocompatibility antigens. L o d scores w e r e calculated w i t h the c o m p u t e r p r o g r a m LINKMAP. Close l i n k a g e o f the ataxia g e n e with the H L A s y s t e m i n this family could b e e x c l u d e d 0==0,02, z = ( 2 , 1 7 ) a n d t h e o v e r a l l a n a l y s i s of the l o d s c o r e s s u g g e s t a n o t h e r c h r o m o s s o m a l location than c h r o m o s o m e 6.

Ataxia cerebelar hereditria de incio tardio: descrio de uma famlia com estudo de ligao com o sistema H L A . R E S U M O Descreve-se u m a famlia afetada p o r f o r m a autossmica dominante de ataria cerebelar de incio tardio (acima dos 20 anos). Oito m e m b r o s da famlia so estudados e dados de outros quatro afetados pela doena foram obtidos por anamnese. A mdia de idade d e i n c i o d a d o e n a f o i 3 7 , 1 5 , 4 a n o s (27-47 a n o s ) . O quadro clnico consistia basicamente de sndrome cerebelar de carter lentamente progressivo, sem ocorrncia concomitante de sinais ou sintomas decorrentes de envolvimento de outros sistemas. Estudo tomogrfico c o m p u t a d o r i z a d o mostrava atrofia cerebelar difusa c o m relativa preservao do t r o n c o cerebral e das estruturas supratentoriais. Estudos neurofisiolgicos (neuroconduo motora/sensitiva, p o t e n c i a i s e v o c a d o s v i s u a i s e a u d i t i v o s ) f o r a m n o r m a i s . Vinte e seis pessoas da famlia foram tipados para antgenos de histocompatibilidade H L A . Escores lod foram calculados utilizando programa de computador denominado L I N K M A P . L i g a o estreita c o m o s i s t e m a H L A n e s t a f a m l i a f o i e x c l u d a 0==0,02, z = ( 2 , 1 7 ) e a anlise g l o b a l d o s e s c o r e s l o d s u g e r e m q u e o g e n e m u t a n t e nesta f a m l i a n o s e l o c a l i z a n o c r o m o s s o m o 6 .

Pierre Marie 22 reviewed the cases of cerebellar ataxia reported by Fraser, Nonne, Sanger-Brown and Klippel-Durant, and proposed the term hrdoataxie crbelleuse to this hereditary form of ataxia distinct from that described by Friedreich. Since then additional reports on cases of hereditary cerebellar ataxia have been accumulated and several classifications of these disorders have been proposed 4,9,13,19. In most families described with late onset autosomal dominant cerebellar ataxia (mean onset age above 20 years), the affected members showed a complex clinical picture, most commonly including dementia, ophthalmoplegia, optic atrophy, extrapyramidal

F r o m the D e p a r t m e n t o f N e u r o l o g y , U n i d a d e d e Cincias N e u r o l g i c a s * , Department of Genetics, Universidade Federal do Paran**, Curitiba, Brazil, and Institute of Psychiatry, C o l u m b i a U n i v e r s i t y ***, N e w Y o r k , U S A . Dr. Walter O. Curitiba PR Arruda Brasil. Unidade de Cincias Neurolgicas Rua Gonalves Dias 713 80240

syndrome, amyotrophy, peripheral neuropathy, myoclonus and deafness 14. A gene linked to the H L A system on the short arm of chromosome 6 has been detected in some families 10,17,39. Nevertheless, genetic heterogeneity of this group of autosomal dominant cerebellar ataxia is likely 1. A family with several members suffering a noncomplicated form of late onset autosomal dominant cerebellar ataxia is described and the results of linkage study with the H L A system are r e p o r t e d .
2

CASUIST1CS,

METHODS AND RESULTS

This is the description of a family presenting an autosomal dominant form of cerebellar ataxia (Fig. 1 ) . T h e proband patient (111-18) took her first consultation with us in November 1986. She and her sister's initial diagnosis was multiple sclerosis. The patient 1-1 was born in France and details of her disease were not obtainable. A l l the sibship ( I I I ) were born in the state Santa Catarina, Southern Brazil. The members 111-10, 111-18, 111-20, I V - 2 , IV-10, IV-26, IV-28 and I V - 3 0 were admitted to our Service, where they were submitted to clinical laboratory tests, electrophysiological studies and CT-scan. The member 111-12 was affected and died in 1978. Data of his disease were obtained from his wife. The mean onset age was 3 7 . 1 5 . 4 years, with a range from 27 to 47. The age of onset did not differ significantly between the male ( 3 6 . 3 3 . 4 ) and female patients ( 3 9 . 2 8 . 6 ) . The clinioal picture was quite uniform and consisted basically of a slowly progressive, cerebellar syndrome, with dysarthria, gait ataxia, and dysmetria of the upper limbs as the first clinical features. None of the family members suffered from the following signs/symptoms: dementia, ophthalmoplegia, optic atrophy, deafness, bulbar cranial palsies, postural hypotensoin, cogwheel rigidity, involuntary movements, fasciculations, amyotrophy, sensory disturbances, sphincteric dysfunction, and skeletal defprmities. Clinical, tomographic and electrophysiological findings are summarized in Table 1. Only individual IV-30 suffered epilepsy (primary generalized) since aged 7. An E E G was normal. She was medicated with carbamazepine and clonazepam with good control of her epileptic fits. No other member of this family suffered epilepsy. The affected individuals I I - 4 , I I - 5 , I I I - 6 and 111-12 died at 80, 65, 67, and 62 years-old, respectively. The cause of death could not be elucidated. A l l family members of generation V were normal. Their ages ranged from 1.7 year to 26 years. A five-point clinical disability sciale28 was applied to 11 affected family members. The progression rate (degree of disability/years from onset) was calculated for each affected member and plotted against the age of onset with the use of the Spearman's correlation coefficient. No significant correlation was observed between these two parameters. On the other hand, a significant positive correlation rate was found between the duration of disease and the grade of disability (rs t= 0.826, p < 0.01). Laboratory tests The following laboratory tests were performed for 8 of the affected individuals, with normal or negative results: complete hemogram, erythrocyte sedimentation rate, V D R L , sodium, potassium, calcium, phosphorus, cholesterol, triglycerides. B U N , creatinine, glucose, uric acid, T3, T4 and T S H , hepatic transaminases. Cerebrospinal fluid examination, including protein electrophoresis, was performed in 7 affected family members and was normal in all of them. Electrocardiogram and chest X - r a y were performed in 8 affected individuals and were normal. H L A - t y p i n g and linkage study Blood samples were obtained from 8 affected family members, 12 free of the disease, and 6 at risk. Lymphocytes were isolated from heparinized blood by a ficoll-hypaque method 6 and were typed for histocompatibility antigens by a microlymphocytotoxicity techniques. T h e panel of antisera included reagents from the 8th and 9th International Histocompatibility Workshops and local antisera for typing of 17 H L A - A , 32 H L A - B , and 8 H L A - C specificities. Lod scores were calculated with the computer program L I N K M A P 21. T h e results are depicted in Table 2. Electrophysiological studies Nerve conduction studies (motor and sensory) were performed in patients 111-20, I V - 2 , IV-10, and I V - 3 0 by conventional methods, and the results were within normal range. Pattern-reversal visual evoked potential and brainstem evoked potential studies were performed in 7 affected individuals (111-18, 111-20, I V - 2 , IV-26, IV-28, and I V - 3 0 ) , and were normal. CT-scan examinations Eight affected family members were examined with a Tomoscan 305 (matrix 254x254, Phillips, Netherlands). T h e scanning plane was parallel to the orbitomeatal line. Slice thickness was 3mm for the posterior fossa evaluation. In all patients,

with the exception of patient IV-26, there was widening and increase of number of the hemispheral and vermian cerebellar sulci. In earlier cases (e.g., case I V - 2 6 ) , the atrophy was almost limited to the anterior portion of the vermis. The dimensions of the brainstem .and fourth ventricle were normal, as well as the supratentorial structures. Therapeutic trials Patients IV-10, IV-26 and I V - 2 8 were medicated with choline chloride l.Og tid, baclofen lOmg tid, sodium valproat 500mg tid, each one tor three months, with one month of washout period between each drug. No subjective nor objective improvement could be observed. Patient IV-28 received intramuscular i.00 ug of T^LH (thyrotropin releasing hormone) each day, for 30 days, without improvement. COMMENTS

T h e family described has a late onset form (mean age of onset after 20 years) of hereditary a t a x i a . T h e mode of inheritance is clearly autosomal dominant. The involvement of other neurological systems leading to a complex clinical picture besides the cerebellar syndrome is the rule rather the exception in this proup of neurogenetic diseases. Therefore, Oppenheimer proposed the denomination of multiple system a t r o p h y .
14 26

Pure hereditary cerebellar ataxia as observed in this family is uncommon - . S t o n e , in 1933, made the first description of a family affected by this form of hereditary ataxia, but only H a r d i n g , in 1982, proposed a distinct position for this kind of ataxia ( T a b l e 3 ) . T h e age of onset observed by other authors is usually around the middle age, sometimes only over 60 years 12,30, differing significantly from the family hereby described. T h e Hoffmann's cases 15, where the debut of the disease was before the age of 40 in some affected members, an acute febrile illness seems to have triggered the disease, a fact not observed by other authors and by ourselves. We believe this observation is in keeping with the genetic heterogeneity within this group of pure form of heredoataxia, and emphasizes the provisional character of the clinical classification proposed by Harding 13. Electrophysiological (neuroconduction studies, B A E P , V E P and S S E P ) and neuroimaging methods (CT-scan, M R I ) seems to give little help to a better identification of distinct forms of hereditary ataxias, for their findings are not specific, and they give few data regarding the pathogenesis of these d i s e a s e s ^ . Electro-oculographic studies may help in detecting potential new cases in some families, giving support to a better genetic counseling, but there are few works in this field 8,16.
32 12

1 7

2 3

T h e final step to classify the autosomal dominant hereditary ataxias will be the mapping and identification of the mutant genes. Several authors studied the possibility of the presence of the ataxia gene locus on the sixth chromosome near the H L A loci 3,10,18,20,23,25,27,34,37,38. i only three families, linkage with H L A could be shown 10,17,39. T h e reported recombination fraction w a s around 2 0 % . Although the mutant genes of these families are syntenic (located in the same chromosome), they seem to differ, since in two families they are centromeric 38,40, and in the third one, telomeric with respect to H L A . Besides this, the two families, in which the ataxia locus w a s mapped centromeric to H L A , have a quite different phenotypic expression of the d i s e a s e . . This observation suggests the occurrence of different mutations in the same locus. In some studies, linkage with the H L A system could excluded for recombination fractions less than 1 0 - 2 0 % , suggesting the existence of at least one ataxia gene different from the one assigned to chromosome 6. In fact, the gene locus of Machado-Joseph's disease, another form of autosomal dominant ataxia ( A D C A T y p e l ) , has been mapped on the first c h r o m o s o m e .
n 2 9 7 39 31

In the family hereby described, close linkage of the ataxia gene with the HLA system could be excluded ( T a b l e 2 ) , and the overall analysis of the lod scores o b tained suggests another chromosomal location.
A c k n o w l e d g m e n t s We thank Prof. Luiz A. Franco de Andrade, Escola Paulista de M e d i c i n a , a n d P r o f . L u i z A . B a s c h e s c h i , U n i v e r s i d a d e d e S o P a u l o , S o P a u l o , f o r their helpful s u g g e s t i o n s . D r . R i c a r d o R . S e i x a s p e r f o r m e d the e l e c t r o p h y s i o l o g i c a l s t u d i e s .

In the family hereby described, close linkage of the ataxia gene with the HLA system could be excluded ( T a b l e 2 ) , and the overall analysis of the lod scores o b tained suggests another chromosomal location.
Acknowledgments We thank Prof. Luiz A. Franco de Andrade, Escola Paulista de Medicina, and Prof. Luiz A. Bascheschi, Universidade de So Paulo, So Paulo, for their helpful suggestions. Dr. Ricardo R. Seixias performed the electrophysiological studies. REFERENCES 1. Arruda W O . Ataxia Cerebelar Hereditria Autossmica Dominante. Dissertao de Mestrado. U n i v e r s i d a d e F e d e r a l d o P a r a n , C u r i t i b a , 1989. 2. A r r u d a W O , Petz-Erler M L , Cardoso, M A , Seixas R R , L e h n e r T, Ott J. Late-onset autosomal dominant cerebellar ataxia: description of a family with HLA typing ( a b s t r a c t ) . N e u r o l o g y 1990, 4 0 ( S u p l 1) : 439. 3 . B a l e A E , B a l e SJ, S c h l e s i n g e r S L , M c F a r l a n d H F . L i n k a g e analysis in spinopontine atrophy: correlation o f H L A linkage with p h e n o t y p i c findings i n hereditary ataxia. Am J M e d G e n e t i c s 1987, 27 : 595. 4. Barbeau A, Sadibelouiz M, Sadibelouiz A, R o y M. A clinical classification of hereditary a t a x i a s . Can J N e u r o l S c i 1984, 11 : 501. 5. Bodmer W F , Bodmer J. Cytofluorochromasia. I n R a y J G Jr, H a r e D B , P e d e r s e n P D , Mullaly DI (eds) : N I A I D Manual of Tissue T y p i n g Techniques. D r e w Publications Nr ( N I H ) 1978, 78-545. 6. B o y u m A. Separation of leukocytes from b l o o d and b o n e m a r r o w . Scand J. L a b Invest 1968, 21 : 1. 7. Currier R D , Glover G, Jackson JF, Tipton A F . Spinocerebellar ataxia: study of a large kindred. I. G e n e r a l i n f o r m a t i o n a n d g e n e t i c s . N e u r o l o g y 1972, 22 : 1040. 8. Dawson DM, Feudo P, Zubick HH, Rosenberg R, Fowler H. Electro-oculographic findings in M a c h a d o - J o s e p h disease. N e u r o l o g y 1982, 32:1272. 9. Greenfield JG. T h e Spino-Cerebellar Degenerations. O x f o r d : B l a c w e l i , 1954. 10. H a i n e s J N , S c h u t L J , W e i t k a m p L R , T r a y e r M , A n d e r s o n V E . Spinocerebellar ataxia in a large k i n d r e d : a g e at onset, reproduction, and genetic linkage studies. Neurology 1984, 34 : 1542. 11. H a l l B , N o a d K B , L a t h a m O . Familial cortical cerebellar atrophy. B r a i n 1941, 64:178. 12. H a r d i n g A E . T h e clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of the D r e w family of W a l w o r t h . B r a i n 1982, 105 : 1. 13. H a r d i n g A E . Classification of the hereditary ataxias and paraplegias. L a n c e t 1983, 1 : 1151. 14. H a r d i n g A E . The Hereditary Ataxias and Related Disorders. London: Churchill- - L i v i n g s t o n e , 1984. 35. H o f f m a n n P M , Stuart W H , Earle K M , B r o d y JA. Hereditary late-onset cerebellar d e g e n e r a t i o n . N e u r o l o g y 1971, 21 : 771. 16. H o t s o n J R , L a n g s t o n E B , L o u i s A A , R o s e n b e r g R N . T h e search for a psysiologic marker of M a c h a d o - J o s e p h d i s e a s e . N e u r o l o g y 1987, 37 : 112. 17. J a c k s o n J F , C u r r i e r R D , T e r a s a k i P I , M o r t o n N E . Spinocerebellar ataxia and H L A l i n k a g e : r i s k p r e d i c t i o n b y H L A t y p i n g . N E n g l J M e d 1977, 296-1138. 18. K o e p p e n A H , G o e d d e W , H i l l e r C , H i r t h L , B e n k m a n n H S . H e r e d i t a r y a t a x i a a n d the s i x t h c h r o m o s s o m e . A r c h N e u r o l 1981, 38:158. 19. K o n i g s m a r k B W , W e i n e r L P . The olivopontocerebellar atrophies: a review. Medicine 1970, 49:227. 20. K u m a r D , B l a n k C E , G e l s t h o r p e K . Hereditary cerebellar ataxia and genetic linkage w i t h H L A . H u m G e n e t 1986, 72:327. 21. L o t h r o p G M , L o l o c i e l J M , J u l i e n C , O t t J . Strategies for multilocus linkage analysis i n h u m a n s . P r o c N a t A c a d S c i U S A 1984, 8 1 : 3443. 22. M a r i e P . S u r l ' h r d o a t a x i e c r b e l l e u s e . S e m M e d ( P a r i s ) 1893, 13:444. 23. M o e l l e r E , H i n d f e l d B , O l s s o n J E . H L A - d e t e r m i n a t i o n i n f a m i l i e s w i t h h e r e d i t a r y atax i a . T i s s u e A n t i g e n s 1978, 12 : 337. 24. M o r t o n N E , L a l o u e l J M , J a c k s o n J F , C u r r i e r R D , Y e e S . L i n k a g e studies in spinocerebellar ataxia ( S C A ) . A m J M e d G e n e t i c s 1980, 6:251. 25. N i n o H , N o r e e n H J , D u b e y D P . A family with hereditary ataxia: H L A typing. Neur o l o g y 1980, 30:12. 26. O p p e n h e i m e r D R . Diseases of the basal ganglia, cerebellum and m o t o r neurons. In A d a m s J H , Corsellis JAN, Duchen L W : Greenfield's Neuropathology. L o n d o n : Edward A r n o l d , 1984.
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40.