L A T E ONSET AUTOSOMAL DOMINANT CEREBELLAR A T A X I A
A F A M I L Y D E S C R I P T I O N A N D L I N K A G E A N A L Y S I S W I T H T H E H L A S Y S T E M
WALTER O. ARRUDA * — M. LUIZA PETZL-ERLER **
MOEMA A. CARDOSO * — THOMAS LEHNER *** — J U R G OTT ***
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 l a t e o n s e t h e r e d i t a r y c e r e b e l l a r a t a x i a i s d e s c r i b e d . E i g h t a f f e c t e d f a m i l y m e m b e r s w e r e p e r s o n a l l y s t u d i e d , a n d d a t a f r o m a n o t h e r f o u r w e r e o b t a i n e d t h r o u g h a n a m n e s i s . T h e m e a n a g e o f o n s e t w a s 3 7 . 1 ± 5 . 4 y e a r s (27-47 y e a r s ) . T h e c l i n i c a l p i c t u r e c o n s i s t e d b a s i c a l l y o f a p u r e a t a x i c c e r e b e l l a r s y n d r o m e . C T - s c a n d i s c l o s e d d i f f u s e c e r e b e l l a r a t r o p h y w i t h r e l a t i v e s p a r i n g o f 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 s t u d i e s
( n e r v e c o n d u c t i o n , V E P a n d B A E P ) w e r e n o r m a l . T w e n t y - s i x i n d i v i d u a l s w e r e t y p e d f o r H L A h i s t o c o m p a t i b i l i t y a n t i g e n s . L o d s c o r e s w e r e c a l c u l a t e d w i t h t h e c o m p u t e r p r o g r a m L I N K M A P . C l o s e l i n k a g e o f t h e a t a x i a g e n e w i t h t h e H L A s y s t e m i n t h i s f a m i l y c o u l d 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 o f t h e 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 l o c a t i o n t h a n c h r o m o s o m e 6 .
Ataxia cerebelar hereditária de início tardio: descrição de u m a família com estudo de ligação com o sistema H L A .
R E S U M O — D e s c r e v e - s e u m a f a m í l i a a f e t a d a p o r f o r m a a u t o s s ô m i c a d o m i n a n t e d e a t a r i a c e r e b e l a r d e i n í c i o t a r d i o ( a c i m a d o s 2 0 a n o s ) . O i t o m e m b r o s d a f a m í l i a s ã o e s t u d a d o s e d a d o s d e o u t r o s q u a t r o a f e t a d o s p e l a d o e n ç a f o r a m o b t i d o s p o r a n a m n e s e . A m é d i a d e i d a d e d e i n í c i o d a d o e n ç a f o i 3 7 , 1 ± 5 , 4 a n o s (27-47 a n o s ) . O q u a d r o c l í n i c o c o n s i s t i a b a s i c a m e n t e d e s í n d r o m e c e r e b e l a r d e c a r á t e r l e n t a m e n t e p r o g r e s s i v o , s e m o c o r r ê n c i a c o n c o m i t a n t e d e s i n a i s o u s i n t o m a s d e c o r r e n t e s d e e n v o l v i m e n t o d e o u t r o s s i s t e m a s . E s t u d o t o m o g r á f i c o c o m p u t a d o r i z a d o m o s t r a v a a t r o f i a c e r e b e l a r d i f u s a c o m r e l a t i v a p r e s e r v a ç ã o d o t r o n c o c e r e
b r a l e d a s e s t r u t u r a s s u p r a t e n t o r i a i s . E s t u d o s n e u r o f i s i o l ô g i c o s ( n e u r o c o n d u ç ã o m o t o r a / s e n -s i t i v a , 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 . V i n t e e -s e i -s p e -s -s o a -s d a f a m í l i a f o r a m t i p a d o s p a r a a n t í g e n o s d e h i s t o c o m p a t i b i l i d a d e H L A . E s c o r e s l o d f o r a m c a l -c u l a d o s u t i l i z a n d o p r o g r a m a d e -c o m p u t a d o r d e n o m i n a d o L I N K M A P . L i g a ç ã o e s t r e i t a -c o m o s i s t e m a H L A n e s t a f a m í l i a f o i e x c l u í d a — 0==0,02, z = ( — 2 , 1 7 ) — e a a n á l i s e 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 n e s t a f a m í l i a n ã 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 «hérédoataxie céré-belleuse» 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 t h e 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 C i ê n c i a s N e u r o l ó g i c a s * , D e p a r t m e n t o f G e n e t i c s , 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 á * * , C u r i t i b a , B r a z i l , a n d I n s t i t u t e o f P s y c h i a t r y , 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 .
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.
C A S U I S T 1 C S , M E T H O D S A N D R E S U L T S
T h i s 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. T h e patient 1-1 was born in France a n d details of her disease were not obtainable. A l l the sibship ( I I I ) were born in the state Santa Catarina, Southern Brazil. T h e members 111-10, 111-18, 111-20, I V - 2 , IV-10, IV-26, I V - 2 8 and I V - 3 0 were admitted to our Service, where they were submitted to clinical laboratory tests, electrophysiological studies and CT-scan. T h e member 111-12 was affected and died in 1978. Data of his disease were obtained from his wife. T h e 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 ) . T h e 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 s i g n s / s y m p t o m s : dementia, ophthalmople-gia, optic atrophy, deafness, bulbar cranial palsies, postural hypotensoin, cogwheel rigidity, involuntary movements, fasciculations, amyotrophy, sensory disturbances, sphincteric d y s -function, and skeletal defprmities. Clinical, tomographic and electrophysiological findings are summarized in Table 1. Only individual I V - 3 0 suffered epilepsy (primary generalized) since aged 7. An E E G w a s normal. She was medicated with carbamazepine and clonazepam with good control of her epileptic fits. No other m e m b e r 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. T h e cause of death could not be elucidated. A l l family m e m b e r s of generation V were normal. Their a g e s ranged from 1.7 year to 26 years. A five-point clinical disability sciale28 was applied to 11 affected family members. T h e progression rate (degree of disabili-ty/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 , creati-nine, 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 W o r k s h o p s and local antisera for typing of 17 H L A - A , 32 H L A - B , a n d 8 H L A - C specificities. L o d scores were calculated with the computer program L I N K M A P 21. T h e results are depicted in T a b l e 2.
Electrophysiological studies — Nerve conduction studies (motor and sensory) were performed in patients 111-20, I V - 2 , I V - 1 0 , 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 ) , a n d were normal.
with the exception of patient IV-26, there w a s 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. T h e 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 impro-vement could be observed. Patient IV-28 received intramuscular i.00 ug of T^LH (thyrotropin releasing hormone) each day, for 30 days, without improvement.
C O M M E N T S
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
1 4. T h e mode of inheritance is clearly autosomal dominant. T h e
involvement of other neurological systems leading to a complex clinical picture
besi-des the cerebellar syndrome is the rule rather the exception in this proup of
neuroge-netic diseases. Therefore, Oppenheimer proposed the denomination of «multiple
sys-tem a t r o p h y »
2 6.
«Pure» hereditary cerebellar ataxia as observed in this family is uncommon
1 7-
2 3.
S t o n e
3 2, 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
1 2, 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 ( C T - s c a n ,
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.
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
pos-sibility 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
nonly 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
2 9. 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
7.
3 9. T h i s 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
3 1In 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. L u i z A. Bascheschi, Universidade de São Paulo, São Paulo, for their helpful suggestions. D r . Ricardo R. Seixias performed the electrophysiological studies.
R E F E R E N C E S
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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.
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