Clin Genet 2002: 61: 375–379 Copyright C Blackwell Munksgaard 2002Printed in Denmark. All rights reserved

CLINICAL GENETICS0009-9163

Short Report

A patient homozygous for the SCA6 genewith retinitis pigmentosa

Fukutake T, Kamitsukasa T, Arai K, Hattori T and Nakajima T. A T Fukutakea, I Kamitsukasaa,patient homozygous for the SCA6 gene with retinitis pigmentosa. K Araia, T Hattoria, andClin Genet 2002: 61: 375–379. C Munksgaard, 2002 T Nakajimab

a Department of Neurology, ChibaThe present authors studied a 55-year-old-patient homozygous for theUniversity Graduate School of Medicine,SCA6 gene who experienced frequent attacks of positional vertigo at 37 Chiba, and b Department of Neurology,

years of age with subsequent staggering gait and night blindness. Retinitis National Sanitarium Saigata Hospital,pigmentosa (RP), as well as cerebellar ataxia and vertical antidirectional Niigata, Japannystagmus, were detected. The subject’s parents were first cousins, andtwo of his three male cousins, whose parents were also first cousins, had Key words: CAG repeat – hereditaryRP without ataxia or nystagmus. The numbers of CAG repeats in the ataxia – homozygote – icthyosis – retinalexpanded alleles of the SCA6 gene found by molecular analysis were 21 degeneration – retinitis pigmentosa –

SCA6 – spinocerebellar degeneration –and 21. The genetic results were negative for SCA1, SCA2, SCA3, SCA7upbeat nystagmusand dentatorubral pallidoluysian atrophy. The retinal degeneration in

this patient is most likely to be secondary to a genetic disorder of Corresponding author: Dr Toshio Fukutake,autosomal or X-linked recessive inheritance rather than SCA6. Other Department of Neurology (D3), Chibareported cases of patients homozygous for the SCA6 gene are also University Graduate School of Medicine,

1-8-1 Inohana, Chuo-ku, Chiba 260–8670,reviewed.Japan. Tel.: π 81-43-226-2129;fax: π 81-43-226-2160;e-mail: f1040/eb.mbn.or.jp

Received 2 November 2001, revised andaccepted for publication 10 January 2002

Spinocerebellar ataxia type 6 (SCA6), an auto-somal dominant disorder with late-onset spinocer-ebellar degeneration, was first described in 1997when it was established that this condition wascaused by CAG repeat expansions in the humana1A voltage-dependent calcium channel subunitgene which maps to chromosome 19p13 (1). Itsphenotype comprises predominantly cerebellarataxia in accord with isolated cerebellar atrophyon magnetic resonance imaging (2). Non-cerebellarsystems are only mildly affected with externalophthalmoplegia, spasticity, peripheral neuropathyand parkinsonism (2). To the present authors’knowledge, retinal degeneration has never been re-ported before.

This report describes the case of a patient homo-zygous for the SCA6 gene who not only presentedwith cerebellar ataxia and vertical anti-directionalnystagmus, but also with retinitis pigmentosa(RP). Previously reported cases of patients homo-zygous for the SCA6 gene are also reviewed.

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Case report

A 48-year-old man was admitted to the presentauthors’ hospital in 1993 suffering from positionalvertigo, unsteady gait and night blindness. At 37years of age, he felt as if the ceiling was fallingin on him while gargling one morning. Thereafter,whenever his head moved back or forth, he hadthe vertiginous sensation of his surroundings mov-ing in a direction opposite to the inclination of hishead. This sensation lasted for 10s or more. Fiveyears before admission, at 43years of age, the sub-ject experienced being unable to walk sure-footedly on a narrow path, slurred speech andnight blindness. Except for an appendectomy at 21years of age, his prior medical history was unre-markable.

Examination on admission showed mild ichthy-osis of the lower extremities, moderately advancedtypical retinal degeneration with bone spicule pig-mentation of both eyes, as well as mild ataxia of

Fukutake et al.

speech, limbs and gait. Visual acuity was 0.9 (18/20) on the right and 0.7 (14/20) on the left, thelatter being corrected to 0.9 with π0.75-diopterglass. The subject’s pupils were equal, round andsluggish to light. Ocular saccades were slightly hy-permetric and smooth pursuit movements weresaccadic. Jerky nystagmus was present on horizon-tal gaze to either side and on vertical upward gaze.Other cranial nerve functions, sensations, musclestrength and tendon reflexes of the extremities werenormal. Over the 7years after his discharge, hisstaggering gait and night blindness graduallyworsened, but at 55years of age, he could walk stillwithout a cane. Routine haematology, bloodchemistry, urinalysis and the examination of cere-brospinal fluid were normal. Peripheral nerve con-duction, needle electron micrograph and somato-sensory evoked potentials in the extremities wereall normal. Magnetic resonance imaging of thebrain detected moderate cerebellar atrophy (whichwas greatest medially) with no atrophy of thebrainstem and cerebrum. Results of electrical neu-ro-otological tests showed abnormal findings, in-cluding poor visual suppression (3), consistentwith the characteristics described in SCA6 (4).

The subjects’ father (III-1) and mother (III-2)were first cousins (Fig.1), and both had staggeringgait and slurred speech late in their lives. His uncle

Fig.1. Family pedigree: (squares) males; (circles) females; (triangles) no information on gender; (closed half of symbols) memberswith ataxia; (hatched half of symbols) members with night blindness (retinitis pigmentosa); (symbols marked with a slash) deceasedmembers; (numbers under symbols) age at present or at death; and (double lines) consanguineous marriage. The patient describedin the present report is indicated by the arrow.

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(III-3) and aunt (III-4) were also first cousins. Twoof their three male children (IV-7 and IV-10) suffer-ed weakening eyesight in childhood and typical RPwas diagnosed later. The elder cousin died sud-denly at 16years of age of heart disease. The elderof the present subject’s children (V-7) died of un-known cause at birth and the next child (V-8) hadan Arnold–Chiari I anomaly. The other livingmembers of the family show no signs of neurologi-cal diseases, but the medical histories of the de-ceased members are not clear. Molecular analysisin the present subject for SCA1, SCA2, SCA3/Ma-chado–Joseph disease, SCA6, SCA7 and dentato-rubral-pallidoluysian atrophy showed only that thenumbers of CAG repeats in the expanded allelesof the SCA6 gene were 21 and 21. The presentauthors could not examine the numbers in theother family members.

Discussion

The present subject showed adult-onset, slowlyprogressive ataxia, and positional vertigo or oscil-lopsia, which was associated with RP and ichthy-osis. The presence of consanguinity and familialretinal degeneration suggests that the illness maybe transmitted in an autosomal recessive fashion.Although this illness shares ataxia, RP, ichthyosis

Hom

ozygousS

CA

6and

retinitispigm

entosa

Table 1. Clinical and genetic characteristics of patients homozygous for the SCA6 gene: (A) asymptomatic; (N) normal; (ND) not described; (π) positive; and (–) negative

Reference

8 10 11

Characteristic 6 7 Case 1 Case 2 9 Case 1 Case 2 Case 3 Case 1 Case 2 12 Presentstudy

Age (years) 47 47 50 49 ND 63 52 50 44 41 55Sex F F M F ND M M M F F F MAge at onset (years) 39 40 48 44 36 60 52? A 27 27 33 37 (43

for gaitproblems)

Initial symptoms Unsteady Loss of Unsteady Gait Visual Unsteady Unsteady None Unsteady Unsteady Cerebellar Episodicgait balance gait imbalance disturbance

and ataxiagait gait gait gait ataxia vertigo

Clinical course At age 47, At age 46, ND ND Much At age 63, – – Rapidly: Slowly: At age 43, Slowlyunableto walk

greatdifficultywalking

morerapidly

able towalkwithoutassistance

at age 44,could notstand

at age 41,able towalkwithoutassistance

markedgaitataxia

CAG repeatlength forexpanded alleles 22/22 21/22 21/21 21/22 23/23 21/21 21/21 21/21 25/25 25/25 19/19 21/21Cerebellar ataxia π π π π ND π π – π π π πNystagmus Horizontal Vertical Horizontal Horizontal ND Vertical Horizontal/

verticalNone Horizontal None Horizontal Horizontal/

verticalVertigo ND – ND ND ND ND ND – ND ND ND πMuscle tone N Increased ND ND ND ND ND N ND N ND N

in legsTendon reflex Slightly N Hypo- N ND Increased ND N N N Brisk N

brisk reflexiaBabinski sign – – ND ND ND – ND – – – Bilateral –Sensoryimpairment – Vibration Negative Negative ND – ND – – – Mild –

at ankles forvibration

forvibration

proprio-ceptivesensoryloss inlegs

Retinaldegeneration ND ND ND ND ND ND ND ND ND ND ND π

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Fukutake et al.

and possibly autosomal recessive inheritance withRefsum disease (5), the normal results of periph-eral nerve studies and serum phytanic acid are dif-ferentiating factors. A definitive diagnosis of SCA6would have been difficult in the case of the presentsubject until the advent of molecular gene analysis.

The present authors found 11 genetically verifiedpatients homozygous (including compound hetero-zygotes) for SCA6 in the literature (MEDLINE,January 1966 to November 2001) (6–11). The clin-ical and genetic features of 12 homozygous pa-tients, including the present subject, are given inTable1. One of two subjects reported by Takiyamaet al. (10) was asymptomatic at 50years of age.The male:female ratio was 5:6 and the age at onsetof gait problems ranged from 27 to 60years (nΩ11; mean ∫SDΩ40∫10). The numbers of CAGrepeats in the paired alleles were 19/19 in one case,21/21 in five, 21/22 in two, 22/22 in one, 23/23 inone and 25/25 in two cases. No number greaterthan 25 has been reported, although the affectedSCA6 chromosomes of the heterozygotes con-tained up to 30 repeat units (9). On the scat-tergram of the correlation between age at onsetand CAG repeat length (figure not shown), thedots representing the homozygotes were clearlylocated lower (earlier) and more to the left(smaller) than those of the heterozygotes reportedin several other articles (6–9, 14). This finding sug-gests a gene dosage effect in homozygotes forSCA6 as do several more reports (7, 8, 12), al-though some other studies have found no apparentdifferences in clinical phenotype between homozy-gotes and heterozygotes (10, 14). In the presentstudy, it was not clear whether these symptoms ofthe homozygotes became more severe with age ormore rapidly progressive than those of the hetero-zygotes.

Out of the symptomatic homozygous patients,nine showed onset of gait disturbance, one of vis-ual disturbance and ataxia, and one of episodicvertigo. Based on findings for 25 genetically veri-fied heterozygous patients, Yabe et al. (13) re-ported that the most frequent initial symptom isrecurrent episodes of transient vertigo (78%),which is more common than unsteady gait (28%).Only the present subject was described as havingretinal degeneration. There was also no character-istic non-cerebellar symptom in the homozygotes.

Retinal degeneration characterizes the ADCAtype II category of Harding (15), and especiallySCA7 mapping to chromosome 3p12-13 (16), thefundus changes of which are mainly macular (17).In addition to SCA7, a familial spinocerebellarataxia of the Holmes type associated with hypo-gonadism and retinal degeneration, called Bouch-er–Neuhauser syndrome, has been reported (18–

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22). Vertical gaze was abnormal in one such pa-tient (18). A small number of cases of what ap-pears to be a specific syndrome, i.e. spinocerebellarataxia, vertical paralysis of gaze and atypical (ir-regular) retinal degeneration, have been reported(23–25). Three other families which have memberswith spinocerebellar ataxia and retinal degenera-tion have been reported (26–28). None of thesecases were verified genetically. The clinical pheno-type of the present subject may be related solely toconsanguinity and his retinal degeneration may besecondary to another genetic disorder (29). Thepedigree of this patient’s family suggests that auto-somal recessive or X-linked recessive inheritance ismost likely responsible for retinal degeneration, al-though a possible association between ataxia andretinal pigmentation cannot be excluded in the ab-sence of molecular analysis in other family mem-bers. Several genes for familial RP have now beenmapped on various chromosomes, but to the pres-ent authors’ knowledge, no mutation has been re-ported in 19p or near the SCA6 locus.

In summary, homozygotes of SCA6 appear tohave a smaller CAG repeat size than hetero-zygotes. Paired alleles with a CAG repeat size ofmore than 25 may preclude the birth or survivalto adulthood of the carriers. The present subject’sretinal degeneration may be secondary to anothergenetic disorder, and he and his family membersmay have two separate genetic disorders.

Acknowledgements

We are grateful to Profesor Kiyotaro Kondo, University of theAir, Chiba, Japan, for his helpful comments on the geneticproblem in this case.

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