Clin Genet 1999: 56: 232–234Printed in Ireland. All rights reser6ed

Letter to the Editor

Definition of the smallest pathological CAGexpansion in SCA7

To the Editor:Spinocerebellar ataxia 7 (SCA7), one of theknown diseases caused by the expansion of acoding region CAG repeat [reviewed in (1, 2)], isa neurodegenerative disorder affecting the cere-bellum, brainstem and retina. It is characterisedby the phenotype of autosomal dominant cerebel-lar ataxia (ADCA) associated with macular de-generation (type II phenotype) (3). The SCA7gene encodes a nuclear 892 amino acid protein ofunknown function, whose N-terminal segmentcontains a polyglutamine stretch believed to exerta toxic effect when expanded.

Normal SCA7 alleles range from six to 17CAG repeats; the ten-repeat allele is the mostcommon, with a frequency of 71.5% (4). Patho-logical alleles from 37 to 130 CAGs (5), from 40to 200 CAGs (6) and from 38 to 103 CAGs (4)have been reported. Alleles bearing 28–35 repeatscan give rise, during paternal transmission, todisease alleles, but do not seem to be associatedwith SCA7 phenotype (7). However, the lowerboundary of the pathological range is still con-troversial.

We have analysed SCA7 CAG repeat numberin 2 patients and 11 relatives of an ItalianADCA type II family (Man family; Table 1).Polymerase chain reaction (PCR) products ob-tained from genomic DNA amplified usingprimers 4U1024 5%-HEX-labelled and 4U716 (8)were separated on an ABI Prism 377 automatedDNA sequencer and analysed with the Genescan2.0 software (Perkin Elmer, Monza, Italy).

CAG expansions of the SCA7 gene were firstfound in patient II-2 (10/36 repeats) and his sonIII-1 (8/42). Unsteadiness in the gait arose at 63years of age in the father and at 23 years of agein the son, followed by decreased visual acuityafter 2 and 6 years, respectively. Both patientspresented with cerebellar ataxia and dysarthria inassociation with pyramidal signs, hyper-reflexiaof the lower limbs and Babinski’s sign. When ex-amined at 30 years of age, the son also showed adecrease in saccadic velocity, supranuclear oph-

thalmoparesis, hypo-acusia, decreased vibratorysensitivity and dystonic movements in the distallimbs. Optic atrophy without maculopathy and amarked Tritan axis defect on D-15 dichromatousFarnsworth test were found in both patients.

Molecular analysis of other relatives demon-strated a 34 CAG allele in II-3 (65 years of age)and in III-3, one of her sons (41 years of age)(Fig. 1). II-3 presented unsteadiness of the gait,especially when running, generalised hyper-refl-exia, except for hypo-reflexia of the ankles, exten-sor plantar reflex and decreased vibratorysensitivity of the lower limbs. Visual acuity wasalso decreased and angiofluorography demon-strated initial signs of pigmentary macular dys-trophy. Magnetic resonance of the cerebellumfailed to demonstrate any sign of atrophy. Theson carrying the 34 CAG allele was asymp-tomatic.

All SCA genes show a limited polymorphismof normal alleles and a wide range of pathologi-cal unstable CAG expansions. SymptomaticSCA7 individuals show a number of CAG re-peats \37. Gouw et al. (4) described an asymp-tomatic individual, 48 years of age, who carried a

Table 1. Molecular and clinical characteristics of SCA7 patients in Manfamily

II-2 III-1 II-3 III-3

CAG expansion 36 42 34 34Age of onset (years) 63 23 65 − at 41

+++++Cerebellar ataxia −+/−+Dysarthria −++ −

Pyramidal signs + ++ + −Extrapyramidal signs − + − −Decrease of visual acuity ++ ++ + −

−+ + +/−Optic atrophy−Maculopathy − − +−− + −Slow saccades

++++ n.d.n.d.Tritan axis defect

+++, severe; ++, medium; +, mild; −, no symptom; n.d., not deter-mined.

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Letter to the Editor

Fig. 1. Partial pedigree of Man family. SCA7 alleles are re-ported. Black symbols indicate symptomatic patients; greysymbols indicate subjects with very mild symptoms.

pathological. In patients carrying such alleles, thefirst signs of disease will appear late in life, i.e. inthe sixth decade, and will likely be very mild,possibly depending on additional modifying fac-tors. Therefore, analysis of more families isneeded to assess the prognostic significance of ex-pansions near the pathological threshold, as wellas to investigate the role of other genetic or non-genetic factors affecting phenotype and pene-trance.

A NardacchioneL Orsi

A BruscoA FrancoE Grosso

E DragoneP MortaraD Schiffer

M De Marchi

AcknowledgementsThe authors would like to thank all the patients and theirrelatives for collaboration and Professor N Migone and DrEnza Ferrero for critical revision of the manuscript. Thiswork was supported by ‘Associazione Emma ed ErnestoRulfo per la Genetica Medica’.

References

1. Reddy P, Housman D. The complex pathology of trinu-cleotide repeats. Curr Opin Cell Biol 1997: 9: 364.

2. Koshy B, Zoghbi H. The CAG/polyglutamine tract dis-ease: gene products and molecular pathogenesis. BrainPathol 1997: 7: 927.

3. Harding AE. The inherited ataxias. Adv Neurol 1988: 48:37–46. Review.

4. Gouw LG, Castaneda MA, McKenna CK, Digre KB,Pulst SM, Perlman S, Lee MS et al. Analysis of the dy-namic mutation in SCA7 gene shows marked parental ef-fects on CAG repeat transmission. Hum Mol Genet 1998:7: 525.

5. David G, Durr A, Stevanin G, Cancel G, Abbas N,Benomar A, Belal S et al. Molecular and clinical correla-tion in autosomal dominant cerebellar ataxia with pro-gressive macular dystrophy (SCA7). Hum Mol Genet1998: 7: 165.

6. JOHANSSON J, FORSGREN L, SANDGREN O, BRICE A,

HOLMGREN G, HOLMBERG. Expanded CAG repeats inSwedish spinocerebellar ataxia type 7 (SCA/) patients: ef-fect of CAG repeat length on the clinical manifestation.Hum Mol Genet 1998: 7:171.

7. Stevanin G, Giunti P, David G, Belal S, Durr A, RubergM, Wood N, Brice A. De novo, expansion of intermediatealleles in spinocerebellar ataxia 7. Hum Mol Genet 1998:7 (11): 1809.

34 CAG repeat, which is about twice the upperlimit of the unexpanded alleles. Based on this ob-servation, he hypothesized that this expanded al-lele originated by gene conversion and wasendowed with a prospective pathogenic potential.Two ‘asymptomatic atrisk’ individuals, a 58-year-old man and a 53-year-old woman, were reportedby David et al. (5) that both were carrying allelesof 35 CAGs. The female also transmitted the 35CAG allele to three offspring without size varia-tion. Stevanin et al. (7) have also reported 28–35CAG alleles in several subjects where lack ofpenetrance could be excluded, since carriers were50–84 years of age. In contrast, Koob et al. (9)report a single individual with 35 CAGs, whoshowed early stage symptoms of ataxia. Thus,the data available on intermediate alleles stillseem too scanty to allow a definitive assessmenton the minimal number of CAGs needed to de-velop SCA7 phenotype.

The finding of an expanded CAG of 36 and 34repeats in our family contributes to a better defi-nition of the minimal expansion necessary for thedisease. A 36 CAG expansion, never reported todate, is present in subject II-2, with a definedSCA7 phenotype at 63 years of age. The pheno-type is not expressed in the two relatives carrying34 repeats (II-3 and III-3). However, II-3 showedmild clinical symptoms, consisting of maculopa-thy, with onset at 65 years of age. Though macu-lopathy might be independent from the diseaseand attributed to age, a careful follow-up seemsnecessary to monitor possible appearance of clini-cal signs of SCA at a later age.

These observations support the view that alle-les with 36 CAG repeats should be considered

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8. David G, Abbas N, Stevanin G, Durr A, Yvert G, CancelS, Weber C et al. Cloning of the SCA7 gene reveals ahighly unstable CAG repeat expansion. Nat Genet 1997:17: 65.

9. Koob MD, Benzow KA, Bird TD, Day JW, MoseleyM, Ranum L. Rapid cloning of expanded trinucleotiderepeat sequences from genomic DNA. Nat Genet 1998:18: 72.

Correspondence:Dott. Alfredo BruscoDipartimento di Genetica, Biologia e Biochimicavia Santena 1910126 TorinoItalyFax: +39 011 674040E-mail: a.brusco@cios.to.cnr.it

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