Objective: To study the extent of phenotypic variability in SCA2 families of Indian origin and to identify factors associated with it.

Background: SCA2 is a inherited cerebellar ataxia characterized by cerebellar ataxia, slowing of saccades and combination of other neurological features. This phenotype is caused by expansion of CAG repeat >32 at ATXN2 loci. SCA2 is also the commonest SCA subtype observed in Indian population.

Methods: Clinically and genetically confirmed 279 SCA2 were identified from consecutive patients enrollment from 1997-2015 in the ataxia clinic for SCA mutation screening. Clinical, genetic and other paraclinical parameters were analyzed in detail for 150 SCA2 patients.

Results: In brief, SCA2 patients comprised 186(Male), 93(female) with mean±SD(range) of age at examination, 35.2±12.8(9-78)years, age at onset(AO), 29.6± 11.1(2-63)years and expanded-CAG repeats between 32-64 and mean(SD) of 42.5(4.6). Over and above features of cerebellar-ataxia, slow-saccades(83%), upper-limb arreflexia(42%), tremor(43%) and extrapyramidal(29%) features were noted as common manifestations but variable association. Phenotype based categorization of all SCA2 patient was possible with following five different clinical subtype, 1) SCA2-type-I(n=24):ataxia ± extrapyramidal ± pyramidal and without brain-stem involvement, 2)SCA2-type-II(n=25):ataxia-plus slow-saccades, 3)SCA2-type-III(n=52):ataxia, slow-saccades with peripheral-neuropathy, 4)SCA2-type-IV(n=34):ataxia,slow-saccades, extrapyramidal ± peripheral-neuropathy; 5)SCA2-type-V(n=12):ataxia, slow-saccades plus hyper-reflexia. We found statistically significant difference in mean(ANOVA) of expanded CAG between type-A(40.2) vs type-C(42.75) and type-D(43.62). Interestingly, the correlation coefficient of CAG and age at onset also varied between these categories such that Type-I(R2=0.024), Type-II(R2=76), Type-III(R2=47), Type-IV(R2=81) and Type-V(R2=61).

Conclusions: SCA2 represent clinic-genetically a heterogeneous disorder with phenotypic spectrum of amyotrophic-lateral-sclerosis, Parkinson-disease and cerebellar-ataxia. Genetically, these phenotype associate with intermediate alleles (27-30), low abnormal CAG with CAA interruption(32-40) and pure CAG stretch>32 respectively. The clinical subtypes and phenotypic variability suggest CAG repeats to be major molecular correlate which may further shed insight into molecular pathology in SCA2.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-largest-case-series-study-of-spinocerebellar-ataxia-type-2sca2-from-india-do-sca2-clinical-subtypes-exists/