Cerebellar ataxia is a disabling neurological symptom with extreme clinical and etiological heterogeneity. The objective of this study is to investigate the clinical and molecular characteristics in patients with degenerative cerebellar ataxia. 150 South-Indian patients with degenerative cerebellar ataxia underwent a phenotype guided, sequential tiered testing. Phenotypic features studied included cerebellar symptoms, pyramidal and extrapyramidal features, and ophthalmic and systemic findings. Tier one included conventional tests such as short PCR/fragment analysis for spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 12, 17, and 36 and TP-PCR for Friedreich ataxia (FA). Tier two testing comprised next-generation sequencing (NGS)-based strategies reserved for select undiagnosed cases. The clinical features were highly overlapping and had limited specificity, except in autosomal recessive ataxias and SCA 34. The overall diagnostic yield of our study was 49.3%. SCA 1, 2, and 3 were noted in 13 (12.6%), 12 (11.6%) and 14 (13.5%), respectively, out of the 103 tested, and FA was noted in 17/55 (30.9%) patients. SCA subtypes 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. Targeted Sanger sequencing and NGS revealed some rare diagnoses in 17 among the 18 patients tested. Whole exome sequencing uncovered a novel genotype-phenotype association in a sibling-pair with ataxia, dysmorphism, and retinopathy. SCA 1, 2, 3 and FRDA were the most common causes of ataxia. SCA 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. NGS testing revealed several rare forms of ataxia. Clinical features based testing is cost-effective, achieves good genotype-phenotype correlation, and prioritizes variants for further studies.

Read the Full article here