Objective: To characterize the genetic landscape of early-onset cerebellar ataxia excluding repeat expansion disorders.

Background: Early-onset cerebellar ataxia (EOCA, age at onset ≤ 20 years) encompasses a diverse group of disorders with significant genetic heterogeneity. While repeat expansion disorders such as Friedreich’s ataxia, SCA1, 2, 3, and 12 account for many inherited ataxia, the genetic landscape of non-repeat cerebellar ataxia remains incompletely understood. This study explores the genetic spectrum of EOCA in a tertiary care neurology center in India.

Method: This prospective, cross-sectional study was conducted at NIMHANS, Bangalore, from January 2023 to November 2024. Patients with EOCA of probable genetic etiology (excluding repeat expansion disorders) were included. The patients underwent detailed clinical, blood, electrophysiological, and radiological evaluations. After excluding secondary causes, whole exome and mitochondrial sequencing (WEMS) was performed.

Results: We screened 38 patients of EOCA after excluding acquired causes. An additional 6 patients were excluded as they were positive for SCA1,2,3,12, or FA. The remaining 32 patients (Males: 12) underwent WEMS. The mean age at onset was 7.23±5.51 years (Range: 1-19 years) with a duration of illness of 6±6 years. 12 patients (37.5%) had consanguinity, while 5 (15.6%) had a positive family history. Ataxia was present in all. Dystonia (n=19, 59.4%) was the next common phenomenology. Abnormal fundus was noted in 9 patients (28.1%), abnormal ocular findings in 32 (100%), dysarthria in 26 (81.3%), and pyramidal signs in 14 (43.8%). The most common gait pattern was ataxic (24 patients, 75%). The mean ICARS and SARA scores were 33.25±14.46 and 12.8±5.46, respectively. Abnormal NCS was noted in 15 patients (46.9%) and abnormal MRI in 27 (84.4%).Twenty-three cases (71.9%) had a definite genetic etiology of which ATX-APTX (n=3), ATX-SETX (n=2),ATX-ATM (n=2), and ATX-CACNA1A (n=2) were the commoner ones [Figure1]. The genetic yield was highest in the 5-10 years age-of-onset subgroup (6/7, 85.7%), followed by 1-5 years (13/16, 81.3%) [Figure2].

Conclusion: These findings highlight the genetic heterogeneity of EOCA in India, reinforcing the role of comprehensive genetic testing in diagnosis. A broad range of genetic etiologies was identified with a yield of 72%, emphasizing genetic testing even without a family history.

Figure 1

Figure 2

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-spectrum-of-early-onset-cerebellar-ataxia-in-india-a-tertiary-care-center-experience/