Objective: To study the genetic profile of patients presenting with adult-onset cerebellar ataxia of probable genetic aetiology using whole exome and mitochondrial sequencing (WEMS)

Background: There is a notable gap in research focused on the practical use of next-generation sequencing (NGS) for diagnosing highly heterogeneous conditions like ataxia in routine clinical settings. Most of the studies focus on trinucleotide repeat expansion disorders and hence monogenic causes are undiagnosed

Method: In this prospective study from NIMHANS, India, we recruited patients of adult-onset cerebellar ataxia (AOCA, age at onset>20 years) of probable genetic etiology between 2023-2024. We excluded those with acquired ataxia. As the focus was on non-repeat disorders, we excluded SCA1, 2, 3, 12, and Friedreich’s ataxia (FA). Detailed clinical, electrophysiological, and radiological assessments were done.

Results: We screened 42 patients of AOCA after exclusion of acquired causes. An additional 11 patients were excluded as they were positive for SCA1,2,3,12, or FA. The remaining 31 patients (Males: 16) underwent WEMS. The mean age at onset was 35.0±14.1 years (Range: 20-61 years) with a duration of illness of 5.7±4.9 years (Range: 6 months–20 years). Ataxia was present in all. Dystonia was the next frequent phenomenology observed [Figure1]. Abnormal fundus was noted in 5 patients (16.1%), abnormal ocular findings in 29 (93.5%), dysarthria in 27 (87.1%), and pyramidal signs in 16 (51.6%). The commonest gait pattern was ataxic (23 patients, 74.2%). The mean ICARS and MOCA scores were 39±16.8 and 25.9±4.71, respectively. Abnormal NCS was noted in 10 patients (32.3%) and abnormal MRI in 27 (87.1%).Thirteen cases (41.9%) had a definite genetic etiology (2 patients of ATX-ANO10 and 1 patient each of ATX-CACNA1G, ATX-STUB1, ATX-GFAP, ATX-COQ8A, ATX-POLG, ATX-SYNE1, ATX-TPP1, ATX-NPC1, ATX-NUS1, ATX-NEU1, and ATX-STUB1/TBP) [Figure2]. The age at onset was early [Figure3] in genetically positive cases (29.8±10.3 years) compared to genetically negative cases but not significant (38.8±12.0 years, p=0.055). Parkinsonism and myoclonus were mostly associated with genetically positive cases (p=0.029).

Conclusion: Our study highlights the diverse spectrum of genetically determined ataxia seen at a tertiary care centre, with a diagnostic yield of 41.9% with NGS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-profile-of-patients-presenting-with-adult-onset-cerebellar-ataxia-of-probable-genetic-aetiology/