Cerebellar ataxia is a condition affecting coordination, with symptoms such as tremors, speech issues, and abnormal eye movements. It may result from acquired causes (e.g., infections, autoimmune diseases, toxins) or hereditary ones, including genetic mutations linked to conditions like leukodystrophies and mitochondrial disorders. Genetic ataxias are classified into congenital (early-onset) and progressive (later-onset) forms. Spinocerebellar ataxias (SCAs) are the most common adult-onset genetic ataxias. SCA Type 2 (SCA2) is typically adult-onset but can rarely appear in childhood.
Genetic analysis varied among participants. Analysis included regions with at least 30x coverage and utilized the BWA Aligner/DRAGEN system and Geneyx Analysis software (Version 5.15) for variant filtering and prioritization. Gene preference was guided by OMIM, HPO, and GeneReviews resources. Additionally, CAG repeat expansions in SCA-related genes were analyzed using fluorescent primer PCR, capillary electrophoresis, and GeneMapper 4.1. A publications assessment was also conducted via PubMed using terms related to pediatric SCA2 and ATXN2, screening references for further cases.
This study reports on three pediatric cases of SCA2, highlighting diverse clinical presentations. Subject 1, a 9 years of age male, showed early motor coordination issues, cerebellar atrophy, subcortical myoclonus, and a 58 CAG expansion in ATXN2, inherited from a healthy father with a 37-repeat allele. Subject 2, with a strong family history, had a severe early-onset form, rapid disease progression, and died at age of 18 after complications from respiratory infection; he carried a 61-repeat ATXN2 allele. His younger brother, Subject 3, showed milder symptoms including developmental delay, seizures, and cerebellar atrophy, with a 45-repeat expansion. A literature review identified 19 pediatric SCA2 cases, mostly with large repeat expansions (92-884) and early-onset encephalopathy, while a few with 62-75 repeats showed neurodevelopmental disorders and progressive ataxia. Paternal inheritance was the most common.
In conclusion, pediatric-onset SCA2 is rare and linked to medium-to-large CAG repeat expansions in the ATXN2 gene. Due to the limitations of standard next-generation sequencing (NGS) in detecting repeat expansions, PCR-based or long-read sequencing is essential for diagnosis. Targeted testing for CAG expansions should be prioritized in early-onset ataxia, especially with family history or inconclusive NGS results. Ataxin-2’s pathological role involves altered cellular processes due to polyglutamine tract expansions, and disease severity appears correlated with repeat length, though variability exists even within families.
