Mitochondrial DNA Haplogroups and Age at Onset of Spinocerebellar Ataxia Type 2: A Study in Indian Patients

Background and Objectives: Spinocerebellar ataxia type 2 (SCA2) is caused by cytosine-adenine-guanine (CAG) nucleotide repeat expansion in the ATXN2 gene. Mitochondrial DNA (mtDNA) haplogroups may have an influence on the disease presentation of SCA2. Methods: A total of 217 SCA2 patients were subjected to D-loop region sequencing for inferring mitochondrial haplogroups (mt-haplogroups). The association of age of onset (AO) and mt-haplogroup was assessed using the analysis of covariance (ANCOVA) method. Results: The major haplogroups found in SCA2 patients were H (24.9%), L (6.5%), U (17.1%), W (1.8%), M (24.9%), G (0.5%), A (2.3%), N (6.0%), J (0.9%), I (1.4%), T (2.8%), R (3.2%), D (0.9%), C (0.5%), K (0.9%), P (3.2%), and S (2.3%). AO was significantly different at the same expanded CAG repeats in SCA2 patients, showing the role of other genetic factors in the AO modifiers. The ANCOVA model revealed a significant effect of mtDNA haplogroup on AO ( P = 0.005), with variations in haplogroups adjusted for CAG repeat length. Post-hoc analyses further confirmed that haplogroup T ( P = 0.004) and haplogroup M ( P = 0.01) were significantly associated with AO compared to other haplogroups. Specifically, haplogroup M was linked to an early AO, while haplogroup T was associated with a late AO. Conclusions: The study suggests an association between mt-halogroups and AO in SCA2, independent of CAG repeat length, with haplogroups T and M emerging as potential modifiers that may modulate disease progression. Further research is needed to explore the mechanisms behind these associations and validate the findings in larger cohorts.