Genetically Mediated ALS: Genotype-Phenotype Correlation and Disease Outcome in an Indian Cohort
Muddasu Keerthipriya1, Saraswati Nashi1, Priya Thomas2, Gautham Arunachal Udupi3, Seena Vengalil1, Atchayaram Nalini1
1Neurology, 2Psychiatric Social Work, 3Human Genetics, National Institute of Mental Health and Neurosciences
Objective:
To describe genetic patterns, clinical phenotypes and disease outcome of Indian ALS patients.
Background:
Around 70% of familial and 10% of sporadic ALS forms are attributed to a known genetic cause. More than 40 genes are linked to ALS, highlighting heterogeneity in molecular basis of the disease. There are very few ALS genetics studies from India, the most populous and diverse country.
Design/Methods:
Retrospective analysis of genetically confirmed ALS cases evaluated between 2016 and 2023, who underwent Next Generation Sequencing (NGS). In 2024, patients were contacted telephonically to know disease outcome. The study was conducted at a tertiary care referral center for ALS.
Results:
We identified 47 individuals from 47 different families with genetically mediated ALS. 28 were sporadic and 19 were familial cases. 17 different genes were identified, among them SOD1 (11), C9orf72 (6), TARDBP (5), FUS (4), and OPTN (4) were common and other rare ones were SETX, CHCHD10, ERBB4, SPG11, CCNF, FIG4, MATR3, NEFH, NEK1, SIGMAR1, TUBA4A, VCP. Familial and sporadic cases had median age at onset of 43.0 and 49.5 years respectively, both groups had median duration of illness of 12 months. Overall, spinal onset of the disease was common (82.98%) than bulbar onset (17.02%). Mean survival time was greater in sporadic forms compared to familial ones (142.90 vs 77.30 months, CI 95%) however significance in difference of means couldn’t be proven due to less sample size. 4 patients had Juvenile forms of ALS with mutations in SOD1 (2/4, both homozygous), TARDBP (1/4), and FUS (1/4), with LMN predominant symptoms. 3 of them had rapid progression of illness with disease duration ranging from 8-15 months and died due to respiratory failure.
Conclusions:
SOD1 mutations are the most common genetic cause of ALS. Familial forms had shorter survival. Larger studies are needed to know exact genetic spectrum of ALS in India.
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