Founder mutations in movement disorders: global distribution, molecular mechanisms, and clinical consequences-a...

Founder effects are important population genetic mechanisms that influence the distribution of inherited neurological diseases. To review the global distribution of founder mutations across the spectrum of inherited movement disorders, summarize the molecular mechanisms, and discuss their clinical implications for diagnosis, genetic counselling, and emerging precision therapies. A scoping review was conducted following PRISMA-ScR principles, searching PubMed/MEDLINE and secondary reference lists for studies reporting founder mutations, shared haplotypes, or population-specific mutation enrichment in inherited movement disorders; studies lacking genetic or epidemiological evidence for a founder effect were excluded. Seventy-one studies described 53 founder-mutation entries across 40 movement-disorder phenotypes and 48 genes or repeat-expansion loci (Table 1), most frequently spinocerebellar ataxias, dystonia, and NBIA syndromes. Shared haplotypes, mutation-age estimation, and genealogical evidence consistently supported a founder origin (e.g., TOR1A dystonia in Ashkenazi Jews, LRRK2/GBA1-associated Parkinson disease in Ashkenazi Jewish and North African populations, SCA2 in Cuba, SCA3 in the Azores and Brazil). These founder mutations enable ancestry-targeted diagnostic testing, inform genetic counselling and carrier screening in endogamous populations, and identify genetically homogeneous cohorts increasingly used for natural-history studies and precision therapeutic trials, including antisense and gene-silencing approaches. Founder effects, driven predominantly by endogamy, geographic isolation, and migration-associated bottlenecks, account for a disproportionate share of the mutational spectrum in spinocerebellar ataxias, dystonia, and NBIA syndromes. Ancestry-informed testing algorithms, targeted carrier screening, and enrolment of genetically homogeneous founder cohorts into precision therapeutic trials represent the most immediate translational applications of these findings.