Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by a progressive loss of motor neurons of the cerebral cortex and spinal cord.¹ Clinically, the disease results in spasticity as well as progressive muscle weakness and atrophy, which typically leads to death within 3 to 5 years following symptoms onset. Approximately 5% to 10% of patients with ALS have a family history of ALS (FALS), most frequently with autosomal dominant transmission; the remaining 90% of patients with ALS who are clinically indistinguishable from patients with FALS are referred to as patients with sporadic ALS (SALS).

Machado-Joseph disease (MJD) is an autosomal dominant ataxia first described in families of Portuguese-Azorean extraction (Machado, Thomas, and Joseph families) in the United States.^1-3 Since then, MJD has been reported in many ethnic backgrounds and is known to be the most common spinocerebellar ataxia worldwide. Its relative frequency among the spinocerebellar ataxias is higher in Portugal (49%),⁴ China (49%),⁵ Brazil (44%⁶; 92% in Rio Grande do Sul, Brazil⁷), the Netherlands (44%),⁸ Japan (43%),⁹ and Germany (42%)¹⁰; its relative frequency is lower in France (33%),¹¹ the United States (21%),¹² and Australia (12%)¹³; and it is rare in the United Kingdom (5%),¹⁴ India (3%),¹⁵ and Italy (1%).¹⁶

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.

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