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Revisiting MSUD in Portuguese Gypsies: Evidence for a Founder Mutation and for a Mutational Hotspot within the BCKDHA Gene

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched‐chain amino acid metabolism. In the context of the wide mutational spectrum known for this disease, a few common mutations have been described in populations where founder effects played a major role in modeling diversities. In Portugal, for instance, a high proportion of patients are of Gypsy origin and all share the same mutation (c.117delC‐α; p.R40GfsX23), causing the neonatal severe form of MSUD. In this study, we used four microsatellite markers closely flanking the BCKDHA gene (E1α protein) to demonstrate that c.117delC‐α is a founder mutation responsible for the high incidence of the disorder among Portuguese Gypsies. These results are of medical relevance since carrier tests and prenatal diagnosis can be offered to families at risk, particularly because the carrier frequency of c.117delC‐α was estimated at 1.4% among the healthy Portuguese Gypsies from the South of the country. Finally we present evidence that the genomic region of the BCKDHA gene where c.117delC‐α is located is likely a mutational hotspot, since recurrence of c.117delC‐α was observed in two distinct population groups.