Evidence of a single origin for the most frequent mutation (R402W) causing glutaryl-CoA dehydrogenase deficiency: identification of 3 novel polymorphisms and haplotype definition.

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia, biochemically by excretion of glutaric and 3-hydroxyglutaric acids in urine, and pathologically by neural degeneration of the caudate and putamen. To date, over 70 mutations in GCDH gene have been identified, single prevalent mutations have been found in communities in which GA I is particularly common, but generally GA I is heterogeneous. The most frequent mutation in Caucasians, R402W, has been identified in 12-16% of alleles. Here we report the frequency of mutation R402W in GA I Spanish patients, the characterization of three novel GCDH polymorphisms (IVS2+48T>C, IVS2-82T>G and 3'UTR 1518A>G) which, in combination with the two polymorphisms previously described (IVS2+64G>C, 1209G>T) gave rise to the first definition of GCDH haplotypes and their frequencies in control population. Linkage disequilibrium has been found between mutation R402W and a specific haplotype, suggesting a single origin for this mutation. Hum Mutat 15:207, 2000.