3-Methylglutaconic aciduria: a marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a 'new' type ('type 4').

The Mendelian disorder known as 3-methylgutaconic aciduria (McKusick 250950) gives evidence of allelic and locus heterogeneity. Type 1 has a mild clinical phenotype and confirmed 3-methylgutaconyl-CoA hydratase deficiency; inheritance is autosomal recessive. Other forms have major clinical manifestations and subdivide into X-linked (type 2), a form in Iraqi Jews with optic atrophy (so-called type 3); and untyped (putative autosomal recessive) forms without identified enzyme defects. In the latter, 3-methylglutaconic aciduria may simply be a marker for another metabolic disorder. We describe a male proband with 3-methylglutaconic aciduria designated here as 'type 4' (autosomal recessive, with severe psychomotor phenotype and cerebellar dysgenesis). He is the offspring of Italian consanguineous parents. Born with congenital malformations, he has been followed for 18 years, showing profound developmental delay and cerebellar dysgenesis. Measures of hydratase activity in cultured fibroblasts from the proband and 11 additional patients (two with type 1 disease, 9 with either type 2 or an unspecified form) revealed deficient enzyme activity in type 1 cases and normal activity in the proband and the other 11 cases. Two of the untyped cases probably have 3-methylglutaconic aciduria of the type described here. Prenatal diagnosis in the form described here may be feasible by analysis of amniotic fluid metabolites in pregnancies at risk if the mother does not entirely remove elevated concentrations. A female sibling of the proband had normal metabolite values in amniotic fluid. Postnatal follow-up confirmed absence of the disease. We give the normal values for amniotic fluid and results on these additional fetuses at risk (none affected).