Atypical and variable clinical presentation of glutaric aciduria type I

We report atypical and variable clinical presentation of glutaric aciduria type I (GA I) in four children from two Greek families. In one family, a bo y with typical biochemical and neuroradiological features of GA I suffered a metabolic crisis at 16 months of age resulting in a severe movement disor der. His sister, two years older and showing identical biochemical features , has remained neurologically normal throughout childhood and at six years of age is attending normal primary school. Both children are homozygous for P217 L, a novel missense mutation in exon 7 of the glutaryl-CoA dehydrogen ase (GCDH) gene. In the other family, monozygotic twins presented at 6 year s of age with mild developmental delay and a single episode of hypoglycaemi a. Cranial magnetic resonance imaging (MRI) scans in both twins revealed al most identical high-signal alterations in the periventricular white matter and in the centrum semiovale. Biochemical analyses showed massive urinary e xcretion of glutaric and 3-hydroxyglutaric acids and carnitine depletion. M olecular studies showed compound heterozygosity for two novel putative null mutations, IVS6-1 G >A and Y413X, in the GCDH gene. The milder clinical co urse of GA I in three of the four Greek patients demonstrates the phenotypi c heterogeneity of the disease even within families. Asymptomatic siblings of GA I patients should always be investigated, and molecular studies may b e useful for confirming the diagnosis, particularly when the presentation i s atypical.