3-Hydroxy-3-methylglutaric aciduria in an Italian patient is caused by a new nonsense mutation in the HMGCL gene

3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive inborn er ror of metabolism caused by deficiency of the mitochondrial enzyme 3-hydrox y-3-methylglutaryl-CoA lyase (HMGCL). Up to now only a few mutations have b een reported in the HMGCL gene. We report the first Italian patient, a fema le who presented metabolic acidosis at 3 days of age and then 3 months late r. Analysis of urinary organic acids showed the excretion of 3-hydroxy-3-me thylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hy droxyisovaleric acid. A defect of HMGCL activity was suspected and then con firmed on cultured skin fibroblasts. Brain RM showed a diffuse mild abnorma lity of cerebral white matter in the periventricular regions, and the singl e voxel proton MRI spectroscopy showed abnormal peaks. In the patient's ful l-length HMGCL-cDNA a new c286C > T transition that leads to the stop codon Q96X was detected at the homozygous level. This mutation, that gives rise to a truncated protein, was confirmed in the patient's and also her parents ' genomic DNA. The severe genetic lesion identified in the patient, which i s in contrast with the mild clinical phenotype, stresses the importance of early diagnosis and therapy in HMGCL deficiency. (C) 2001 Academic Press.