Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGS)
is a recessive disorder of ketogenesis that has been previously diagnosed
in two children with hypoglycaemic hypoketotic coma during fasting periods.
Here, we report the results of molecular investigations in a third patient
affected by this disease. Sequencing of the entire coding region of the HM
GCS2 gene revealed two missense mutations, G212R and R500H. Mendelian inher
itance was confirmed by the analysis of parental samples and neither of the
mutations was found on 200 control chromosomes. Functional relevance was c
onfirmed by in vitro expression studies in cytosolic HMGS-deficient cells.
Whereas wild-type cDNA of the HMGCS2 gene reverted the auxotrophy for meval
onate, the cDNAs of the mutants did not. The disease may be recognised by s
pecific clinical and biochemical features but it is difficult to confirm en
zymatically since the gene is expressed only in liver and testis. Molecular
studies may facilitate or confirm future diagnoses in affected patients.