The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonlyrecognized defect of mitochondrial beta-oxidation. It is potentially fatal,but shows a wide clinical spectrum. The aim of the present study was toinvestigate whether any correlation exists between MCAD genotype anddisease phenotype. We determined the prevalence of the 14 known and sevenpreviously unknown non-G985 mutations in 52 families with MCAD deficiencynot caused by homozygosity for the prevalent G985 mutation. This showedthat none of the non-G985 mutations are prevalent, and led to theidentification of both disease- causing mutations in 14 families in whomboth mutations had not previously been reported. We then evaluated theseverity of the mutations identified in these 14 families. Using expressionof mutant MCAD in Escherichia coli with or without co-overexpression of themolecular chaperonins GroESL we showed that five of the missense mutationsaffect the folding and/or stability of the protein, and that the residualenzyme activity of some of them could be modulated to a different extentdepending on the amounts of available chaperonins. Thus, some of themissense mutations may result in relatively high levels of residual enzymeactivity, whereas the mutations leading to premature stop codons willresult in no residual enzyme activity. By correlating the observed types ofmutations identified to the clinical/biochemical data in the 14 patients inwhom we identified both disease-causing mutations, we show that agenotype/phenotype correlation in MCAD deficiency is not straightforward.Different mutations may contribute with different susceptibilities fordisease precipitation, when the patient is subjected to metabolic stress,but other genetic and environmental factors may play an equally importantrole.