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 comm only recognized defect of mitochondrial beta-oxidation, It is potentia lly fatal, but shows a wide clinical spectrum, The aim of the present study was to investigate whether any correlation exists between MCAD g enotype and disease phenotype, We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families w ith MCAD deficiency not caused by homozygosity for the prevalent G985 mutation, This showed that none of the non-G985 mutations are prevalen t, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. W e then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showe d that five of the missense mutations affect the folding and/or stabil ity of the protein, and that the residual enzyme activity of some of t hem could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may res ult in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations ident ified to the clinical/biochemical data in the 14 patients in whom we i dentified both disease-causing mutations, we show that a genotype/phen otype correlation in MCAD deficiency is not straightforward, Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.