The Molecular Basis of Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency in Compound Heterozygous Patients: Is There Correlation between Genotype and Phenotype?

Abstract

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease-causing mutations in 14 families in whom both mutations had not previously been reported. We 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 showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result 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 identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype 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.

Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

“…The c.799G>A (p.G267R) mutation has been previously reported in symptomatic patients (Yokota et al 1991;Andresen et al 1997;Zschocke et al 2001). Glycine 267 is highly conserved in humans and other organisms and are found at the equivalent positions in human short-chain and branched-chain acylCoA dehydrogenases (Zschocke et al 2001).…”

“…It seems that there is no clear relationship between genotype and phenotype (Andresen et al 1997;Lehotay et al 2004;Waddell et al 2006;Hsu et al 2008), but patients homozygous for the common mutation have higher levels of C8 (Andresen et al 2001;Waddell et al 2006;Smith et al 2010), and it is associated with a greater predisposition to suffer decompensation in situations of metabolic stress (Arnold et al 2010). Thus, compound heterozygous for the prevalent c.985A>G mutation and a milder mutation in the other allele may have a risk reduction due to their greater residual enzyme activity (Lehotay et al 2004).…”

“…Glycine 267 is highly conserved in humans and other organisms and are found at the equivalent positions in human short-chain and branched-chain acylCoA dehydrogenases (Zschocke et al 2001). Expression studies in Escherichia coli revealed a decrease of the enzyme activity that could be increased by co-overexpression of the GroESL chaperonins (Andresen et al 1997).…”

“…To date, 81 ACADM mutations have been described in the Human Genome Mutation database http://www.hgmd.cf.ac.uk, but a clear genotypephenotype correlation has not been established, and there is a wide phenotypic variability even within the same family (Yokota et al 1991;Andresen et al 1997;Lehotay et al 2004;Waddell et al 2006;Hsu et al 2008).…”

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

“…There is ongoing discussion, whether patients with this potentially mild mutation would ever show any clinical phenotype (Andresen et al 2001) or might not require treatment at all (Sturm et al 2012). However, findings on associations between genotype and biochemical phenotype in MCADD are divergent (Andresen et al 1997;Maier et al 2005;Rhead 2006;Sturm et al 2012). A straightforward correlation between clinical phenotype and genotype could not be demonstrated so far (Wilcken et al 1994;Andresen et al 1997).…”