Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants

Abstract

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is the most common inherited disorder of fatty acid metabolism presenting with hypoglycaemia, hepatopathy and Reye-like symptoms during catabolism. In the past, the majority of patients carried the prevalent c.985A>G mutation in the ACADM gene. Since the introduction of newborn screening many other mutations with unknown clinical relevance have been identified in asymptomatic newborns. In order to identify functional effects of these mutant genotypes we correlated residual MCAD (OMIM 607008) activities as measured by octanoyl-CoA oxidation in lymphocytes with both genotype and relevant medical reports in 65 newborns harbouring mutant alleles. We identified true disease-causing mutations with residual activities of 0 to 20%. In individuals carrying the c.199T>C or c.127G>A mutation on one allele, residual activities were much higher and in the range of heterozygotes (31%–60%). Therefore, both mutations cannot clearly be associated with a clinical phenotype. This demonstrates a correlation between the octanoyl-CoA oxidation rate in lymphocytes and the clinical outcome. With newborn screening, the natural course of disease is difficult to assess. The octanoyl-CoA oxidation rate, therefore, allows a risk assessment at birth and the identification of new ACADM genotypes associated with asymptomatic disease variants.

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

“…In contrast to results from an Australian cohort (Waddell et al 2006), we found no difference between patients homozygous for c.985A>G and compound heterozygous for c.985A>G in combination with mutations other than c.199T>C. This is in accordance with the report by Maier and colleagues (2005). Other authors (Sturm et al 2012) reported a lack of association between genotype and octanoylcarnitine levels at screening due to an overlap between patients homozygous for c.985A>G and compound heterozygous for c.985A>G and c.199T>C. However, this study did not consider ratios between acylcarnitines and did not apply statistical methods to compare biochemical parameters between genotypes.…”

“…Thus, c.985A>G was the most frequent disease-causing allele accounting for 63.5%, followed by c.199T>C with 14.9% of all alleles. Information on individual patients and assumed severity of mutations other than c.985A>G or c.199T>C according to literature (Andresen et al 2001;Waddell et al 2006;ter Veld et al 2009;Smith et al 2010;Yusupov et al 2010;Sturm et al 2012) is given in Table 1.…”

“…The patient never showed a symptomatic episode and never required inpatient emergency treatment. Sturm et al described this mutation under a different nomenclature as c.397_399delATT in a homozygous patient associated with residual enzyme activity of 3% (Sturm et al 2012).…”

“…In addition to this most common mutation in Europe, in screening cohorts other mutations, especially c.199T>C, are frequently found (Ziadeh et al 1995;Andresen et al 2001;Maier et al 2005;Waddell et al 2006;Hsu et al 2008). 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).…”

“…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).…”