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.
Highlights
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450), initially identified in 1982 [1], is the most common autosomal recessive disorder of the mitochondrial ßoxidation with a regional incidence of 1:9,000 to 1:10,000 in Northern Europe [2] and has been part of many newborn screening programs for the past ten years [3,4,5]
Heterozygotes commonly presented with residual activities of .50% of normal and did not present clinical manifestations of MCAD deficiency
We are able to clearly determine the functional impairment of the MCAD enzyme in different genotypes by measurement of octanoyl-CoA oxidation in lymphocytes. Using this technique we demonstrate that in addition to identifying children that may develop clinical features of MCAD deficiency, newborn screening coupled with genetic analysis alone may identify children who are likely to be asymptomatic and will never go on to manifest clinically significant MCAD deficiency
Summary
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450), initially identified in 1982 [1], is the most common autosomal recessive disorder of the mitochondrial ßoxidation with a regional incidence of 1:9,000 to 1:10,000 in Northern Europe [2] and has been part of many newborn screening programs for the past ten years [3,4,5]. With the advent of newborn screening, where many newborns are identified in the absence of a clinical presentation, a second prevalent mutation was identified c.199T.C (allele frequency approximately 6%). This mutation has never been conclusively linked to clinical symptoms [7,9,10,14,15]. Most children with the c.199T.C allele are placed on preventative measures, which potentially masks the natural clinical course of the disease This mutation has only been identified in the heterozygous state raising questions as to whether it may even be responsible for the elevated octanoyl-carnitines identified in the newborn screen
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