A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report.


A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi-body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial β-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation.





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Publication Info

Dessein, Anne-Frédérique, Monique Fontaine, Brage S Andresen, Niels Gregersen, Michèle Brivet, Daniel Rabier, Silvia Napuri-Gouel, Dries Dobbelaere, et al. (2010). A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report. Orphanet J Rare Dis, 5. p. 26. 10.1186/1750-1172-5-26 Retrieved from https://hdl.handle.net/10161/4385.

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David Stuart Millington

Professor Emeritus of Pediatrics

Development of new mass spectrometric methods for the analysis of disease-specific metabolites in human physiological fluids for application to the diagnosis of inborn errors of metabolism. The development of automated methods based on tandem mass spectrometry for the analysis of these metabolites in blood spots and urine from neonates, with a view to revolutionizing newborn screening methodology.
Development and application of mass spectrometry based biomarker assays for monitoring treatment and diagnosis of lysosomal storage diseases (LSDs).
Development and application of methods for analysis of drugs used in human clinical trials.
Application of "lab-on-a-chip" technology, based on digital microfluidics, to enzymatic and DNA- based assays used in newborn screening and at the point of care.
Development and application of new methods for studing clucose metabolism both in vivo and in vitro using stable isotope labeling with tandem mass spectrometry.
Development and application of methods for the analysis of urine markers of oxidative stress, using tandem mass spectrometry.

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