Abstract
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.
Highlights
Mitochondrial fatty acid oxidation defects (FAOD) are rare inherited diseases with clinical presentation ranging from severe outcome to asymptomatic status
We report here on a patient with mild MCAD deficiency (MCADD) having undergone a severe metabolic decompensation and subsequent clinical sequels
Our patient undoubtedly suffered from a deficiency of MCAD, presenting with a mild phenotype of the disease as ascertained by relatively high residual activity from lymphocytes and fibroblasts and by a low urinary excretion of hexanoylglycine and suberylgycine during metabolic decompensation
Summary
Mitochondrial fatty acid oxidation defects (FAOD) are rare inherited diseases with clinical presentation ranging from severe outcome to asymptomatic status. The patient has to face concomitantly the increased energy demand and the sudden lowering of the fatty acid oxidation-derived energy production secondary to a drop in residual MCAD activity. This might explain why one quarter of the patients with classical MCADD do not survive their first life-threatening episode and why this disease is present in the etiology list for sudden infant death syndrome [29,30,31]. Biochemical investigations of the patient are reported along with clinical data from the same time and an assessment of the impact of the new mutant protein variant is discussed
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