Newborn screening · Fatty acid oxidation disorder
Medium-Chain Acyl-CoA Dehydrogenase Deficiency · MCADD
The most common fatty acid oxidation disorder. Sudden death during fasting illness is the prevented outcome.
Description
Medium-chain acyl-CoA dehydrogenase deficiency, MCADD, is an autosomal recessive fatty acid oxidation disorder. Pathogenic variants in ACADM reduce or abolish medium-chain acyl-CoA dehydrogenase activity, the enzyme that initiates beta-oxidation of medium-chain fatty acids in the mitochondrion. When fasting or illness exhausts glucose stores, an affected child cannot mobilize fat for energy. Hypoglycemia, hyperammonemia, and acute encephalopathy follow. Untreated, the first metabolic crisis is fatal in roughly one in four children and leaves a substantial fraction of survivors with neurological injury.
A single common variant, c.985A>G (p.Lys329Glu), accounts for the majority of pathogenic alleles in people of Northern European ancestry. Reported live-birth incidence in Western newborn screening programs runs about 1 in 10,000 to 1 in 25,000, with lower rates in East Asian and African populations.
Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry to measure medium-chain acylcarnitines. Octanoylcarnitine, C8, is the primary marker, and the C8 to C10 ratio improves specificity. Confirmation uses plasma acylcarnitine and urine organic acid profiles followed by ACADM gene sequencing. MCADD entered expanded newborn screening when tandem mass spectrometry reached state laboratories in the late 1990s and early 2000s, and it is now on the US RUSP core panel.
Treatments to date
Standard of care is avoidance of prolonged fasting and aggressive glucose support during illness. Infants feed on demand and on a fasting schedule appropriate for age. During febrile illness, vomiting, or reduced intake, families administer oral carbohydrate at home and seek intravenous dextrose at the emergency department when oral intake fails. An emergency letter and a medical alert identifier travel with the child. Long-chain fat is not restricted in classical MCADD management.
No FDA-approved drug treats MCADD. Triheptanoin, marketed as Dojolvi, was approved by the FDA in June 2020 as a source of medium and odd-chain fatty acids for long-chain fatty acid oxidation disorders, and the label does not include MCADD. L-carnitine supplementation is used in selected children with documented secondary carnitine depletion, and its routine use in asymptomatic MCADD is debated in the metabolic literature.
Outcomes after universal screening are well documented. Cohort studies from the United Kingdom, the Netherlands, Germany, Australia, and the United States report mortality below two percent in screen-detected children managed with fasting avoidance, compared with roughly twenty-five percent mortality at first crisis in the pre-screening era. The intervention is knowledge applied early, and the screening test is a few dollars on a multiplexed panel.