Medium-chain acyl-coenzyme A dehydrogenase deficiency

Medium - chain acyl -CoA dehydrogenase deficiency, also MCAD deficiency (English medium -chain acyl- CoA dehydrogenase deficiency ( MCADD ) ) called, is one of the most common congenital metabolic diseases. It is a protein misfolding disease, due to a mutation in the enzyme medium chain acyl-CoA dehydrogenase ( MCAD) is inoperative. The defect in MCAD causes a reduced degradation of medium ( medium chain ) fatty acids. These fatty acids can therefore be used only deficient in intermediary metabolism. The inheritance of MCAD deficiency is an autosomal recessive trait.

Pathology

For energy production in the cells fatty acids are progressively shortened by removal of small molecules by two carbon atoms. Under normal conditions, the fatty acids are converted into carbon dioxide with the release of energy and water. This process is called β - oxidation. A complex of seven enzymes is necessary to remove any twin unit. Because the process involves the removal of hydrogen atoms from an acyl group, the acyl -enzyme complex called dehydrogenase. The oxidation process of fatty acids occurs in the mitochondria. Fatty acids of the cytoplasm are bound to transport through the mitochondrial membrane to a carnitine molecule. The combination of carnitine and fatty acid called acyl -carnitine. Patients with MCAD deficiency have an increased concentration of medium-chain acyl- carnitines in the cytoplasm of the cells, as they can break down the Acylcarnitines inadequate. The medium chain fatty acids consist of 8 to 12 carbon atoms. The medium-chain acyl- carnitines are secreted in part by the cells and thus pass into the bloodstream.

Patients with reduced MCAD activity have a disorder of fatty acid oxidation. In normal health, this leads to no damage. However, the disorder may in case of another disease which causes a longer fasting period, lead to hypoglycemia ( low blood sugar ), hyperammonemia and possibly sudden death. With early detection of MCAD deficiency can be countered very secure adequate food supply and if necessary by glucose infusions in hospital in these situations, a metabolic imbalance, however. While a few years ago an undiscovered MCAD deficiency at the first occurrence of a metabolic imbalance even led to death in about 25 % of cases, can be the occurrence of such a metabolic crisis, due to the now early taking place finding of MCAD deficiency, in almost all cases very effectively prevent.

Genetics

Mutations in the gene ACADM lead to misfolding of the MCAD enzyme. The gene is located on chromosome 1 locus in human p31. The misfolded enzymes are separated from the protein quality control and disassembled in the proteasome. Therefore, the affected patients have a lack of medium - chain acyl -CoA dehydrogenase. The disease is inherited as an autosomal recessive trait. This means that two copies of a defective gene is necessary in each cell to cause the shortage. If only one copy is faulty, then the person is a asymtomatischer carrier and not affected with MCAD deficiency. It goes off when a MCAD deficiency from a frequency of about 1:10 000.

Diagnosis

In plasma, the medium-chain acyl -carnitine can be detected for example by means of tandem mass spectrometry. This can be done through a newborn screening. An increased concentration of activated fatty acids of medium chain length (8-12 carbon units ) within the acyl -carnitine suggests a suspected MCAD deficiency. As a leading parameter here is the concentration of Octanoylcarnitin. A conspicuous First detection is usually checked by a control screening and, where appropriate, by a molecular genetic analysis (DNA analysis).

The clinical suspicion of an MCAD deficiency can be confirmed by a blood count, if so hyperglycemia, metabolic acidosis and hyperuricemia is diagnosed.

Variants

Before the introduction of the expanded newborn screening of MCAD deficiency in most cases it was found only in the investigations after an acute metabolic decompensation. ( A point mutation another name c.985A > G) homozygous, ie The K329E mutation was in 80 % of cases found on both gene copies. In another 18 % of cases, this genetic defect was involved in communication with a different mutation ( compound heterozygotes ). For this reason, K329E is classified as high-risk variant worldwide.

In the molecular genetic investigations for suspicious screening findings, however, also a number of other mutation combinations are now found, the never before appeared clinically apparent. It is believed, therefore, that it is a mild phenotype of MCAD deficiency in most of these cases. Patients with these mild variants are probably remain lifelong asymptomatic without treatment, however, persuasive evidence could only provide a correspondingly extended fasting test (> 24 hours). Since such a test would be associated with an increased risk of still occurring metabolic imbalance, usually both patients with high-risk variant, as well as those with a probable mild MCAD deficiency - expression in the metabolic centers are treated in the same way (eg with glucose infusions in case of illness ).

First description

The medium - chain acyl -CoA dehydrogenase deficiency was first described in 1976 by the Danish molecular geneticist Niels Gregersen and colleagues.