The inhibitory effect of cytoplastic malonyl-CoA on CPT1 varies, so it inhibits roughly 100-fold greater in cardiac and skeletal muscles than in the liver. Diagnosis
Due to a wide range of clinical symptoms and largely slipping through newborn screening programs, CMAMMA is thought to be an under-recognized condition. Newborn screening programs
Because CMAMMA due to ACSF3 does not result in accumulation of methylmalonyl-CoA, malonyl-CoA, or propionyl-CoA, nor are abnormalities seen in the acylcarnitine profile, CMAMMA is not detected by standard blood-based newborn screening programs.A special case is the province of Quebec, which, in addition to the blood test, also screens urine on the 21st day after birth with the Quebec Neonatal Blood and Urine Screening Program. This makes Quebec province interesting for CMAMMA research, as it represents the only patient cohort in the world without selection bias. Between 1975 and 2010, an estimated 2 695 000 newborns were thus screened, with 3 detections of CMAMMA due to ACSF3. However, based on this lower detection rate to the predicted rate by heterozygous frequencies, it is likely that not all newborns with this biochemical phenotype were detected by the screening program. A 2019 study then identified as many as 25 CMAMMA due to ACSF3 patients in the province of Quebec. All but one came to clinical attention through the Provincial Neonatal Urine Screening Program, 20 of them directly and 4 after the diagnosis of an older sibling.
However, intracellular esterases are also capable of cleaving the methyl group of methylmalonic acid and generating the parent molecule malonic acid.Bacterial fermentation in the gut is a quantitatively significant source of propionate, which is a precursor for methylmalonic acid. Alongside this, propionic acid is also absorbed through the diet, as it is naturally present in certain foods or is added as a preservative by the food industry, especially in baked goods and dairy products. In addition, methylmalonate is formed during catabolism of thymine.In a study with fibroblasts, increased accumulations of triglycerides, an altered profile of fatty acid chain length and the presence of odd chain fatty acids were detected. A partial degradation due to accumulated methylmalonic acid and the use of propionyl-CoA as a starter unit for fatty acid synthesis is suggested as a possible cause, supported by the observation of a higher expression of CD36, which imports fatty acids into the cell.In vitro, a connection between free methylmalonic acid and malonic acid to neurotoxicity could be established. Malonyl-CoA decarboxylase deficiency
Malonyl-CoA decarboxylase acts as a catalyst in the conversion of malonyl-CoA to acetyl-CoA and CO2. It is speculated that in MCD deficiency, the excess of mitochondrial malonyl-CoA increases methylmalonic acid levels, as a result of an inhibitory effect on methylmalonyl-CoA mutase. In the cytoplasm, malonyl-CoA acts as an inhibitor of the mitochondrial outer membrane enzyme carnitine palmitoyltransferase I (CPT1), which consequently inhibits fatty acid oxidation.