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.
Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected. Symptoms and signs
The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms. The underlying pathophysiology is not yet understood. The following symptoms are reported in the literature:

metabolic acidosis
coma
hypoglycemia
seizures
gastrointestinal disease
developmental delay
speech delay
failure to thrive
psychiatric disease
memory problems
cognitive decline
encephalopathy
cardiomyopathy
dysmorphic featuresWhen the first symptoms appear in childhood, they are more likely to be intermediary metabolic disorders, whereas in adults they are usually neurological symptoms. Causes
CMAMMA can be divided by causation into two separate inherited disorders: one is a deficiency of the mitochondrial enzyme acyl-CoA synthetase family member 3, encoded by the ACSF3 gene (OMIM#614265); the other disorder is a malonyl-CoA decarboxylase deficiency encoded by the MLYCD gene (OMIM#248360). ACSF3 deficiency
CMAMMA due to ACSF3 is inherited in an autosomal recessive manner. The ACSF3 gene is located on chromosome 16 locus q24.3 and consists of 11 exons and encodes a 576-amino-acid protein. CMAMMA can be caused by homozygous or compound heterozygous variants in the ACSF3 gene. Based on minor allele frequency (MAF), a population incidence of ~ 1: 30 000 can be predicted for CMAMMA due to ACSF3.