This leads to treatment measures such as the administration of antibiotics and laxatives. Vitamin B12
Since some forms of methylmalonic acidemia respond to vitamin B12, treatment attempts in CMAMMA due to ACSF3 with vitamin B12 have been made, also in the form of hydroxocobalamin injections, which, however did not lead to any clinical or biochemical effects. L-Carnitin
One study also mentions treatment with L-carnitine in patients with CMAMMA due to ACSF3, but only retrospectively and without mentioning results. messenger RNA
Preclinical proof of concept studies in animal models have shown that messenger RNA (mRNA) therapy is also suitable for use in rare metabolic diseases. In this regard, the phase 1/2 study (mRNA-3704 & mRNA-3705) for the treatment of isolated methylmalonic acidemia, which has been ongoing since 2019 by the biotechnology company Moderna, is worth mentioning. Research
In 1984, CMAMMA (due to malonyl-CoA decarboxylase deficiency) was described for the first time in a scientific study. Further studies on this form of CMAMMA followed until 1994, when another form of CMAMMA with normal malonyl-CoA decarboxylase activity was discovered. In 2011, genetic research through exome sequencing identified the ACSF3 gene as a cause of CMAMMA with normal malonyl-CoA decarboxylase. With a study published in 2016, calculation of the MA/MAA ratio in plasma presented a new possibility for rapid, metabolic diagnosis of CMAMMA.
Malonyl-CoA decarboxylase deficiency
CMAMMA due to malonyl-CoA decarboxylase is also inherited in an autosomal recessive manner. The MLYCD gene is located on chromosome 16 locus q23.3. Pathophysiology
ACSF3
ACSF3 encodes an acyl-CoA synthetase, which is localized in the mitochondria and has a high specificity for malonic acid and methylmalonic acid. Thus, the synthetase catalyzes the synthesis of malonyl-CoA as well as methylmalonyl-CoA. Malonic acid
The conversion of malonic acid to malonyl-CoA by acyl-CoA synthetase represents the first step in the mitochondrial fatty acid synthesis (mtFASII) pathway, which plays an important role in the regulation of energy metabolism and which should not be confused with the more familiar fatty acid synthesis that occurs in the cytoplasm. The dysfunctional mtFASII pathway leads to an accumulation of malonic acid, which has a competitive inhibitory effect on complex II, and also leads to a deficiency of malonyl-CoA. These deficiencies can be continued to the end-product of the mtFASII pathway, octanoyl-ACP. The consequences of this are diminished oxidative phosphorylation and major alterations in complex lipids, such as increased levels of sphingomyelins and cardiolipins and lower levels of phosphatidylcholines, phosphatidylglycerol and ceramides. Since octanoyl-ACP is the direct precursor in lipoic acid synthesis, this results in diminished lipoylation, since lipoic acid acts as an essential cofactor for several mitochondrial multienzyme complexes, such as pyruvate dehydrogenase complex (PDHC) and α-ketoglutarate dehydrogenase complex (α-KGDHC), among others. This diminished lipoylation also leads to a reduced glycolytic flux.