Combined malonic and methylmalonic aciduria
[4][5] The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms.
[4][7] CMAMMA is an inborn, autosomal-recessive metabolic disorder, resulting in a deficiency of the mitochondrial enzyme Acyl-CoA synthetase family member 3 (ACSF3).
[9][3] The mtFASII - not to be confused with the better known fatty acid synthesis (FASI) in the cytoplasm - plays an important role in the regulation of energy metabolism and in lipid-mediated signaling processes.
[12] While malonic acid competitively inhibits complex II and has a cytotoxic effect, the deficiency of the substrate malonyl-CoA in turn leads to reduced malonylation of mitochondrial proteins, which affects the activity of metabolic enzymes and alters cell metabolism.
[12] However, the malonyl-CoA demand can still be met in part via the enzyme mtACC1, a mitochondrial isoform of acetyl-CoA carboxylase 1 (ACC1), which explains the broad clinical phenotype of CMAMMA.
[13] Nevertheless, there is a close metabolic interaction between glial cells in the form of astrocytes and neurons to maintain cellular functionality.
[13] It is therefore speculated that CMAMMA also leads to an upregulation of β-oxidation in brain cells, resulting in an increased risk of hypoxia and oxidative stress, which may contribute to neurological symptoms in the long term.
[13] Furthermore, there are also massive changes in the cellular complex lipids, such as increased levels of bioactive lipids like sphingomyelins and cardiolipins, as well as triacylglycerides, which are additionally accompanied by altered fatty acid chain length and the presence of odd chain species.
[21][20] Due to a wide range of clinical symptoms and largely slipping through newborn screening programs, CMAMMA is thought to be an under-recognized condition.
[23] The final diagnosis is confirmed by molecular genetic testing if biallelic pathogenic variants are found in ACSF3 gene.
[2] Preclinical proof of concept studies in animal models have shown that mRNA therapy is also suitable for use in rare metabolic diseases.
[26] In this context, the mut methylmalonic acidemia therapy candidate mRNA-3705 from the biotechnology company Moderna, which is currently in phase 1/2, is worth mentioning.
[29][8] In 2011, genetic research through exome sequencing identified the ACSF3 gene as a cause of CMAMMA with normal malonyl-CoA decarboxylase.
[4][7] With a study published in 2016, calculation of the MA/MAA ratio in plasma presented a new possibility for rapid, metabolic diagnosis of CMAMMA.
[2] 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.
