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Combined malonic and methylmalonic aciduria

This article is about CMAMMA due to ACSF3 deficiency. For CMAMMA due to malonyl-CoA decarboxylase deficiency, see malonic aciduria.

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.[1] However, the methylmalonic acid levels exceed those of malonic acid.[2] CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII).[3] 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.[4] Due to being infrequently diagnosed, it most often goes undetected.[4][5]

Combined malonic and methylmalonic aciduria
Other namesACSF3 deficiency, non-classic CMAMMA
SpecialtyMedical genetics

Symptoms and signs

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The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms.[6][7] The underlying pathophysiology is not yet understood.[3] The following symptoms are reported in the literature:

When the first symptoms appear in childhood, they are more likely to be intermediary metabolic disorders, whereas in adults they are usually neurological symptoms.[4][7]

Causes

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CMAMMA is an inborn, autosomal-recessive metabolic disorder, resulting in a deficiency of the mitochondrial enzyme Acyl-CoA synthetase family member 3 (ACSF3). The ACSF3 gene is located on chromosome 16 locus q24.3 and consists of 11 exons and encodes a 576-amino-acid protein.[7][6] CMAMMA can be caused by homozygous or compound heterozygous variants in the ACSF3 gene.[6] Based on minor allele frequency (MAF), a population incidence of ~ 1: 30 000 can be predicted for CMAMMA.[4]

Pathophysiology

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ACSF3 encodes an acyl-CoA synthetase, which is localized in the mitochondria and has a high specificity for malonic acid and methylmalonic acid.[9] It is responsible as malonyl-CoA synthetase for the conversion of malonic acid into malonyl-CoA and as methylmalonyl-CoA synthetase for the conversion of methylmalonic acid into methylmalonyl-CoA.[10]

 
Schematic overview of the pathophysiology of CMAMMA

Defect of mitochondrial fatty acid synthesis (mtFASII)

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ACSF3, in its function as a malonyl-CoA synthetase, catalyzes the conversion of malonic acid to malonyl-CoA, which is the first step of the mitochondrial fatty acid synthesis pathway (mtFASII).[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.[11][3] The deficiency of ACSF3 in CMAMMA leads to an accumulation of malonic acid and a mitochondrial deficiency of malonyl-CoA.[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 ACC1, which explains the broad clinical phenotype of CMAMMA.[13] The deficiencies of intermediates can be continued to the major mtFASII product, octanoyl-ACP, which is required as a starting substrate for the biosynthesis of lipoic acid, for the assembly of the complexes of oxidative phosphorylation and as an endogenous substrate for β-oxidation.[3] Important mitochondrial multienzyme complexes such as those from energy metabolism, the pyruvate dehydrogenase complex (PDHC), the α-ketoglutarate dehydrogenase complex (α-KGDHC) and from amino acid metabolism, the branched-chain alpha-keto acid dehydrogenase complex (BCKDHC), the oxoadipate dehydrogenase complex (OADHC) and the glycine cleavage system (GCS), are dependent on lipoic acid as a covalent cofactor for their functionality.[14][15] As a consequence, the reduced lipoylation of the pyruvate dehydrogenase complex and the α-ketoglutarate dehydrogenase complex leads to a reduced glycolytic flux, measured in glycolysis and glycolytic capacity.[3] To likely compensate for the cell's energy demand, an upregulation of fatty acid β-oxidation and a decreased concentration of amino acids that feed anaplerotically into the citric acid cycle, such as glutamine, aspartate, leucine, isoleucine, and threonine, could be detected.[3] In summary, this reduced mitochondrial respiration and glycolytic flux results in impaired mitochondrial flexibility with a large dependence on fatty acid β-oxidation and an increased consumption of anaplerotic amino acids.[3][13]

However, neurons, with the exception of hypothalamic neurons, are not capable of satisfying their large energy demands by degrading fatty acids.[13] It is speculated that an upregulation of β-oxidation also occurs in brain cells due to the hypofunctional mtFASII.[13] The consequence would be an increased risk for 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.[3]

Methylmalonic aciduria

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Methylmalonic acid metabolism

ACSF3, in its function as methylmalonyl-CoA synthetase, catalyzes the conversion of methylmalonic acid into methylmalonyl-CoA so that it can be degraded via the citric acid cycle. The deficiency of ACSF3 in CMAMMA therefore leads to reduced degradation and consequently to an increased accumulation of methylmalonic acid in body liquids and tissues, which is also known as methylmalonic aciduria. Methylmalonyl-CoA is formed from the essential amino acids valine, threonine, methionine and isoleucine, from odd-chained fatty acids, from propionic acid and from cholesterol side chain and can be converted into methylmalonic acid by D-methylmalonyl-CoA hydrolase even before it reaches the citrate cycle via the succinyl-CoA side.

Bacterial fermentation in the gut is a quantitatively significant source of propionate, which is a precursor for methylmalonic acid.[16][17] 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[18] and dairy products.[19] In addition, methylmalonate is formed during catabolism of thymine.[16][17]

However, intracellular esterases are also capable of cleaving the methyl group of methylmalonic acid and generating the parent molecule malonic acid.[20]

In vitro, a connection between free methylmalonic acid and malonic acid to neurotoxicity could be established.[21][20]

Diagnosis

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Due to a wide range of clinical symptoms and largely slipping through newborn screening programs, CMAMMA is thought to be an under-recognized condition.[1][2]

Newborn screening programs

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Because CMAMMA 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.[7][4][2]

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, although it is likely that not everyone with CMAMMA will be detected.[22][7]

Routine and biochemical labs

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CMAMMA has elevated methylmalonic acid levels, but these are much lower compared to methylmalonic acidemias of the types mut0, mut-, cblA, cblB and cblDv2.[23] However, methylmalonic acid levels exceed those of malonic acid (MMA/MA >5).[8][23] By calculating the methylmalonic acid/malonic acid ratio in blood plasma, CMAMMA can be clearly distinguished from a classic methylmalonic acidemia.[1] This is true for both, vitamin B12 responders and non-responders forms of methylmalonic acidemia.[1] The use of malonic acid values and methylmalonic acid values from urine is not suitable for calculating this ratio.[1] In malonic aciduria, the MMA/MA ratio is less than 1.[8]

In CMAMMA, the homocysteine level is in the normal range.[23] In addition, CMAMMA is unresponsive to vitamin B12 in vivo.[23]

Molecular genetic testing

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The final diagnosis is confirmed by molecular genetic testing if biallelic pathogenic variants are found in ACSF3 gene. There are specific multigene panels for methylmalonic acidemia, but the particular genes tested may vary from laboratory to laboratory and can be customized by the clinician to the individual phenotype.[23][24]

Extended carrier screening (ECS) in the course of fertility treatment can also identify carriers of mutations in the ACSF3 gene.[25]

Treatments

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Dietary

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One approach to reduce the accumulating amount of malonic acid and methylmalonic acid is diet. Here, a diet high in carbohydrate and low in protein has been shown to be best. Changes in malonic acid and methylmalonic acid excretion can be seen as early as 24-36 h after a change in diet.[8]

Bacteria-reducing measures

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Another quantitatively significant source of malonic acid and methylmalonic acid, in addition to dietary protein intake, is bacterial fermentation.[16][17] This leads to treatment measures such as the administration of antibiotics and laxatives.

Vitamin B12

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Since some forms of methylmalonic acidemia respond to vitamin B12, treatment attempts in CMAMMA with vitamin B12 have been made, also in the form of hydroxocobalamin injections, which, however did not lead to any clinical or biochemical effects.[2]

L-Carnitine

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One study also mentions treatment with L-carnitine in patients with CMAMMA, but only retrospectively and without mentioning results.[2]

messenger RNA

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Preclinical proof of concept studies in animal models have shown that messenger RNA (mRNA) therapy is also suitable for use in rare metabolic diseases.[26] 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.[27][28]

Research

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In 1984, CMAMMA due to malonyl-CoA decarboxylase deficiency was described for the first time in a scientific study.[29][8] Further studies on this form of CMAMMA followed until 1994, when another form of CMAMMA with normal malonyl-CoA decarboxylase activity was discovered.[30][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.[1]

The Quebec Neonatal Blood and Urine Screening Program makes Quebec province interesting for CMAMMA research, as it represents the only patient cohort in the world without selection bias.[2] Between 1975 and 2010, an estimated 2 695 000 newborns were thus screened, with 3 detections of CMAMMA. 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.[7] A 2019 study then identified as many as 25 CMAMMA patients in the province of Quebec.[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.[2]

Phenotypic series

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The following diseases also have biochemically elevated levels of malonic acid and methylmalonic acid:

See also

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Notes

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The term combined malonic and methylmalonic aciduria with the suffix -uria (from Greek ouron, urine) has become established in the scientific literature in contrast to the other term combined malonic and methylmalonic acidemia with the suffix -emia (from Greek aima, blood). However, in the context of CMAMMA, no clear distinction is made, since malonic acid and methylmalonic acid are elevated in both blood and urine.

In malonic aciduria, malonic acid and methylmalonic acid are also elevated, which is why it used to be called combined malonic and methylmalonic aciduria (CMAMMA). Although ACSF3 deficiency was not discovered until later, the term combined malonic and methylmalonic aciduria has now become established in medical databases for ACSF3 deficiency.[31][32]

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References

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  22. ^ "Blood and Urine Screening in Newborns". www.quebec.ca. Archived from the original on 2022-05-23. Retrieved 2022-06-15.
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  25. ^ Gabriel, Marie Cosette; Rice, Stephanie M.; Sloan, Jennifer L.; Mossayebi, Matthew H.; Venditti, Charles P.; Al-Kouatly, Huda B. (2021). "Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria". Molecular Genetics & Genomic Medicine. 9 (4): e1621. doi:10.1002/mgg3.1621. ISSN 2324-9269. PMC 8123733. PMID 33625768.
  26. ^ Martini, Paolo G.V.; Guey, Lin T. (2019). "A New Era for Rare Genetic Diseases: Messenger RNA Therapy". Human Gene Therapy. 30 (10): 1180–1189. doi:10.1089/hum.2019.090. ISSN 1043-0342. PMID 31179759. S2CID 182947527.
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  29. ^ Brown, G. K.; Scholem, R. D.; Bankier, A.; Danks, D. M. (1984). "Malonyl coenzyme a decarboxylase deficiency". Journal of Inherited Metabolic Disease. 7 (1): 21–26. doi:10.1007/BF01805615. ISSN 0141-8955. PMID 6145813. S2CID 33045087.
  30. ^ Ozand, P.T.; Nyhan, W.L.; Al Aqeel, A.; Christodoulou, J. (1994). "Malonic aciduria". Brain and Development. 16: 7–11. doi:10.1016/0387-7604(94)90091-4. PMID 7537025. S2CID 4768844.
  31. ^ "COMBINED MALONIC AND METHYLMALONIC ACIDURIA; CMAMMA". OMIM. Retrieved 2024-04-20.
  32. ^ "Combined malonic and methylmalonic acidemia". National Library of Medicine. Retrieved 2024-04-20.
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