Combined malonic and methylmalonic aciduria

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

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] 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. [3] Due to being infrequently diagnosed, it most often goes undetected. [3] [4]

Contents

Symptoms and signs

The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms. [5] [6] The underlying pathophysiology is not yet understood. [7] 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. [3] [6]

Causes

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. [6] [5] CMAMMA can be caused by homozygous or compound heterozygous variants in the ACSF3 gene. [5] Based on minor allele frequency (MAF), a population incidence of ~ 1: 30 000 can be predicted for CMAMMA. [3]

Pathophysiology

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. [9]

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. [10] [9] 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. [11] [12] To likely compensate for the cell's energy demand, an upregulation of fatty acid β-oxidation and a decreased concentration of certain amino acids that feed anaplerotically into the citrate cycle, such as glutamine (via the fifth site of the citrate cycle), leucine, isoleucine, threonine (all via the sixth site of the citrate cycle) and aspartate (via the 10th site of the citrate cycle), could be detected. In summary, this reduced mitochondrial respiration and glycolytic flux results in impaired mitochondrial flexibility with a large dependence on fatty acid β-oxidation. [7] [12]

However, neurons, with the exception of hypothalamic neurons, are not capable of satisfying their large energy demands by degrading fatty acids. It is speculated that an upregulation of β-oxidation also occurs in brain cells due to the hypofunctional mtFASII pathway. The consequence would be an increased risk for hypoxia and oxidative stress, which may contribute to neurological symptoms in the long term. [12]

Methylmalonic acid

Mitochondrial methylmalonic acid synthesis Methylmalonic acid synthesis in mitochondrion.png
Mitochondrial methylmalonic acid synthesis

Methylmalonic acid is formed from the essential amino acids valine, methionine, threonine and isoleucine, from odd-chained fatty acids, from propionate and from cholesterol side chain, on the degradation path into the citrate cycle. In this process, the last intermediate methylmalony-CoA can be converted to methymalonic acid by a deacylase before incorporation at the succinyl-CoA site of the citrate cycle. At this point, the acyl-CoA synthease encoded by ACSF3 could convert the methylmalonic acid back to methylmalonyl-CoA and then feed it to the citrate cycle with the help of the methylmalonyl-CoA mutase and its cofactor vitamin B12. However, intracellular esterases are also capable of cleaving the methyl group of methylmalonic acid and generating the parent molecule malonic acid. [13]

Bacterial fermentation in the gut is a quantitatively significant source of propionate, which is a precursor for methylmalonic acid. [14] [15] 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 [16] and dairy products. [17] In addition, methylmalonate is formed during catabolism of thymine. [14] [15]

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. [7]

In vitro, a connection between free methylmalonic acid and malonic acid to neurotoxicity could be established. [18] [13]

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. [1] [2]

Newborn screening programs

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. [6] [3] [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. [19] This 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. [6] 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]

Malonic acid to methylmalonic acid ratio

The use of plasma rather than urine is recommended for determining the ratio of malonic acid to methylmalonic acid. Since even with an increase in sensitivity for malonic acid (MA), concentrations in urine samples can be so subtle that they are easily missed. In contrast, if only urinary methylmalonic acid (MAA) is used as the sole matrix, then CMAMMA due to ACSF3 may be misdiagnosed as classic methylmalonic acidemia. Also the calculation of the MA/MAA ratio in urine is not useful, because due to overlapping, healthy individuals cannot be clearly distinguished from CMAMMA affected individuals. Whereas, by calculating the MA/MMA ratio in plasma, a CMAMMA can be clearly distinguished from a classic methylmalonic acidemia. This is true for both, vitamin B12 responders and non-responders in methylmalonic acidemia. [1]

In CMAMMA, methylamlonic acid levels exceed those of malonic acid. In contrast, in malonic aciduria, the MMA/MA ratio is less than 1. [8] [2]

Genetic testing

Extended carrier screening (ECS) in the course of fertility treatment can also identify carriers of mutations in the ACSF3 gene. [20]

Treatments

Dietary

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

Another quantitatively significant source of malonic acid and methylmalonic acid, in addition to dietary protein intake, is bacterial fermentation. [14] [15] 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 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-Carnitin

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

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. [21] 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. [22] [23]

Research

In 1984, CMAMMA due to malonyl-CoA decarboxylase deficiency was described for the first time in a scientific study. [24] [8] Further studies on this form of CMAMMA followed until 1994, when another form of CMAMMA with normal malonyl-CoA decarboxylase activity was discovered. [25] [8] In 2011, genetic research through exome sequencing identified the ACSF3 gene as a cause of CMAMMA with normal malonyl-CoA decarboxylase. [3] [6] 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]

See also

Notes

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 methylmalonic and malonic aciduria (CMAMMA). Although ACSF3 deficiency was not discovered until later, the term combined methylmalonic and malonic aciduria has now become established in medical databases for ACSF3 deficiency. [26] [27]

Related Research Articles

<span class="mw-page-title-main">Methylmalonic acidemia</span> Medical condition

Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency, is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia.

<span class="mw-page-title-main">Malonic acid</span> Carboxylic acid with chemical formula CH2(COOH)2

Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's diethyl ester. The name originates from the Greek word μᾶλον (malon) meaning 'apple'.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders. Another term used to describe these disorders is "enzymopathies". This term was created following the study of biodynamic enzymology, a science based on the study of the enzymes and their products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Acetyl-CoA carboxylase</span> Enzyme that regulates the metabolism of fatty acids

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the cytoplasm of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs—ACACA and ACACB.

<span class="mw-page-title-main">Malonyl-CoA</span> Chemical compound

Malonyl-CoA is a coenzyme A derivative of malonic acid.

<span class="mw-page-title-main">Malonyl-CoA decarboxylase deficiency</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

<span class="mw-page-title-main">William Nyhan</span> American physician (born 1926)

William Leo Nyhan is an American physician best known as the co-discoverer of Lesch–Nyhan syndrome.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase</span> Mammalian protein found in Homo sapiens

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

<span class="mw-page-title-main">Malonyl-CoA decarboxylase</span> Class of enzymes

Malonyl-CoA decarboxylase, is found in bacteria and humans and has important roles in regulating fatty acid metabolism and food intake, and it is an attractive target for drug discovery. It is an enzyme associated with Malonyl-CoA decarboxylase deficiency. In humans, it is encoded by the MLYCD gene.

<span class="mw-page-title-main">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

<span class="mw-page-title-main">Methylmalonyl-CoA</span> Chemical compound

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle. The compound is sometimes referred to as "methylmalyl-CoA".

In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is converted into fatty acids is derived from carbohydrates via the glycolytic pathway. The glycolytic pathway also provides the glycerol with which three fatty acids can combine to form triglycerides, the final product of the lipogenic process. When only two fatty acids combine with glycerol and the third alcohol group is phosphorylated with a group such as phosphatidylcholine, a phospholipid is formed. Phospholipids form the bulk of the lipid bilayers that make up cell membranes and surrounds the organelles within the cells. In addition to cytosolic fatty acid synthesis, there is also mitochondrial fatty acid synthesis (mtFASII), in which malonyl-CoA is formed from malonic acid with the help of malonyl-CoA synthetase (ACSF3), which then becomes the final product octanoyl-ACP (C8) via further intermediate steps.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

<span class="mw-page-title-main">ACSF3</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA synthetase family member 3 is an enzyme that in humans is encoded by the ACSF3 gene.

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