 | This article needs additional citations for verification .(June 2020) |
| Malonic aciduria | |
|---|---|
| Other names | Malonyl-CoA decarboxylase deficiency, classic CMAMMA |
 | |
| Malonyl-CoA | |
Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive [1] metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA (a fatty acid precursor and a fatty acid oxidation blocker) into acetyl-CoA and carbon dioxide.
The signs and symptoms of this disorder typically appear in early childhood. Almost all affected children have delayed development. Additional signs and symptoms can include weak muscle tone (hypotonia), seizures, diarrhea, vomiting, and low blood sugar (hypoglycemia). A heart condition called cardiomyopathy, which weakens and enlarges the heart muscle, is another common feature of malonic aciduria.
Malonic aciduria is caused by mutations in the MLYCD gene, located on chromosome 16q23.3. [2] The gene encodes the enzyme malonyl-CoA decarboxylase. Within cells, this enzyme helps regulate the formation and breakdown of a certain group of fats called fatty acids.
Many tissues, including heart muscle, use fatty acids as a major source of energy. Mutations in the MLYCD gene reduce or eliminate the function of malonyl-CoA decarboxylase. A lack of this enzyme disrupts the normal balance of fatty acid formation and breakdown. As a result, fatty acids cannot be converted to energy, which can lead to characteristic features of this disorder, such as low blood sugar and cardiomyopathy. By-products of fatty acid processing build up in tissues, which also contributes to the signs and symptoms of malonic aciduria.
Malonic aciduria is inherited in an autosomal recessive pattern. [1] This means that the defective gene is located on an autosome (chromosome 16 is an autosome), and two copies of the defective gene - one inherited from each parent - are required to be born with the disorder. The parents of a child with an autosomal recessive disorder both carry one copy of the defective gene, but are usually not affected by the disorder.
Malonic aciduria is extremely rare, evidence suggests that it is caused by the abnormality in the protein transcription regulation. [3] Looking at the molecular basis, two distinct homozygous mutations are found to cause malonic aciduria in human. The first mutation is the transversion of gene from C to G causing a premature stop signal in the protein. The second mutation is a base pair insertion in the mature RNA that will eventually result in the protein truncation. [4]
A research has also confirmed that the homozygous mutation which eventually leads to malonic aciduria is caused by the isodisomy of maternal UPD. This indicates that such disease is likely to be inherited from mother’s gene profile, not from paternal source. [5]
According to Orphanet (2006), the prevalence is less than 1 in 1,000,000. [6]
In 1984, malonic aciduria was described for the first time in a scientific study. [7]
By 1999, only seven cases of malonic aciduria had been reported in human in Australia; however, this deficiency predominately occurs during childhood. Patients from the seven reported cases of malonic aciduria have an age range between 4 days to 13 years, and they all have the common symptom of delayed neurological development. [4]
By 2006, 17 cases of malonic aciduria had been published in the literature worldwide, ranging in age from 8 days to 12 years. [3]
By 2017, less than 30 cases were known in the literature. [8]
Malonyl-CoA decarboxylase acts as a catalyst in the conversion of malonyl-CoA to acetyl-CoA and CO2. [9] Without the enzymatic activity of malonyl-CoA decarboxylase, cellular malonyl-CoA increases so dramatically that at the end it is instead broken down by an unspecific short-chain acyl-CoA hydrolase, which produces malonic acid and CoA. Malonic acid is a Krebs cycle inhibitor, preventing the cells to make ATP through oxidation. In this condition, the cells, to make ATP, are forced to increase glycolysis, which produces lactic acid as a by-product. The increase of lactic and malonic acid drastically lowers blood pH, and causes both lactic and malonic aciduria (acidic urine). It is also speculated that the excess of mitochondrial malonyl-CoA increases the methylmalonic acid level, which is due to an inhibitory effect on the methylmalonyl-CoA mutase. [10] [11]
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. [3] The inhibitory effect of cytoplastic malonyl-CoA on CPT1 varies, so it inhibits roughly 100-fold greater in cardiac and skeletal muscles than in the liver. [12]
Some common symptoms in malonic aciduria, such as cardiomyopathy and metabolic acidosis, are triggered by the high concentrations of malonyl-CoA in the cytoplasm.
Although we have not yet gained a clear understanding of the pathogenic mechanism of this deficiency, some researchers have suggested a brain-specific interaction between malonyl-CoA and CTP1 enzyme which may leads to unexplained symptoms of the malonic aciduria. [5]
Research has found that large amount of malonyl-CoA carboxylase are detached in the hypothalamus and cortex of the brain where high levels of lipogenic enzymes are found, indicating that malonyl-CoA decarboxylase plays a role in lipid synthesis in the brain. [3] Disturbed interaction between malonyl-CoA and CPT1 may also contributed to abnormal brain development. [3]
Malonyl-CoA decarboxylase plays an important role in the β-oxidation processes in both mitochondria and peroxisome. [4] Some other authors have also hypothesized that it is the Malonyl-CoA carboxylase deficiency induced inhibition of peroxisomal β-oxidation that contributes to the development delay. [4]
Screening for elevated organic acids, especially malonic acid and methylmalonic acid and for high malonylcarnitine. [6] The diagnosis can then be confirmed by determining the enzyme activity of malonyl-coA decarboxylase in cultured skin fibroblasts. [6] Molecular genetic testing of the MLYCD gene may also be useful. [6]
By calculating the malonic acid to methylmalonic acid ratio in blood plasma, malonic aciduria can be clearly distinguished from combined malonic and methylmalonic aciduria (CMAMMA) and classic methylmalonic acidemia. [13] The latter applies for both, vitamin B12 responders and non-responders in methylmalonic acidemia. [13] In malonic aciduria, the results of the ratio are greater than 1, as the malonic acid value is higher than the methylmalonic acid value. [3] In CMAMMA, on the other hand, the result is less than 1 because the methylmalonic acid is higher than the malonic acid. [10]
A research conducted in Netherlands has suggested that carnitine supplements and a low fat diet may help to reduce the level of malonic acid in our body. [5]
As both malonic acid and methylmalonic acid levels are elevated in malonic aciduria, it used to be referred to as 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. [14] [15]
Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.
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.
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.
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.
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.
Malonyl-CoA is a coenzyme A derivative of malonic acid.
Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products can accumulate and cause damage to the brain, but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.
Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT-II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source. The disorder presents in one of three clinical forms: lethal neonatal, severe infantile hepatocardiomuscular and myopathic.
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.
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.
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.
Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.
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".
Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often Palmitoylcarnitine, but other fatty acids may also be substrates. It is part of a family of enzymes called carnitine acyltransferases. This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.
Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.
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.
Methylmalonate-semialdehyde dehydrogenase [acylating], mitochondrial (MMSDH) is an enzyme that in humans is encoded by the ALDH6A1 gene.
Acyl-CoA synthetase family member 3 is an enzyme that in humans is encoded by the ACSF3 gene.
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. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). 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.
