Malonyl-CoA decarboxylase deficiency
Encyclopedia
Malonyl-CoA decarboxylase deficiency (MCD), or Malonic aciduria is an autosomal
recessive metabolic disorder
caused by a genetic mutation which 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
.
), seizure
s, diarrhea
, vomiting, and low blood sugar (hypoglycemia
). A heart condition called cardiomyopathy
, which weakens and enlarges the heart muscle, is another common feature of malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase deficiency is caused by mutations in the MLYCD gene, located on chromosome
16q24
. 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 acid
s.
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 malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase deficiency is inherited in an autosomal recessive pattern. This means 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.
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). This condition is very rare, as fewer than 20 cases have been reported.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive metabolic disorder
Inborn error of metabolism
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others...
caused by a genetic mutation which disrupts the activity of Malonyl-Coa decarboxylase
Malonyl-CoA decarboxylase
Malonyl-CoA decarboxylase is an enzyme associated with Malonyl-CoA decarboxylase deficiency.It catalyzes the conversion of malonyl-CoA into acetyl-CoA and carbon dioxide.To some degree, it reverses the action of Acetyl-CoA carboxylase....
. This enzyme breaks down Malonyl-CoA
Malonyl-CoA
Malonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
(a fatty acid precursor and a fatty acid oxidation blocker) into Acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
.
Signs and symptoms
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 (hypotoniaHypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
), seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, vomiting, and low blood sugar (hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
). A heart condition called cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
, which weakens and enlarges the heart muscle, is another common feature of malonyl-CoA decarboxylase deficiency.
Cause and Genetics
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
16q24
Chromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
. 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 acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s.
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 malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase deficiency is inherited in an autosomal recessive pattern. This means the defective gene is located on an autosome
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
(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.
Pathophysiology
Without the enzymatic activity of Malonyl-CoA decarboxylase, cellular Mal-CoA increases so dramatically that at the end it is instead broken down by an unspecific short-chain acyl-CoA hydrolase which produces malonic acidMalonic acid
Malonic acid is a dicarboxylic acid with structure CH22. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester...
and CoA. Malonic acid is a krebs cycle inhibitor preventing the cells to make ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
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
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, and causes both lactic and malonic aciduria (acidic urine). This condition is very rare, as fewer than 20 cases have been reported.