Malonyl-CoA decarboxylase deficiency

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 (a fatty acid precursor and a fatty acid oxidation blocker) into Acetyl-CoA and carbon dioxide.

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 (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 malonyl-CoA decarboxylase deficiency.

Some common symptoms in Malonyl-CoA decarboxylase deficiency, such as cardiomyopathy and metabolic acidosis, are triggered by the high concentrations of Malonyl-CoA in the cytoplasm. High level of Malonyl-CoA will inhibits β-oxidation of fatty acids through deactivating the carrier of fatty acyl group, CPT1, and thus, blocking fatty acids from going into the mitochondrial matrix for oxidation.

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.

Genetics

Malonyl-CoA decarboxylase deficiency has an autosomal recessive pattern of inheritance.

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 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 malonyl-CoA decarboxylase deficiency.

Malonyl-CoA decarboxylase deficiency is inherited in an autosomal recessive pattern. 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.

Malonyl-CoA decarboxylase deficiency is extremely rare, evidence suggests that it is caused by the abnormality in the protein transcription regulation. Looking at the molecular basis, two distinct homozygous mutations are found to cause Malonyl-CoA Decarboxylase deficiency 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.

A research has also confirmed that the homozygous mutation which eventually leads to MCD deficiency 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.

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 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). This condition is very rare, as fewer than 20 cases have been reported.

By 1999, only seven cases of Malonyl- CoA decarboxylase deficiency had been reported in human in Australia; however, this deficiency predominately occurs during childhood. Patients from the seven reported cases of Malonyl- CoA decarboxylase deficiency have an age range between 4 days to 13 years, and they all have the common symptom of delayed neurological development. Similar study was conducted in Netherland, and found seventeen reported cases of Malonyl- CoA decarboxylase deficiency in children age range from 8 days to 12 years.

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 MCD deficiency.

Research has found that large amount of MCD are detached in the hypothalamus and cortex of the brain where high levels of lipogenic enzymes are found, indicating that MCD plays a role in lipid synthesis in the brain. Disturbed interaction between Malonyl-CoA and CPT1 may also contributed to abnormal brain development.

Malonyl-CoA decarboxylase plays an important role in the β-oxidation processes in both mitochondria and peroxisome. Some other authors have also hypothesized that it is the MCD deficiency induced inhibition of peroxisomal β-oxidation that contributes to the development delay.

Diagnosis

The diagnosis of malonic aciduria can be made by detecting elevated levels of organic acids (in particular malonic and methylmalonic acid) in the urine and high levels of malonylcarnitine in the blood. The diagnosis is confirmed by demonstrating reduced enzyme activity in cultured skin fibroblasts. Identification of the MLYCD gene mutation may also be useful for diagnosis and for genetic counselling. Antenatal diagnosis Screening of newborns may be possible through detection of elevated blood levels of malonylcarnitine using electrospray ionisation tandem mass spectrometry (ESI-MS/MS). Prenatal screening is theoretically possible through enzyme or DNA analysis of amniocytes or chorionic villus samples.

Treatment

The principle treatment is dietary, with patients being recommended to follow a low fat/high carbohydrate diet. Carnitine supplements may also be recommended.

Prognosis

The prognosis for patients is variable but the disease can be lethal in the neonatal period.

External links

Classification	ICD-10: E72.8 OMIM: 248360 MeSH: C535702 DiseasesDB: 33804
External resources	Orphanet: 943

• Malonyl-CoA decarboxylase deficiency at NLM Genetics Home Reference