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 levels of Malonyl-CoA will inhibit 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 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.
The committee stated that there was not enough evidence supporting efficacy of the drug, and requested additional clinical trials.In August 2018, the FDA approved patisiran, an siRNA-based treatment, at an expected cost of up to $450,000 per year.In August 2021 six patients with hereditary ATTR amyloidosis with polyneuropathy were given doses of NTLA-2001, based on a CRISPR gene editing system. Researchers reported mild adverse events and decreases in serum misfolded transthyretin protein concentrations through targeted knockout. Prognosis
In the absence of a liver transplant, FAP is invariably fatal, usually within a decade. The disadvantage of liver transplantation is that approximately 10% of the subjects die from the procedure or complications resulting from the procedure, which is a form of gene therapy wherein the liver expressing wild type and mutant TTR is replaced by a liver only expressing wild type TTR. Moreover, transplanted patients must take immune suppressants (medications) for the remainder of their life, which can lead to additional complications. In late 2011, the European Medicines Agency approved the transthyretin kinetic stabilizer Tafamidis or Vyndaqel discovered by Jeffery W. Kelly and developed by FoldRx pharmaceuticals (acquired by Pfizer in 2010) for the treatment of FAP based on clinical trial data. Tafamidis (20 mg once daily) slowed the progression of FAP over a 36-month period and importantly reversed the weight loss and muscle wasting associated with disease progression.