Molybdenum cofactor deficiency – MOCS1, MOCS2, or GPHN genes
The deficiency of the molybdenum cofactor is a rare disease characterized by encephalopathy that gets worse over time. Affected newborns appear normal at birth, but after one week they have difficulty feeding and develop seizures that do not improve with treatment. Brain abnormalities, including brain tissue atrophy, result in severe developmental delay. Because of this, affected individuals usually do not learn to sit or talk without help. Additional features may include hyperplexia (exaggerated abrupt onset of movement response), microcephaly, and prominent facial features.
The tests reveal that the affected individuals have high concentrations of sulfite, S-sulfocysteine, xanthine and hypoxanthine in the urine, as well as low concentrations of uric acid in the blood. In general, due to the serious health problems associated with the deficiency of the molybdenum cofactor, the affected people do not survive beyond early childhood.
The deficiency of the molybdenum cofactor is due to mutations in the MOCS1, MOCS2 and GPHN genes. There are three forms of the disease, types called A, B, and C (or complementation groups A, B, and C). The three forms have the same signs and symptoms but are distinguished by their genetic cause. The proteins encoded from each of these genes are involved in the biosynthesis of the molybdenum cofactor. The molybdenum cofactor, which contains the molybdenum element, is essential for the function of the enzymes sulfite oxidase, aldehyde oxidase, xanthine dehydrogenase and amidoxime mitochondrial reducing component (MARC). These enzymes help metabolize different substances in the body, some of which are toxic if they are not metabolized.
Mutations in the MOCS1, MOCS2 and GPHN genes reduce or eliminate the function of the associated protein, which damages the biosynthesis of the molybdenum cofactor. Without the cofactor, the metabolic enzymes that depend on this cofactor cannot work. The resulting loss of enzyme activity leads to the accumulation of certain chemicals, including sulfite, S-sulfocysteine, xanthine, and hypoxanthine, and low concentrations of uric acid. Sulfite, which is normally broken down by sulfite oxidase, is toxic, especially to the brain. It is believed that damage caused by abnormally high concentrations of sulfite, and possibly other chemicals, leads to encephalopathy, seizures, and other characteristics of molybdenum cofactor deficiency.
The MOCS1 gene, located on the short arm of chromosome 6 (6p21.3), encodes two different proteins, MOCS1A and MOCS1B, involved in the biosynthesis of the molybdenum cofactor. Specifically, MOCS1A and MOCS1B perform the first of a series of reactions that produce the cofactor, although the function of the MOCS1B protein in this process is not completely understood. At least 32 mutations have been identified in the MOCS1 gene that give rise to type A or complementation group A. This is the most common form of the disease, representing approximately two-thirds of the cases.
The MOCS2 gene, located on the long arm of chromosome 5 (5q11), encodes the MOCS2A and MOCS2B proteins, which combine to form the enzyme molybdopterin synthase. This enzyme performs the second of a series of reactions in the biosynthesis of the molybdenum cofactor. At least 12 mutations have been identified in the MOCS2 gene responsible for type B or complementation group B. These genetic changes eliminate the function of the MOCS2A protein, the MOCS2B protein, or both, although in rare cases that are less severe, it can remain part of the function of proteins. Without the enzyme molybdopterin synthase, the biosynthesis of the molybdenum cofactor deteriorates, which impedes the function of the metabolic enzymes that depend on it.
The GPHN gene, located in the arm of chromosome 14 (14q23.3), encodes the gephyrin protein, which has two main functions in the body: contributing to the biosynthesis of the molybdenum cofactor and participating in the communication between the neurons. Gephyrin performs the final two steps in the biosynthesis of molybdenum cofactor. In addition, gephyrin also plays an important role in neurons, participating in the transmission of signals, a process in which neurons release neurotransmitters, which bind to receptor proteins in neighboring neurons. Gephyrin anchors certain receptor proteins to the correct location in the neurons so that the receptors can receive the signals transmitted by the neurotransmitters. At least 2 mutations have been identified in the GPHN gene responsible for the so-called type C or complementation group C. This is the rarest form of the disease, which affects only a small number of individuals. These genetic changes probably reduce or eliminate the function of gephyrin, which impairs the ability of gephyrin to carry out either or both of the last two steps of molybdenum cofactor biosynthesis. Without the cofactor, the metabolic enzymes that depend on it cannot work.
The deficiency of the molybdenum cofactor has a pattern of autosomal recessive inheritance, which means that both copies of the gene in each cell must have the mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. At least one person with a molybdenum cofactor deficiency has inherited two mutated copies of the MOCS1 gene through a mechanism called uniparental isodysomy. In this case, an error occurred during the formation of the ovum or sperm, and the child received two copies of the mutated gene from one of the parents instead of a copy of each parent.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Molybdenum cofactor deficiency by means of the complete PCR amplification of the exons of the MOCS1, MOCS2 or GPHN genes, respectively, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).