Molybdenum cofactor deficiency

Molybdenum cofactor deficiency is a rare and life-limiting genetic disorder characterized by rapidly progressive brain dysfunction, seizures that resist treatment, and severe developmental delays beginning shortly after birth.

Overview

Molybdenum cofactor deficiency is a rare condition characterized by brain dysfunction (encephalopathy) that worsens over time. It is estimated to occur in 1 in 100,000 to 200,000 newborns worldwide. While more than 100 cases have been reported in the medical literature, the condition is thought to be underdiagnosed, meaning the actual number of affected individuals may be higher. Because of the serious health problems caused by this deficiency, affected individuals usually do not survive past early childhood.

Symptoms

Babies with molybdenum cofactor deficiency appear normal at birth, but within a week they develop severe symptoms, including:

• Difficulty feeding.
• Seizures that do not improve with treatment (intractable seizures).
• Severe developmental delay caused by brain abnormalities, including the deterioration (atrophy) of brain tissue; affected individuals usually do not learn to sit unassisted or to speak.
• An exaggerated startle reaction (hyperekplexia) to unexpected stimuli, such as loud noises, in a small percentage of affected individuals.
• A small head size (microcephaly).
• Facial features described as "coarse."

Laboratory tests of affected individuals typically reveal abnormal chemical levels:

• High levels of chemicals called sulfite, S-sulfocysteine, xanthine, and hypoxanthine in the urine.
• Low levels of a chemical called uric acid in the blood.

Causes & Genetic Factors

Molybdenum cofactor deficiency is caused by mutations in the MOCS1, MOCS2, or GPHN gene. There are three forms of the disorder, which present with the same signs and symptoms but are distinguished by their genetic cause:

• Type A: Caused by mutations in the MOCS1 gene.
• Type B: Caused by mutations in the MOCS2 gene.
• Type C: Caused by mutations in the GPHN gene.

The proteins produced from these genes are involved in the formation (biosynthesis) of a molecule called molybdenum cofactor. This cofactor, which contains the element molybdenum, is essential to the function of several enzymes that help break down (metabolize) different substances in the body, some of which are toxic if not metabolized.

Mutations in these genes reduce or eliminate the function of the associated protein, which impairs molybdenum cofactor biosynthesis. Without the cofactor, the metabolic enzymes that rely on it cannot function. This loss of enzyme activity leads to a buildup of sulfite, S-sulfocysteine, xanthine, and hypoxanthine, and low levels of uric acid in the blood. Sulfite, which is normally broken down by one of the molybdenum cofactor-dependent enzymes, is highly toxic, especially to the brain. Researchers suggest that damage caused by abnormally high levels of sulfite (and possibly other chemicals) leads to encephalopathy, seizures, and the other features of the condition.

Inheritance

This condition is typically inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. An affected individual usually inherits one altered copy of the gene from each parent. Parents of an individual with an autosomal recessive condition typically do not show signs and symptoms of the condition.

At least one individual with molybdenum cofactor deficiency inherited two mutated copies of the MOCS1 gene through a mechanism called uniparental isodisomy. In this case, an error occurred during the formation of egg or sperm cells, causing the child to receive two copies of the mutated gene from one parent instead of one copy from each parent.

Other Names for This Condition

• Combined deficiency of sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase
• Combined molybdoflavoprotein enzyme deficiency
• Combined xanthine oxidase and sulfite oxidase and aldehyde oxidase deficiency
• Deficiency of molybdenum cofactor
• MOCOD