Molybdenum Cofactor Deficiency Type A

Synonyms

MoCD Type A, 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,

Overview

Molybdenum cofactor deficiency is a rare condition characterized by brain dysfunction (encephalopathy) that worsens over time. Babies with this condition appear normal at birth, but within a week they have difficulty feeding and develop seizures that do not improve with treatment (intractable seizures). Brain abnormalities, including deterioration (atrophy) of brain tissue, lead to severe developmental delay; affected individuals usually do not learn to sit unassisted or to speak. A small percentage of affected individuals have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli such as loud noises.

Other features of molybdenum cofactor deficiency can include a small head size microcephaly and facial features that are described as “coarse.”

Tests reveal that affected individuals have high levels of chemicals called sulfite, S-sulfocysteine, xanthine, and hypoxanthine in the urine and low levels of a chemical called uric acid in the blood.

Because of the serious health problems caused by molybdenum cofactor deficiency, affected individuals usually do not survive past early childhood.

Symptoms

Causes

Molybdenum cofactor deficiency is caused by mutations in the MOCS1, MOCS2, or GPHN gene. There are three forms of the disorder, named types A, B, and C (or complementation groups A, B, and C). The forms have the same signs and symptoms but are distinguished by their genetic cause: MOCS1 gene mutations cause type A, MOCS2 gene mutations cause type B, and GPHN gene mutations cause type C. The proteins produced from each of these genes are involved in the formation (biosynthesis) of a molecule called molybdenum cofactor. Molybdenum cofactor, which contains the element molybdenum, is essential to the function of several enzymes. These enzymes help break down (metabolize) different substances in the body, some of which are toxic if not metabolized.

Mutations in the MOCS1, MOCS2, or GPHN gene 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.

The resulting loss of enzyme activity leads to buildup of certain chemicals, including sulfite, S-sulfocysteine, xanthine, and hypoxanthine (which can be identified in urine), and low levels of uric acid in the blood. Sulfite, which is normally broken down by one of the molybdenum cofactor-dependent enzymes, is toxic, especially to the brain. Researchers suggest that damage caused by the abnormally high levels of sulfite (and possibly other chemicals) leads to encephalopathy, seizures, and the other features of molybdenum cofactor deficiency.

Molybdenum cofactor deficiency has an autosomal recessive pattern of inheritance

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, and the child received two copies of the mutated gene from one parent instead of one copy from each parent.

Diagnosis

When doctors suspect MoCD based what they observe in the baby, they use testing to learn more. Key biochemical markers can point to MoCD: 

• Elevated sulfites (in urine test) 
• Elevated S-sulfocysteine (in urine test) 
• Low uric acid (in blood or urine test) 
• High levels of xanthine and hypoxanthine (in blood test) 

Finally, genetic testing can confirm the diagnosis and type of MoCD.  

Prognosis

The infant mortality rate for MoCD Type A is high, and median survival age is 4 years. Those who survive beyond the first few months often have severe developmental delays. MoCD is a rare IEM. Individually, IEMs are uncommon, but when combined, they rise to a rate of 1:1000

Treatment

Until recently, the only treatment options for MoCD included supportive care and therapy for complications. The first drug treatment, fosdenopterin, was approved in 2021 for treating MoCD type A by the FDA.  

It is only effective at treating MoCD type A, not the other types. Lifelong therapy is recommended. Starting treatment as early as possible is recommended. This can reduce disease severity, as the brain injury is irreversible.