Acknowledgement of Molybdenum Cofactor Deficiency has not been added yet.

More than 100 cases of molybdenum cofactor deficiency have been reported. However, it is believed that this condition is underdiagnosed and the numbers are actually higher. Molybdenum deficiency is estimated to occur in 1 in 100,000-200,000 newborns.

 

Name	Abbreviation
Molybdenum cofactor deficiency	MoCD
Combined deficiency of sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase	Molybdenum cofactor deficiency
Combined molybdoflavoprotein enzyme deficiency	Molybdenum cofactor deficiency

Molybdenum cofactor deficiency is caused by mutations in a number of genes including MOCS1, MOCS2, or GPHN. All these genes encode proteins that contribute to the production of a molecule called molybdenum cofactor. MOCS1 mutations are most common, identified in about two-thirds of the affected individuals. A cofactor is a non-protein molecule that is essential for the function of its associated enzyme. As enzymes speed up biological reactions in the body, they are essential for the appropriate breakdown of different molecules. In the case of absence or defect in a cofactor, the enzyme cannot properly break down these molecules which leads to their accumulation in the body which could have toxic levels.

The enzymes that are affected by this condition are called xanthine oxidase and sulfite oxidase. Impairment of the function of these enzymes leads to the accumulation of sulfite, s-sulfocysteine, xanthine, and hypoxanthine molecules as well as reduced amounts of uric acid in the blood. It is suggested that the neurological symptoms of molybdenum cofactor deficiency are due to sulfite accumulation as sulfite is particularly toxic to the brain.

Molybdenum cofactor is an autosomal recessive inherited condition. This means that each parent of the affected individual has one functional copy of the associated gene and one defective copy. An affected individual has inherited the defective gene from both parents, resulting in two defective genes which leads to the presentation of symptoms. Parents with one functional copy are healthy and do not exhibit any symptoms in a recessive disorder.

 

Affected newborns usually appear healthy at birth but symptoms present within the first few days of life. The most common symptoms are seizures that are hard to control (intractable seizures), feeding difficulty and vomiting, screaming episodes, and developmental delay. Less common findings include an abnormally small (microcephaly) or large head (macrocephaly) and coarse facial features such as an elongated face, puffy cheeks, widely-distanced eyes, thick lips, and a small nose.

Molybdenum cofactor deficiency should be suspected in children with atypical facial features, seizures, developmental delay, and low blood uric acid. Further imaging and biochemical tests can help establish the diagnosis.

 

There are a number of biochemical tests that can be utilized in the diagnosis of molybdenum cofactor deficiency. A sulfite strip test is a type of urine analysis in which a specific strip of paper is immersed in a urine sample. If sulfite is present in the urine, the strip will change color. This test can indicate sulfite buildup in the body. An additional diagnostic test involves testing the activity of sulfite oxidase, one of the affected enzymes in molybdenum cofactor deficiency, in specific skin cells called fibroblasts. Molybdenum cofactor deficiency is correlated with a negative sulfite oxidase test which indicates diminished activity of this enzyme. Brain MRIs can be used to supplement biochemical tests and determine the presence of brain abnormalities. Lastly, genetic analysis can identify mutations in MOCS1, MOCS2, or GPHN.

 

Until recently, there were no effective treatments available for the treatment of molybdenum cofactor deficiency. However, recent studies have shown that cyclic pyranopterin monophosphate (cPMP) can be used for the treatment of affected individuals with a MOCS1 mutation. Molybdenum cofactor is synthesized through a series of reactions such that the product of one reaction is required for the next reaction to proceed. cPMP is one of the products in this reaction series which is synthesized by the action of MOCS1 enzyme. If MOCS1 is defective, cPMP cannot be produced and the next reaction cannot proceed to produce the molybdenum cofactor. By cPMP replacement therapy, the defective reaction is effectively bypassed and cPMP can undergo further reactions to produce molybdenum cofactor. Studies have shown that this therapy can reduce toxicity and the effects of MOCS1 deficiency and improve symptoms of molybdenum cofactor deficiency. Although no treatment has been approved yet, the New Drug Application of a cPMP replacement drug was accepted by the FDA to be reviewed for approval. 

 

Molybdenum cofactor deficiency generally has a poor prognosis and affected children usually die within the first few weeks or months of life. However, with the recent development of cPMP replacement therapy, this might change and affected individuals may live longer and experience less severe symptoms. Early diagnosis, ideally before birth, and early treatment initiation is paramount in improving the outlook for the affected children.

 

Tips or Suggestions of Molybdenum Cofactor Deficiency has not been added yet.

Atwal PS, Scaglia F, Molybdenum cofactor deficiency. Molecular Genetics and Metabolism. 2016;117(1):1-4. https://doi.org/10.1016/j.ymgme.2015.11.010.

 

Bayram E, Topcu Y, Karakaya P, et al. Molybdenum cofactor deficiency: Review of 12 cases (MoCD and review). European Journal of Paediatric Neurology. 2013;17(1):1-6. https://doi.org/10.1016/j.ejpn.2012.10.003.

 

Nagappa M, Bindu PS, Taly AB, Sinha S, Bharath RD. Child Neurology: Molybdenum cofactor deficiency Neurology. 2015;85(23):175-178.DOI: 10.1212/WNL.000000000000219

 

Tezel G, Oztekin O, Kalay S. et al. The association of molybdenum cofactor deficiency and pyloric stenosis. J Perinatol. 2012; 32:896–898. https://doi.org/10.1038/jp.2011.192

 

Veldman A, Santamaria-Araujo JA, Sollazzo S, et al. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics. 2010;125 (5):1249-1254. DOI: 10.1542/peds.2009-2192