Author: Geetanjali Rathore, MD
University of Nebraska Medical Center 
Children’s Hospital and Medical Center, Omaha, NE  

Reviewed: July 2021 

SUMMARY

Molybdenum cofactor deficiency (MoCD) type A is a rare but devastating metabolic disease. It first appears in the newborn period. It is estimated to affect 1 in 200,000 newborns worldwide. 

MoCD typically appears in the first few weeks of life as: 

• Seizures 
• Difficulty feeding 

MoCD type A is rapidly progressive. It causes severe developmental delay and death within the first 4 years of life. A gene abnormality is responsible for MoCD. The changed gene causes a toxic sulfite to collect in the brain. The sulfite leads to brain dysfunction. An early diagnosis is critical to any chance of improving outcomes.  

Disorder Overview

DESCRIPTION 

There are three forms of MoCD. They are named types A, B, and C. MoCD type A is the most common form and the only one for which there is definitive therapy that improves outcome. 

The three forms have the same signs and symptoms. They are distinguished only by their genetic cause:  

• MOCS1 gene mutations cause type A 
• MOCS2 gene mutations cause type B 
• GPHN gene mutations cause type C 

MoCD should be considered a possible diagnosis in infants with any of the following symptoms: 

• Profound developmental delay 
• Neonatal seizures 
• Dysmorphic facial features 
• Dislocated eye lenses 

The majority of children with MoCD die of the illness within the first few days or weeks of life. There are some reports of a milder form, with survival into adult life. There are also very rare reports of asymptomatic cases. 

SIGNS AND SYMPTOMS

Babies with this condition can appear normal at birth. However, within a week they develop seizures. The seizures do not improve with treatment. They are called intractable seizures.  

Over the course of illness, the infant can have: 

• Frequent, intractable seizures 
• Abnormal muscle tone (increased or decreased) 
• Difficulty feeding  
• Extreme fussiness 
• Exaggerated startle 
• Small head size (microcephaly) 
• Facial features that may be coarse, with puffy cheeks/lips, a long face, and widely spaced eyes 
• Dislocation of the eye lenses  

Affected babies usually do not survive past early childhood. 

CAUSES

LABORATORY INVESTIGATIONS 

Diagnosing MoCD 

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.  

Other Investigations 

TREATMENT AND THERAPIES  

New Medicine for MoCD Type A 

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.  

Other Treatments 

Several other treatments are sometimes used for children with MoCD. 

OUTLOOK

MoCD type A is a rapidly progressive genetic disease. It cannot be outgrown. It has a high infant mortality rate. The median survival age is 3 years without treatment.  

Those who survive beyond the first few months without treatment often have severe developmental delays. This makes them highly dependent on others for assistance in tasks of daily living.  In addition, seizures are often frequent, daily, and disabling.  They can be very difficult to control.  Frequent hospitalizations are common. 

Early treatment with fosdenopterin has been shown to improve survival and reduce symptoms, including seizures. For this reason, it is critical to diagnose and treat MoCD type A as soon as possible.  

Ongoing interventions for MoCD type A will likely include: 

• Daily injections of fosdenopterin  
• Supportive measures, such as physical, occupational, and speech therapy 
• Modifications in school, based on cognition and severity of disease 

RELATED DISORDERS

MoCD may be confused with other more common newborn seizure disorders. These disorders may look like MoCD type A in terms of clinical observations and brain images. They can be distinguished based on the blood and genetic testing. Lookalikes include: 

• Hypoxic-ischemic encephalopathy (HIE). HIE stems from decreased oxygen to the brain around birth.  
• Isolated sulfite oxidase deficiency (ISOD). Like MoCD, this is a genetic disorder.  

Research 

ClincalTrials.gov for MoCD Type A are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently.  

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.   

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits.  

Nagappa M, Bindu PS, Taly AB, Sinha S, Bharath RD. Child neurology: Molybdenum cofactor deficiency. Neurology. 2015 Dec 8;85(23):e175–8. https://doi.org/10.1212/WNL.0000000000002194   

Molybdenum cofactor deficiency, complementation group A; MOCODA. In: OMIM (Online Mendelian Inheritance in Man) [Genetic database]. https://www.omim.org/entry/252150