Molybdenum Cofactor Deficiency

Disease Overview

Summary

Molybdenum cofactor deficiency (MoCD) is a rare genetic condition that affects the brain and nervous system. There are three subtypes of MoCD, each due to changes (pathogenic variants) in different genes. MoCD, type A is due to variants in the MOCS1 gene, MoCD type B is due to variants the MOCS2 gene and MoCD, type C is due to variants in the GPHN gene. MoCD type A accounts for about half of the cases of MoCD, while most of the other cases are type B. Type C has only been diagnosed in a couple of families.

MoCD type A and type B have an early-onset form and a later-onset form. The three subtypes of MoCD are inherited in an autosomal recessive pattern in families.

All of the symptoms of MoCD are due to the buildup of sulfite in the body, a chemical toxic to the brain and nervous system.

Early-onset MoCD

The symptoms of early-onset MoCD type A or B are identical and begin in the first few weeks after birth. Type C is associated with severe, early-onset disease. The first signs of brain damage include frequent seizures that don’t improve with anti-seizure medication and feeding difficulties. In a short time, babies with MoCD start having muscle spasms and stiffness and develop an exaggerated startle reaction. Some of the other features include loss of consciousness, trouble breathing and loss of vision. Some children with MoCD have characteristic facial features that are sometimes described as coarse. Without treatment, many children with this condition die in infancy or early childhood.

Late-onset MoCD

The late-onset form of MoCD, types A and B, tends to have milder symptoms beginning later in infancy or even adulthood. The first symptoms typically appear after or during an illness in the first year of life. These include uncontrollable muscle movements, weakness and developmental delay. Seizures are less common in the late-onset form. Symptoms may go away and return with another illness. Late-onset MoCD affects people differently and in some individuals the symptoms get better with time, while others have symptoms that get progressively worse. There have been very few individuals diagnosed with the late-onset form of MoCD, so the course of this condition is not well understood. Treatment is based on managing the symptoms.

Fosdenopterin (Nulibry) is a medication approved by the U.S. Food and Drug Administration (FDA) that can help improve survival in babies with MoCD type A.

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Synonyms

combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase
encephalopathy due to sulfite oxidase deficiency
combined molybdoflavoprotein enzyme deficiency
combined xanthine oxidase and sulfite oxidase and aldehyde oxidase deficiency
deficiency of molybdenum cofactor

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Subdivisions

molybdenum cofactor deficiency (MoCD) type A
molybdenum cofactor deficiency (MoCD) type B
molybdenum cofactor deficiency (MoCD) type C

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Signs & Symptoms

Early-onset MoCD

The early-onset form of MoCD is the most common and considered the classic form. Both MoCD types A and B include an early-onset form with symptoms appearing in the first two weeks after birth. The first symptoms include seizures that are difficult to treat and feeding difficulties. Soon after, infants with MoCD develop muscle spasms that cause the spine and neck to arch, rigid or stiff muscles, muscle weakness and an excessive startle reaction to noise or touch. About two thirds of infants with MoCD have characteristic facial features, including a prominent forehead, flattened nasal bridge, thick lips and widely spaced eyes. Over time, brain damage builds up causing brain and head growth to slow. This results in a head size that is smaller than average (acquired microcephaly). Children who survive past one year of age have severe developmental and intellectual delay, eye abnormalities, including blindness and displacement of the lens of the eye and frequent seizures. Most children die by age 2-3 due to complications of their condition. The few individuals that have been reported with MoCD type C have been described as having a similarly severe form of this condition.

Late-onset MoCD

The late-onset form is less common, and has also been described in patients with both MoCD type A and MoCD type B. The symptoms of the late-onset form can be different from person to person. Some individuals have mild symptoms, while others develop severe brain damage. Symptoms of the late-onset form typically begin before age 2, and often occur during, or right after an illness. These can include involuntary muscle movements, low muscle tone, stiffness, changes in thinking and developmental issues. Displacement of the lens of the eye (ectopia lentis) can occur in older individuals. Seizures are less common than in the early-onset form. In some individuals, the symptoms will get better, but may come back with another illness. Because there have not been many individuals described with late-onset MoCD, the long-term outlook is not well known.

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Causes

MoCD is caused by disease-causing (pathogenic) variants in the MOCS1 gene (type A), the MOCS2 gene (type B) or the GPHN gene (type C). Variants in the MOCS3 gene have also been reported as a rare cause of MoCD type B. Variants in any one of these genes can disrupt the way the body processes sulfur and sulfur-containing compounds. The resulting accumulation of sulfites in the body is toxic to nerve cells and white matter in the brain and causes nervous system and brain damage that gets worse over time.

All types of MoCD are inherited in a recessive pattern in families. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease like the parents, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

MoCD is extremely rare and the exact number of people with this condition is unknown. Less than 200 patients have been reported in the medical literature, and it has been diagnosed in people from all ethnic and racial groups. About half of the patients described have MoCD type A, and most of the rest have MoCD type B. Type C has only been described in a few families. It has been estimated that about 1 in 100,000 to 1 in 200,000 people are born with MoCD.

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Disorders with Similar Symptoms

Isolated sulfite oxidase deficiency (ISOD) has very similar symptoms to MoCD and also has an early-onset and late-onset form. The classic early-onset form begins in infancy with symptoms that include seizures that are difficult to treat and feeding difficulties. Individuals with ISOD develop brain damage that gets worse with time. Involuntary muscle movements, muscle stiffness, breathing difficulties and unusual spine and neck arching can occur. Over time, babies with classic ISOD stop responding to their environment except for an exaggerated startle reflex. They usually do not live for more than a few months. Affected individuals who survive past infancy usually develop displacement of the eye lens (ectopia lentis). In the less common, late-onset form, symptoms occur after an illness, and include muscle spasms, low muscle tone, vison problems and developmental delay. In some individuals, the symptoms go away, and in others, the symptoms get worse. The long-term outlook for people with late-onset ISOD is unknown because it is so rare. ISOD is caused by variants in the SUOX gene and is inherited in an autosomal recessive pattern in families. Laboratory and genetic testing are necessary to distinguish between MoCD and ISOD.

Disorder of pyridoxine metabolism includes two forms, and both can be similar to MoCD.

Pyridoxine-dependent epilepsy (PDE) is a rare cause of difficult to control (intractable) seizures appearing in newborns, infants and sometimes older children. About 200 patients have been reported in the medical literature. PDE has a variety of forms with signs and symptoms that can be different from person to person. The one clinical feature characteristic of all patients with PDE is intractable seizures that are not controlled with anticonvulsant drugs, but which do respond clinically and usually on EEG (electroencephalographically) to large daily supplements of pyridoxine. These patients are not pyridoxine deficient. They are metabolically dependent on vitamin B-6. In other words, even though they get the recommended daily allowance of pyridoxine from their normal diet, they require substantially more of the vitamin than an otherwise normal individual. Patients with PDE require pyridoxine therapy for life. PDE is caused by variants in the ALDH7A1 gene or variants in the PLPBP gene which is called PLPBP deficiency. Inheritance is autosomal recessive.

Pyridoxine-dependent epilepsy caused by ALDH7A1 gene variants are treated with supplements of pyridoxine; it is a lifelong treatment. To prevent worsening of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days.

PLPBP deficiency is a treatable early-onset seizure disorder. Seizures usually begin in infancy, although they may begin later in childhood after the newborn period. Seizures are unresponsive to (or only partly responsive to) anti-seizure medications (ASMs) but typically show an immediate positive response to vitamin B6, given as either pyridoxine (PN) or pyridoxal 5′-phosphate (PLP). This therapy needs to be continued lifelong. In addition to vitamin B6 treatment, almost 60% of individuals require ASMs to achieve optimal seizure control.

Although many individuals with PLPBP deficiency have normal motor, speech and intellectual development, more than half have some degree of neurodevelopmental issues, including learning difficulties or intellectual disability (varying from mild to severe), delayed or absent speech development or motor development abnormalities (most commonly mild hypotonia).

(For more information on this disorder, choose “pyridoxine-dependent epilepsy” as your search term in the Rare Disease Database.)

Pyridoxal phosphate-responsive seizures or PPNO deficiency is characterized by seizures that start before two weeks of age. The seizures occur along with muscle contractions and low muscle tone. Many individuals with PNPO deficiency have developmental issues that affect speech, thinking and behavior. The symptoms tend to be worse in people with PNPO deficiency who were diagnosed late and had long periods of uncontrolled seizures. PNPO deficiency is caused by variants in the PNPO gene and is inherited in an autosomal recessive pattern in families. Seizures in this condition do not respond to seizure medication but can be treated with large doses of a form of vitamin B6. This condition is extremely rare and has only been reported in a couple dozen families.

The symptoms of hypoxic-ischemic brain injury, a type of brain damage that occurs when the brain doesn’t get enough oxygen or blood flow, can also look like the symptoms of MoCD. Brain imaging and laboratory testing can be helpful for telling the two conditions apart.

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Diagnosis

MOCD is diagnosed based on the symptoms, clinical examination, a detailed family history and laboratory testing. Laboratory tests include blood tests looking for a decreased level of uric acid and urine tests looking for high levels of chemicals called sulfite, S-sulfocysteine, xanthine and hypoxanthine. In addition, an MRI of the brain can be helpful for looking for differences between hypoxic-ischemic brain injury and MoCD.

Because the symptoms of MoCD can be similar to other seizure disorders, genetic testing is necessary to ultimately confirm a diagnosis. This is especially important for diagnosing MoCD type A which has a specific treatment, and needs to be distinguished from MoCD B and C. Because the symptoms of MoCD can look like several other conditions, doctors often use a gene panel to help with diagnosis. Gene panels test for multiple genetic conditions that have the same or similar symptoms. Genetic testing is usually done on a blood or saliva sample. Genetic counseling is recommended to discuss the risk, benefits and limitations of genetic testing.

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Standard Therapies

There is no cure for MoCD. Treatment is based on managing the symptoms. Many different types of specialists may be involved in the care of people with MoCD, including neurologists, developmental specialists, nutritionists, ophthalmologists and gastroenterologists.

For individuals with MoCD type A, fosdenopterin (Nulibry) is an FDA-approved drug that has been shown to improve survival. The earlier this treatment is started, the more effective it is. Treatment involves daily injections of Nulibry through a port placed under the individual’s skin.

A protein-restricted diet may improve outcomes for individuals with all types of MoCD. Other treatment is based on improving the quality of life and reducing complications.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Markose AP, Gowda VK, Reddy VS, Srinivasan VM. Molybdenum cofactor deficiency (MoCD) masquerading as stroke-like episodes. Indian J Pediatr. Published online December 28, 2023. doi:10.1007/s12098-023-05002-z

Oskarsson A, Kippler M. Molybdenum – a scoping review for Nordic nutrition recommendations 2023. Food Nutr Res. 2023;67:10.29219/fnr.v67.10326. Published 2023 Dec 14. doi:10.29219/fnr.v67.10326

Almudhry M, Prasad AN, Rupar CA, et al. A milder form of molybdenum cofactor deficiency type A presenting as Leigh’s syndrome-like phenotype highlighting the secondary mitochondrial dysfunction: a case report. Front Neurol. 2023;14:1214137. Published 2023 Sep 15. doi:10.3389/fneur.2023.1214137

Lucignani G, Vattermoli L, Rossi-Espagnet MC, et al. A new pattern of brain and cord gadolinium enhancement in molybdenum cofactor deficiency: A case report. Children (Basel). 2023;10(6):1072. Published 2023 Jun 17. doi:10.3390/children10061072

Tofilo M, Voronova N, Nigmatullina L, et al. Live birth of a healthy child in a couple with identical mtDNA carrying a pathogenic c.471_477delTTTAAAAinsG variant in the MOCS2 gene. Genes (Basel). 2023;14(3):720. Published 2023 Mar 15. doi:10.3390/genes14030720

Johannes L, Fu CY, Schwarz G. Molybdenum cofactor deficiency in Humans. Molecules. 2022;27(20):6896. Published 2022 Oct 14. doi:10.3390/molecules27206896

Spiegel R, Schwahn BC, Squires L, Confer N. Molybdenum cofactor deficiency: A natural history. J Inherit Metab Dis. 2022;45(3):456-469. doi:10.1002/jimd.12488

Farrell S, Karp J, Hager R, et al. Regulatory news: Nulibry (fosdenopterin) approved to reduce the risk of mortality in patients with molybdenum cofactor deficiency type A: FDA approval summary. J Inherit Metab Dis. 2021;44(5):1085-1087. doi:10.1002/jimd.12421

Lin Y, Liu Y, Chen S, et al. A neonate with molybdenum cofactor deficiency type B. Transl Pediatr. 2021;10(4):1039-1044. doi:10.21037/tp-20-357

Misko AL, Liang Y, Kohl JB, Eichler F. Delineating the phenotypic spectrum of sulfite oxidase and molybdenum cofactor deficiency. Neurol Genet. 2020;6(4):e486. Published 2020 Jul 14. doi:10.1212/NXG.0000000000000486

Alonzo Martínez MC, Cazorla E, Cánovas E, Anniuk K, Cores AE, Serrano AM. Molybdenum cofactor deficiency: Mega cisterna magna in two consecutive pregnancies and review of the literature. Appl Clin Genet. 2020;13:49-55. Published 2020 Jan 30. doi:10.2147/TACG.S239917

Arican P, Gencpinar P, Kirbiyik O, et al. The Clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 mutations. Pediatr Neurol. 2019;99:55-59. doi:10.1016/j.pediatrneurol.2019.04.021

Scelsa B, Gasperini S, Righini A, Iascone M, Brazzoduro VG, Veggiotti P. Mild phenotype in molybdenum cofactor deficiency: A new patient and review of the literature. Mol Genet Genomic Med. 2019;7(6):e657. doi:10.1002/mgg3.657

INTERNET

Misko A, Mahtani K, Abbott J, et al. Molybdenum Cofactor Deficiency. 2021 Dec 2 [Updated 2023 Feb 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK575630/ Accessed March 5, 2024.

MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP C; MOCODC. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Number: 615501: Last updated: 09/06/2017. https://omim.org/entry/615501 Accessed March 5, 2024.

MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A; MOCODA. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Number: 252150: Last updated: 07/09/2016. https://omim.org/entry/252150 Accessed March 5, 2024.

MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP B; MOCODB. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Number: 252160: Last updated: 11/05/2013. https://omim.org/entry/252160 Accessed March 5, 2024.

Molybdenum cofactor deficiency. MedlinePlus. National Library of Medicine (US); Updated Mar 1, 2014. https://medlineplus.gov/genetics/condition/molybdenum-cofactor-deficiency/ Accessed March 5, 2024.

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