Skip to main content

Because molybdenum cofactor deficiency (MoCD) Type A progresses rapidly, early diagnosis is critical1-3

MoCD Type A is a rare and devastating inborn error of metabolism (IEM) that presents shortly after birth,1,4 progresses rapidly, causes irreparable damage, and often leads to an early death (median survival age is 4 years).1-5 A missed diagnosis can mean a missed opportunity to fight this devastating disease.

When diagnosing MoCD Type A, urgency is critical.

MoCD can have devastating consequences. 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.1,5,6

MoCD is a rare IEM. Individually, IEMs are uncommon, but when combined, they rise to a rate of 1:1000.6 More than 200 of these IEMs can present with seizures, and many occur within the first 1 to 2 days of life; MoCD is one of them.1,7,8

Diagnosing MoCD can be challenging.3,9 If MoCD is missed or confused with another disorder, meaningful intervention could be delayed. Unfortunately, MoCD can be hard to distinguish from hypoxic-ischemic encephalopathy (HIE) or other IEMs such as isolated sulfite oxidase deficiency (ISOD)3:

  • Tests confirming MoCD can take time to provide results, delaying a crucial diagnosis3,4
  • Suspecting and treating for other (metabolic) seizure disorders can also delay diagnosis9

The most common symptoms of MoCD, including MoCD Type A, are neonatal seizures (often intractable) and encephalopathy, which can be mistaken for HIE. However, other symptoms of MoCD are common and often manifest early, including1,3,10,11*:

  • Intractable seizures
  • Feeding difficulties
  • Exaggerated startle reactions
  • Hyper/hypotonia
  • High-pitched cries

*Symptom presentation can vary. Note that a normal or uneventful delivery may also help differentiate MoCD from HIE.12

Act quickly to rule out MoCD Type A.

Substantiating a suspicion of MoCD Type A is an important step in determining possible treatment. You can consider starting therapy when you first suspect a diagnosis of MoCD Type A and stopping if not confirmed by genetic testing.

Follow these 2 steps to diagnose MoCD Type A as quickly as possible:

  • First, biochemical tests can be used to determine high levels of sulfite, S-sulfocysteine (SSC), xanthine, and hypoxanthine in the urine and low levels of uric acid in the blood and urine.2 These results, when paired with clinical presentation, are enough to confirm a diagnosis of MoCD but cannot confirm the subtype
  • The second step, a confirmed diagnosis of MoCD Type A, is reached through molecular testing. Biochemical tests have rapid turnaround and can confirm a diagnosis of MoCD, but only genetic tests can which include MOCS1 confirm the precise subtype1,13

In patients with a presumptive diagnosis of MoCD Type A, confirm the diagnosis of MoCD Type A immediately after initiation of NULIBRY treatment. In such patients, discontinue NULIBRY if the MoCD Type A diagnosis is not confirmed by genetic testing.5

Biochemical tests

Biochemical testing can diagnose MoCD by measuring SSC levels along with other key biochemical markers, such as1,14:

  • Elevated SSC in urine
  • Elevated sulfites in urine
  • Low uric acid
  • High levels of xanthine and hypoxanthine

This can rule out MoCD and other more common causes of neonatal seizures and other presenting symptoms.1

CLIA-certified labs, including the Mayo Clinic and Duke University, have rapid SSC tests available to help rule out sulfite intoxication. Other labs may offer biochemical tests to rule out sulfite intoxication, but it’s important to ensure rapid turnaround time is available when choosing a lab.14,15

Genetic tests

While biochemical tests can screen for a suspected diagnosis of MoCD, only genetic tests can confirm its subtypes—Type A (the most prevalent), Type B, and Type C.1,10,13 It is a mutation in the MOCS1 gene that causes MoCD Type A.1 Many genetic panels, including pediatric panels, include MOCS1, which can help identify MoCD Type A.16,17

When you request a neonatal crisis panel, ensure MOCS1 is included to diagnose MoCD Type A.

MoCD Type A is due to mutations in the MOCS1 gene, which leads to loss of cyclic pyranopterin monophosphate (cPMP) synthesis; cPMP is an essential substance required for the production of molybdenum cofactor (MoCo).1,2,4,10

MoCo is crucial for the functioning of 4 enzymes10:

  • Sulfite oxidase (SOX)
  • Xanthine dehydrogenase
  • Aldehyde oxidase
  • Mitochondrial amidoxime-reducing component

All 4 enzymes are inactive when MoCo is missing, leading to sulfite intoxication and other biochemical abnormalities.1,3 Though all 4 enzymes depend on MoCo to function normally, the loss of SOX activity leads to:

  • Accumulation of sulfite and SSC, also known as sulfite intoxication1,3
  • Excessive levels of sulfite and SSC, which are correlated with rapidly progressive, devastating neurological damage1,3,4,18

MoCo biosynthesis in a healthy child compared to a child with MoCD Type A

Healthy child6,19

A healthy child has an intact M O C S 1 gene which is necessary to help moderate sulfite, allowing for healthy brain function

Child with MoCD Type A1,3,4,19

A child with M O C D Type A has an inactive M O C S 1 gene which causes inactive sulfite oxidase (or SOX) to build up in the brain

Traditionally, care has been limited to managing the symptoms of the disease.3

Now, for the first time, children with MoCD Type A have a fighting chance.

NULIBRY is the first and only FDA-approved therapy for patients with MoCD Type A to reduce the risk of mortality.5

CNS=central nervous system; FDA=Food and Drug Administration; GTP=guanosine triphosphate; MPT=molybdopterin.

References: 

  1. Mechler K et al. Genet Med. 2015;17(12):965-970.
  2. National Institutes of Health. https://ghr.nlm.nih.gov/condition/molybdenum-cofactor-deficiency. Accessed March 5, 2021.
  3. Durmaz MS et al. Radiol Case Rep. 2018;13(3):592-595.
  4. Veldman A et al. Pediatrics. 2010;125(5):e1249-e1254.
  5. NULIBRY [prescribing information]. Boston, MA: Origin Biosciences, Inc.; February 2021.
  6. Atwal PS et al. Mol Genet Metab. 2016;117(1):1-4.
  7. Mercimek-Mahmutoglu S et al. Epilepsia. 2015;56(5):707-716.
  8. Panayiotopoulos CP. https://www.ncbi.nlm.nih.gov/books/NBK2599/?report=printable. Accessed February 19, 2021.
  9. Vasudevan C et al. Semin Fetal Neonatal Med. 2013;18(4):185-191.
  10. Schwahn BC et al. Lancet. 2015;386(10007):1955-1963.
  11. Spiegel R et al. Presented at: Society for the Study of Inborn Errors of Metabolism; September 2019
  12. Allen KA et al. Newborn Infant Nurs Rev. 2011;11(3):125-133.
  13. Zaki MS et al. Eur J Paediatr Neurol. 2016;20(5):714-722.
  14. Mayo Clinic Laboratories. https://www.Mayocliniclabs.com/test-catalog/Overview/41977. Accessed March 5, 2021.
  15. Duke University Health System Biochemical Genetics Laboratory. https://clinlabs.duke.edu/sites/clinlabs.duke.edu/files/Duke%20BGL_mass%20spec_Requisition%20Form_05-07-19.pdf. Accessed March 5, 2021.
  16. LabCorp. https://www.labcorp.com/tests/481518/neurosure-epilepsy-gene-panel. Accessed March 5, 2021.
  17. Invitae. https://www.invitae.com/en/physician/tests/03401/#info-panel-test_sensitivity. Accessed September 25, 2020.
  18. Kumar A et al. J Clin Invest. 2017;127(12):4365-4378.
  19. Reiss J et al. Hum Mutat. 2011;32(1):10-18.
What Is NULIBRY? >

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION

NULIBRY is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) Type A.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Potential for Photosensitivity

NULIBRY can make the patient oversensitive to sunlight. NULIBRY-treated patients or their caregivers are advised to avoid or minimize patient exposure to sunlight and artificial UV light and adopt precautionary measures when exposed to the sun, including wearing protective clothing and sunglasses, and use broad-spectrum sunscreen with high SPF in patients 6 months of age and older. If photosensitivity occurs, caregivers/patients are advised to seek medical attention immediately and consider a dermatological evaluation.

ADVERSE REACTIONS

The most common adverse reactions in NULIBRY-treated patients were infusion catheter–related complications (89%), pyrexia (fever) (78%), viral infection (56%), pneumonia (44%), otitis media (ear infection) (44%), vomiting (44%), and cough/sneezing (44%). Adverse reactions for rcPMP-treated patients were similar to the NULIBRY-treated patients.

PATIENT COUNSELING INFORMATION

Please read the FDA-approved NULIBRY Prescribing Information and Instructions for Use and follow the instructions on how to prepare and administer NULIBRY.

NULIBRY has a potential for photosensitivity; see Warnings and Precautions. Seek medical attention immediately if the patient develops a rash or if they notice symptoms of photosensitivity reactions (redness, burning sensation of the skin, blisters).

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see full Prescribing Information for NULIBRY.