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, immediate action 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:
- MoCD should be considered early on in the diagnostic work-up of seizures.9
- Unfortunately, tests confirming MoCD can take time to provide results, delaying a crucial diagnosis3,4
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*:
- Feeding difficulties
- Exaggerated startle reactions
- 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 start 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 the precise MoCD subtype can only be determined by genetic tests that include MOCS11,13
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 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 in urine or blood
- High levels of xanthine and hypoxanthine in urine
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
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 seizure 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 substrate 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
Child with MoCD Type A1,3,4,19
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 and has been shown to reduce the risk of mortality.5
CNS=central nervous system; FDA=Food and Drug Administration; GTP=guanosine triphosphate; MPT=molybdopterin.
- Mechler K et al. Genet Med. 2015;17(12):965-970.
- National Institutes of Health. https://ghr.nlm.nih.gov/condition/molybdenum-cofactor-deficiency.
- Durmaz MS et al. Radiol Case Rep. 2018;13(3):592-595.
- Veldman A et al. Pediatrics. 2010;125(5):e1249-e1254.
- NULIBRY [prescribing information] https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=736aeea3-f206-454d-95d0-fd30964e8aab.
- Atwal PS et al. Mol Genet Metab. 2016;117(1):1-4.
- Mercimek-Mahmutoglu S et al. Epilepsia. 2015;56(5):707-716.
- Panayiotopoulos CP. https://www.ncbi.nlm.nih.gov/books/NBK2599/?report=printable.
- Vasudevan C et al. Semin Fetal Neonatal Med. 2013;18(4):185-191.
- Schwahn BC et al. Lancet. 2015;386(10007):1955-1963.
- Spiegel R et al. Presented at: Society for the Study of Inborn Errors of Metabolism; September 2019
- Allen KA et al. Newborn Infant Nurs Rev. 2011;11(3):125-133.
- Zaki MS et al. Eur J Paediatr Neurol. 2016;20(5):714-722.
- Mayo Clinic Laboratories. https://www.Mayocliniclabs.com/test-catalog/Overview/41977.
- Duke University Health System Biochemical Genetics Laboratory. https://clinlabs.duke.edu/sites/default/files/2023-03/Duke%20BGL_mass%20spec_Requisition%20Form_040123.pdf.
- LabCorp. https://www.labcorp.com/tests/630268/comprehensive-epilepsy-ngs-panel.
- Invitae. https://www.invitae.com/en/physician/tests/03401/#info-panel-test_sensitivity.
- Kumar A et al. J Clin Invest. 2017;127(12):4365-4378.
- Reiss J et al. Hum Mutat. 2011;32(1):10-18.