Understanding PNPO Deficiency


Overview of PNPO Deficiency

Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is a rare genetic neurometabolic disorder.1,2 PNPO is an essential enzyme in the body, responsible for the activation of vitamin B6.2,3 Vitamin B6 (pyridoxine) is an essential vitamin that we typically get from our diets.4 In healthy individuals, this vitamin is converted via PNPO into the active form, pyridoxal 5'-phosphate (P5P).1,3 Pyridoxal 5'-phosphate is often abbreviated to P5P, but some literature may also refer to it as "PLP".

P5P is essential for many functions in the body such as signaling in the brain.3 Therefore, a lack of P5P from PNPO deficiency can cause dysfunction in this signaling, ultimately resulting in seizures, as well as other neurological and non-neurological manifestations.1,2 Most often, seizures occur within the first 24 hours after birth.1,2,3 If left untreated, this disease can result in the child's death.2,5

The types of seizures can vary, though they are resistant to the typical anti-seizure medications.1,2 There is no approved treatment for PNPO deficiency.6 Some children with PNPO deficiency have partial function of their PNPO gene, and therefore may be responsive to treatment with pyridoxine.2


Epidemiological Insights

PNPO deficiency is rare, though the exact number of cases is difficult to determine. Based on the current available literature, as of 2022 there have been approximately 90 reported cases.1


Causes of PNPO Deficiency

The cause of PNPO deficiency is an autosomal recessive mutation in the PNPO gene.1,2,3 This PNPO gene codes for the PNPO enzyme, which is responsible for the creation of P5P; this loss of P5P results in the features of the disorder such as seizures.1,5

As an autosomal recessive mutation, an individual needs one copy from both parents in order to develop the condition themselves.1,5 Even then, if each parent has one copy of the mutated gene and one unaffected gene, each child only has a 25% chance of inheriting both mutated copies and developing the condition themselves.1


Diagnosis and Testing

PNPO deficiency is typically discovered following the onset of seizures shortly after birth.2,5 When typical anti-seizure medications fail, PNPO deficiency should be considered as a potential cause, and a genetic test is used to confirm or rule out the disease.1 In fact, PNPO deficiency may be suspected even earlier.1 Couples with a family history or other children with confirmed PNPO deficiency are at risk.1 A clear diagnosis, however, cannot be made unless genetic testing is undergone with a positive result of PNPO deficiency.1,4

As this condition is rare, genetic testing for this is not typically completed for most individuals. However, once a mutation is identified, genetic counselling for carriers is possible.1


Current Treatment Options and Prognosis

The two main treatment options reported in the literature are supplementation with vitamin B6 (pyridoxine) and/or nutraceutical P5P (sometimes compounded by a hospital pharmacy), both of which are unapproved treatments.1,2 As reported in the literature, response to pyridoxine is variable and depended on residual activity of the PNPO gene; of the patients that survived, the majority matured with developmental delays.2,3

For those children that received unapproved treatment with nutraceutical P5P, once again, most patients did develop with some level of disability, though time to treatment onset was correlated to a better prognosis (the earlier P5P was administered, the less likely there was to be severe developmental abnormalities).2 Overall early diagnosis and treatment of PNPO deficiency is key.2


What is MC-1?

MC-1 is an investigational product under development by Medicure for the prevention or treatment of seizures associated with PNPO deficiency.6

Currently there are no FDA-approved treatments of PNPO deficiency.6 Medicure is developing MC-1 through quality-controlled manufacturing, as well as non-clinical and clinical studies under its FDA-cleared US Investigational New Drug Application (IND).6,7


Medicure's Clinical Trial Evaluating MC-1

The FDA has granted both a Rare Pediatric Disease Designation and an Orphan Drug Designation to MC-1 for the treatment of seizures associated with PNPO deficiency.7 Additionally, the European Medicines Agency (EMA) has granted an Orphan Drug Designation to MC-1 for the treatment of PNPO deficiency.6 As of November 2023, Medicure Inc. received FDA clearance to initiate enrolment of individuals into its Phase 3 trial to investigate the use of MC-1 for the prevention or treatment of seizures associated with PNPO deficiency.6

This phase 3 trial is open-label, prospective and is enrolling at sites in both the United States and Australia.6,7 The trial will include approximately 10 patients; as this is an especially rare disorder the number of patients is smaller than a typical Phase 3 trial.6 Additional details on the ongoing trial can be found at https://clinicaltrials.gov/study/NCT04706013.

On April 23, Medicure announced that the FDA granted Fast Track designation for MC-1 for the intended indication.8 Fast Track designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.8


  1. Plecko B, Mills P. PNPO Deficiency. 2022 Jun 23. 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/NBK581452/
  2. Alghamdi, M., Bashiri, F. A., Abdelhakim, M., Adly, N., Jamjoom, D. Z., Sumaily, K. M., Alghanem, B., & Arold, S. T. (2020). Phenotypic and molecular spectrum of pyridoxamine‐5'‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5'‐phosphate oxidase deficiency. Clinical Genetics, 99(1), 99–110. https://doi.org/10.1111/cge.13843
  3. Mills, P. B., Camuzeaux, S. S., Footitt, E. J., Mills, K. A., Gissen, P., Fisher, L., Das, K. B., Varadkar, S. M., Zuberi, S., McWilliam, R., Stodberg, T., Plecko, B., Baumgartner, M. R., Maier, O., Calvert, S., Riney, K., Wolf, N. I., Livingston, J. H., Bala, P., ... Clayton, P. T. (2014). Epilepsy due to PNPO mutations: Genotype, environment and treatment affect presentation and outcome. Brain, 137(5), 1350–1360. https://doi.org/10.1093/brain/awu051
  4. Smith, L. D., & Garg, U. (2017). Disorders of vitamins and cofactors. Biomarkers in Inborn Errors of Metabolism, 361–397. https://doi.org/10.1016/b978-0-12-802896-4.00011-0
  5. U.S. National Library of Medicine. (n.d.). Pyridoxal 5'-phosphate-dependent epilepsy. MedlinePlus. https://medlineplus.gov
  7. Pyridox(am)ine 5'-Phosphate Oxidase (PNPO) Deficiency. Medicure Inc. (n.d.). https://www.medicure.com
  8. MEDICURE RECEIVES US FDA FAST TRACK DESIGNATION FOR MC-1 FOR PNPO DEFICIENCY. Medicure Inc. (2024, April 23). https://www.medicure.com