Understanding PNPO Deficiency

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What is PNPO Deficiency?

Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is a rare genetic neurometabolic disorder that causes seizures in newborns most commonly in the neonatal period.^1-4 It occurs because the body cannot produce enough of the active form of vitamin B6.

There are currently no approved treatments for PNPO deficiency.

Because PNPO deficiency is rare, the exact number of affected individuals is unknown. Based on our review of the available medical literature, 107 cases had been reported worldwide as of February 2026.

Vitamin B6 Metabolism

What is PNPO?

In healthy individuals, vitamin B6 (pyridoxine) from the diet is converted into its active form (pyridoxal 5'-phosphate) by an enzyme called PNPO.⁵

Mutations in the PNPO gene (OMIM #603287) reduce or eliminate the activity of this enzyme, which leads to an inability to produce the active form of vitamin B6.¹

What is Pyridoxal 5'-Phosphate (P5P)?

Pyridoxal 5'-phosphate, often abbreviated as P5P or PLP - is the active form of vitamin B6.

P5P is involved in more than 160 enzymatic reactions⁶ in the body, including:

Amino acid metabolism
Sphingoid base synthesis (important for nerve cells)
Glycolysis (energy production)
Neurotransmitter metabolism

A lack of P5P disrupts these processes, especially in the brain.

Vitamin B6 comes from the diet in several forms, including pyridoxine and pyridoxamine, which are converted inside the body into pyridoxine-5'-phosphate (PNP) or pyridoxamine-5'-phosphate (PMP). The enzyme PNPO performs the final step needed to create pyridoxal-5'-phosphate (P5P), the active form of vitamin B6 required for many brain and metabolic functions. Although pyridoxal-5'-phosphate (P5P/PLP) is the active form of vitamin B6 in most tissues, it cannot cross the blood–brain barrier directly. Instead, circulating P5P is first dephosphorylated by tissue non-specific alkaline phosphatase (TNSALP), producing pyridoxal, the only B6 vitamer able to enter the brain. Pyridoxal then crosses the blood–brain barrier and is converted back into P5P inside brain cells by pyridoxal kinase (PK). Once regenerated, P5P is used immediately by neuronal enzymes or is stabilized within the cell by Pyridoxal Phosphate Binding Protein (PLPBP), a protein that binds and protects intracellular P5P from degradation or harmful side reactions. Together, these steps ensure that dietary vitamin B6 can be transformed, transported, and ultimately delivered to the brain in its active form.^5,7,8

PNPO deficiency is an autosomal recessive genetic disorder, meaning a child must inherit two non-working copies of the PNPO gene-one from each parent-to develop the condition. Parents who each carry one mutated PNPO gene are called carriers; they do not have PNPO deficiency because their working copy provides enough enzyme for normal function. When both parents are carriers, each pregnancy has a 25% chance of the child having PNPO deficiency, a 50% chance the child will be a carrier, and a 25% chance the child will inherit two working copies. This inheritance pattern affects all genders equally and does not skip generations.¹

Causes of PNPO Deficiency

PNPO deficiency is an autosomal recessive disorder caused by mutations in the PNPO gene (OMIM #603287).¹

This gene provides instructions for producing the PNPO enzyme, which is required to create P5P.

Over 30 pathogenic variants of the PNPO gene have been reported in the literature.⁴

How PNPO Deficiency Appears in Newborns

Although it can vary from patient to patient, the classical presentation for a patient with PNPO deficiency is intractable neonatal epileptic encephalopathy (NEE) shortly after birth.¹

Most commonly, but not always, children with PNPO deficiency present with:

Seizures shortly after birth
From an analysis of 87 individuals with PNPO deficiency, 59% experienced seizures either in utero or within the first day of life, 81% within the neonatal period (first few weeks), and 96% had seizures within the first year⁴
Seizures that do not improve with standard anti-seizure medications

Diagnosing PNPO Deficiency

PNPO deficiency is typically discovered following the onset of seizures shortly after birth.¹ When typical anti-seizure medications fail, PNPO deficiency should be considered as a potential cause.

PNPO deficiency may be suspected even earlier if there is a family history of PNPO deficiency or other children with confirmed PNPO deficiency.

No single, well-validated diagnostic biomarker for PNPO deficiency currently exists.⁴ However, several recurring biochemical findings can raise clinical suspicion. In a literature review of 87 confirmed cases, commonly reported abnormalities included low CSF P5P (81%), elevated CSF glycine (80%), elevated CSF threonine (75%), and increased urinary vanillactic acid (VLA) (91%).⁴

A clear diagnosis for PNPO deficiecy can only be made through genetic testing.

Treatment Options and Prognosis for PNPO Deficiency

Left untreated, the prognosis of PNPO deficiency is very poor and often results in death.⁴

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),¹ both of which are unapproved treatments. 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.⁹

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).⁴

Overall early diagnosis and treatment of PNPO deficiency is key.⁴

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.¹⁰

Currently there are no FDA-approved treatments of PNPO deficiency. 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).¹⁰

Medicure's Clinical Trial Evaluating MC-1 for PNPO Deficiency (MEND-PNPO)

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.¹¹ Additionally, the European Medicines Agency ("EMA") has granted an Orphan Drug Designation to MC-1 for the treatment of PNPO deficiency.¹¹ Medicure also received fast track designation for use of MC-1 for the treatment of PNPO deficiency, which will facilitate the review of Medicure's New Drug Application ("NDA") by the FDA.¹²

In 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.¹⁰ Medicure provided a further update announcing that 6 patients have been enrolled in the clinical trial as of September 2025.¹¹

This phase 3 trial is open-label, prospective and is enrolling at sites the United States, Australia and Poland.¹⁰ 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.¹⁰ Additional details on the ongoing trial can be found at https://clinicaltrials.gov/study/NCT04706013.

Do you or a loved one have PNPO deficiency?

We want to hear about your experience and how we can best support you in the future.

References

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 Kuo, M.-F., & Wang, H.-S. (2002). Pyridoxal Phosphate-Responsive Epilepsy With Resistance to Pyridoxine. Pediatric Neurology, 146–147. https://doi.org/10.1016/s0887-8994(01)00357-5

4 Mills, P. B., Surtees, R. A. H., Champion, M. P., Beesley, C. E., Dalton, N., Scamber, P. J., Heales, S. J. R., Briddon, A., Scheimberg, I., Hoffmann, G. F., Zschocke, J., & Clayton, P. T. (2005). Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Human Molecular Genetics, 14(8), 1077–1086. https://doi.org/10.1093/hmg/ddi120

5 Pearl PL, Gospe SM Jr. Pyridoxine or pyridoxal-5'-phosphate for neonatal epilepsy: the distinction just got murkier. Neurology. 2014 Apr 22;82(16):1392-4

6 Stach, K., Stach, W., & Augoff, K. (2021). Vitamin B6 in health and disease. Nutrients, 13(9). https://doi.org/10.3390/nu13093229

7 Wilson, M. P., Plecko, B., Mills, P. B., & Clayton, P. T. (2019). Disorders affecting vitamin B6 metabolism. Journal of Inherited Metabolic Disease, 42(4), 629–646. https://doi.org/10.1002/jimd.12060

8 Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. T., Tribollet, E., Haridy, N., Botía, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., ... Tucci, A. (2019). PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation. Annals of Neurology, 86(2), 225–240. https://doi.org/10.1002/ana.25524

9 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

10 MEDICURE ANNOUNCES FDA PROVIDES COMPLETE APPROVAL TO ENROLL PATIENTS IN ITS PIVOTAL PHASE 3 TRIAL FOR TREATMENT OF RARE PEDIATRIC DISEASE. Medicure Inc. (2023, November 23). www.medicure.com

11 MEDICURE ANNOUNCES UPDATE ON ENROLLMENT IN ITS MEND-PNPO PHASE 3 CLINICAL TRIAL AND PRESENTATION OF THE TRIAL DESIGN AND BASELINE DATA AT THE 2025 CHILD NEUROLOGY SOCIETY CONFERENCE (2025, September 25) www.medicure.com

12 MEDICURE RECEIVES US FDA FAST TRACK DESIGNATION FOR MC-1 FOR PNPO DEFICIENCY. Medicure Inc. (2024, April 23). www.medicure.com

Understanding PNPO Deficiency

What is PNPO Deficiency?

Vitamin B6 Metabolism

What is PNPO?

What is Pyridoxal 5'-Phosphate (P5P)?

Causes of PNPO Deficiency

How PNPO Deficiency Appears in Newborns

Diagnosing PNPO Deficiency

Treatment Options and Prognosis for PNPO Deficiency

What is MC-1?

Medicure's Clinical Trial Evaluating MC-1 for PNPO Deficiency (MEND-PNPO)

Do you or a loved one have PNPO deficiency?

References

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