PNPO deficiency (OMIM 6032870) is an autosomal recessive inborn error of metabolism that leads to a seizure disorder, presenting in the newborn period (neonatal epileptic encephalopathy) or early infancy, that can be treated with pyridoxal 5’-phosphate but (classically) not pyridoxine. Seizures are often characterized by irregular involuntary muscle contractions (myoclonus), abnormal eye movements, and convulsions.

Mutations in the PNPO gene are responsible for pyridoxal 5'-phosphate-dependent epilepsy. The PNPO gene is responsible for the production of an enzyme called pyridoxine 5'-phosphate oxidase. This enzyme plays a crucial role in metabolizing vitamin B6 from food, specifically pyridoxine and pyridoxamine, into its active form known as pyridoxal 5'-phosphate (PLP). PLP is crucial for various bodily processes, such as protein metabolism and the creation of neurotransmitters that facilitate brain signaling.

• defined as neonatal onset in premature infants and neonates
• Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements
• Fetal distress before delivery
• Low APGAR scores
• Difficult-to-treat seizures irrespective of a history of fetal distress
• Epileptic encephalopathy or signs of encephalopathy (inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone)
• Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding)
• Cryptogenic infantile or epileptic spasms

• onset after age 28 days in individuals of any age
• Cryptogenic seizures refractory to common anticonvulsants

• A standardized vitamin B6 trial[1] may raise suspicion regarding PNPO deficiency
• 40% of individuals with PNPO deficiency are responsive to pyridoxine (PN) and seizures. In a majority of these patients seizures will remit within 1 to 3 days, but it could take upto several days in some cases
• 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings.
• before initiating the vitamin B6 trial:
  • Save plasma and urine; if available, freeze CSF at -80°
  • Resuscitation equipment should be available due to the increased risk of apnea or respiratory arrest with initial dose of either pyridoxine (PN) or pyridoxal 5'-phosphate (PLP)

Steps1

1. Give PN 100mg IV, followed by 30 mg/kg/day IV or p.o. in 2-3 single doses over 1-3 days
2. If PN is ineffective, consider adding folinic acid 3-5 mg/kg/day p.o. in 1-2 single doses
3. If PN & folinic acid are ineffective, replace PN with PLP, 30 to 60 mg/kg/day p.o. in 4-6 single doses over 3 days

If seizures stop: continue pyridoxine or PLP until results of biochemical and/or molecular testing are available

• increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of pyridoxine-dependent epilepsy – ALDH7A1
• increased sulfocysteine is indicative of molybdenum cofactor deficiency or isolated sulfite oxidase deficiency.
• there are no biomarkers to differentiate from Pyridoxal 5'-Phosphate-Binding Protein Deficiency (PLPBP)( also called PLPHP deficiency). PLPBP gene encodes for the protein PLPHP, believed to be crucial for B6 homeostasis