Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

Abstract

Pyridoxamine-5 0-phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5 0-phosphate (PLP)-vitamin-responsive epileptic encephalopathy. The emerging feature of PNPO deficiency is the occurrence of refractory seizures in the first year of life. Pre-maturity and fetal distress, combined with neonatal seizures, are other associated key characteristics. The phenotype results from a dependency of PLP which regulates several enzymes in the body. We present the phenotypic and genotypic spectrum of (PNPO) deficiency based on a literature review (2002-2020) of reports (n = 33) of patients with confirmed PNPO deficiency (n = 87). All patients who received PLP (n = 36) showed a clinical response, with a complete dramatic PLP response with seizure cessation observed in 61% of patients. In spite of effective seizure control with PLP, approximately 56% of patients affected with PLP-dependent epilepsy suffer developmental delay/intellectual disability. There is no diagnostic biomarker, and molecular testing required for diagnosis. However, we noted that cerebrospinal fluid (CSF) PLP was low in 81%, CSF glycine was high in 80% and urinary vanillactic acid was high in 91% of the cases. We observed only a weak correlation

Early‐onset vitamin B6‐dependent epilepsy due to pathogenic PLPBP variants in a premature infant: A case report and review of the literature

“…4,8,9,11 Prematurity has been reported in the PLP and PN responsive epilepsies, presenting in 18% of ATQ deficiency patients and 46% to 50% of patients with PNPO deficiency. [18][19][20] This also seems to be a feature of EPVB6D with prematurity reported in eight patients (27%), including our patient. 4,8,9,11 Other pregnancy complications (IUGR, 4 abnormal movements 4,8,13 ) and fetal distress (nonreassuring CTG, 4,8 meconium stained liquor 4,8,11 ) occurred in up to half of all cases.…”

“…Seventy‐eight percent of affected infants had seizures in their first week of life, and in all of those born prematurely, seizures developed within 24 hours of life 4,8,9,11 . Prematurity has been reported in the PLP and PN responsive epilepsies, presenting in 18% of ATQ deficiency patients and 46% to 50% of patients with PNPO deficiency 18‐20 . This also seems to be a feature of EPVB6D with prematurity reported in eight patients (27%), including our patient 4,8,9,11 .…”

“…Raised plasma and urinary α-aminoadipic semialdehyde (α-AASA) and its equilibrium partner, Δ 1 -piperideine-6-caboxylate (P6C) are characteristic of antiquitin deficiency, 21 while high plasma pyridoxamine (PM) concentration and high pyridoxamine/pyridoxic acid (PM/PA) ratio show promise as biomarkers for PNPO deficiency, 22 irrespective of vitamin B 6 treatment. 20,21 More specific measurement of PNPO enzyme activity is also available. 23 Specific biomarkers in EPVB6D, however, have remained elusive to date.…”

Treatable inherited metabolic epilepsies

“…This enzyme is essential for converting pyridoxine-5-phosphate and pyridoxamine-5-phosphate into pyridoxal-5′-phosphate (PLP), which is the active form of pyridoxine. 13 Typically, it is present in the neonatal period with refractory epilepsy similar to PDE, but it shows no or partial response to pyridoxine. Neonates have a wide range of non-neurological manifestations, such as prematurity, failure to thrive, hypoglycemia, lactic acidosis, and normocytic anemia.…”

“…PNPO deficiency requires lifelong treatment with PLP 20-70 mg/kg/day divided into four doses. 13 Biotinidase deficiency. It is an autosomal recessive disorder caused by mutations in the BTD gene.…”