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'-phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5'-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 between the severity of PNPO protein disruption and disease outcomes, indicating the importance of other factors, including seizure onset and time of therapy initiation. We found that pre-maturity, the delay in initiation of PLP therapy and early onset of seizures correlate with a poor neurocognitive outcome. Given the amenability of PNPO to PLP therapy for seizure control, early diagnosis is essential.

Keywords: PLP; PNPO; neonatal epileptic encephalopathy; seizures; vitamin-response epilepsy.

FIGURE 1

Vitamin B6 metabolism as it travels from the intestine to the portal circulation, crosses the blood‐brain barrier, and enters the brain cells. A, In the intestine, the dietary phosphorylated form is hydrolyzed to the free form by intestinal hydrolase (IH)/tissue‐specific intestinal phosphatase (TSIP) prior to absorption. This is followed by its uptake by intestinal cells, which is believed to occur through simple diffusion. Through portal circulation, the free B6 forms reach the liver, where metabolism in the liver is catalyzed by many enzymes. (1) Pyridoxal kinase (PK), (2) pyridoxal phosphate phosphatase, (3) pyridox(am)ine‐5′‐phosphate oxidase. B, The unphosphorylated forms of vitamin B6 are able to cross the blood‐brain barrier, probably by facilitated diffusion, mostly at the choroid plexus (CP). The CP traps PLP via pyridoxal kinase and can release PLP to a remarkable extent (and pyridoxal to a lesser extent). C, Excessive PLP in the CSF and extracellular space enters brain cells, and the B6 vitamers must be dephosphorylated so that they can enter brain cells and then metabolically trapped by being rephosphorylated by pyridoxal kinase. Pyridoxine phosphate and pyridoxamine phosphate are then oxidized by PNPO to form the active cofactor, PLP. PLP, pyridoxal 5′‐phosphate

FIGURE 2

Seizure onset data for 87 reported cases with PNPO deficiency. PNPO, pyridoxamine‐5′‐phosphate oxidase

FIGURE 3

Overview of the reported point mutations. The crystal structure (PDB ID 1nrg) shows the post‐catalytic PLP (magenta) and FMN (dark lilac) as stick models. Point mutations are shown in sphere representation. Green coloration indicates that the mutation directly affects the binding and processing of the substrate and cofactor. Orange coloration indicates that the mutation decreases the protein's overall stability. FMN. flavin mononucleotide; PLP, pyridoxal 5′‐phosphate

FIGURE 4

A, The impact of pre‐maturity on clinical outcomes, including death and developmental delay (DD). B, Variable outcomes with variable age of PLP administration. The earlier PLP was introduced as a therapy, the better the prognosis was reported. PLP, pyridoxal 5′‐phosphate