Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency.

Malak Alghamdi,Khalid M Sumaily,Marwa Abdelhakim,Nouran Adly,Dima Z Jamjoom,Fahad A Bashiri,Bandar Alghanem,Stefan T Arold

doi:10.1111/cge.13843

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.

Highlights

We studied the molecular effect of these variants on the Phenotypic and Molecular Spectrum of (PNPO) structure and function, and correlated this information with the disease outcome
Consanguinity was found in 25 patients and 24 cases had a family history of previously affected siblings or an early death with an undiagnosed condition manifested with refractory seizures(Supplementary Table S2). 22% of the patients (n=19) died in the first year of life, one of them only after introduction of PLP
The classical presentation is a neonatal epileptic encephalopathy which is unresponsive to conventional anticonvulsant drugs and to pyridoxine sometimes

Summary

Methods

We searched PubMed and google scholar (http://www.ncbi.nlm.nih.gov/pubmed and https://scholar.google.com; 2002 to 2020) using a combination of the following terms (restricted to humans): pyridoxamine-5’-phosphate oxidase (PNPO), pyridox(am)ine 5’ phosphate oxidase, PNPO, pyridoxal 5′-phosphate-dependent seizures, pyridoxal 5′-phosphate-responsive seizures. Different types of clinical seizures have been observed in patients with PLP-dependent epilepsy. 80% of the cases showed clonic seizures (focal and multifocal), tonic-clonic seizures, generalized seizures, abnormal movement, or a combination of 2 or more of those types in the same episode or in alternation between episodes; absence/staring episodes occurred in 7% of cases7, 8 .paroxysmal movement disorder was observed in 10% of cases 9 Abnormal eye movement such as eye deviation was reported in 17% of cases1, 2, 10-13 .Movement disorder including hyperkinetic movements was identified in one patient[14 ].Approximately 56% of patients affected with PLP-dependent epilepsy suffer developmental delay/intellectual disability. Phenotypic and Molecular Spectrum of (PNPO) Deficiency PLP trial was the second therapeutic option after PN in neonatal refectory seizure, used in 36 patients. In spite of effective seizure control with PLP, approximately 56% of patients affected with PLPdependent epilepsy suffer developmental delay/intellectual disability

Brain Imaging

Non-neurological manifestations of PNPO deficiency

Correlation between molecular effects and clinical outcomes

PNPO Deficiency Outcome

Conclusion