(PNPO gene)
Also known as: Pyridoxal phosphate-responsive seizures; Seizures, pyridoxine-resistant, PLP-sensitive epileptic encephalopathy, PNPO deficiency; neonatal, PNPO-related
OMIM#610090 https://omim.org/entry/610090
1. The disease
A very rare neonatal epileptic encephalopathy disorder characterized clinically by onset of severe seizures within hours of birth that are not responsive to anticonvulsants but are responsive to treatment with pyridoxal phosphate.
2. The Symptoms
The phenotypic spectrum of PNPO deficiency is wide, including a multitude of neurological and systemic manifestations. Its characteristic clinical feature is refractory seizures during 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. Lack of early signs or symptoms does not exclude the diagnosis.
- The most prominent neurological manifestation is a seizure within the first day of life, occurring in 59% of the reported cases. The mother has noticed abnormal fetal movement in the third trimester, in 11% of the patients who have shown seizure within the first day of life.
- Furthermore, paroxysmal movement disorder was observed in 10% of cases. Abnormal eye movement such as eye deviation was reported in 17% of cases. Approximately 56% of patients affected with PLP‐dependent epilepsy suffer developmental delay/intellectual disability.
- All of the responsive patients became PLP‐dependent and dose adjustment was needed to manage sick days.
- In spite of effective seizure control with PLP, approximately 56% of patients affected with PLP‐dependent epilepsy suffer developmental delay/intellectual disability.
3. Actions to take in case of early diagnosis
- Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the PNPO gene) should continue breastfeeding.
- Early treatment is essential in preventing chronic symptoms.
- There is currently no specific biomarker for PNPO deficiency.
- A therapeutical test with pyridoxal phosphate (PLP) could help establishing the diagnosis.
- PNPO deficiency is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and child neurologist, a part from a multidisciplinary approach to care.
- Pre‐maturity, delayed therapeutic intervention and an earlier onset of clinical seizures are correlated with a poorer neurocognitive outcome.
- Given the amenability of PNPO‐dependent epilepsy to treatment with pyridoxal phosphate (PLP) and pyridoxine (PN) therapy for optimal seizure control and favorable developmental outcomes, early diagnosis is essential.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Biblio: Alghamdi M, Bashiri FA, Abdelhakim M, et al. Phenotypic and molecular spectrum of pyridoxamine-5′-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5′-phosphate oxidase deficiency. Clin Genet. 2021;99(1):99-110. PMID: 32888189.