Refractory Seizures in a Neonate with a Rare Coexistence of Variants in Both ALDH7A1 and RHOBTB2 Genes

Background: Pyridoxine-dependent epilepsy due to ALDH7A1 gene mutation is a known, but rare autosomal recessive disorder, presenting with early-onset, refractory seizures. Also, mutations in the RHOBTB2 gene are responsible for a rare developmental and epileptic encephalopathy 64 disorder. We report a neonate with refractory seizures harboring mutations in both the genes. Clinical Description: A 4-day-old female neonate, born to second-degree consanguineous parents, presented with left-sided focal seizures. The antenatal period was uneventful with no birth asphyxia. The elder male sibling had died at 4 years of age due to infantile-onset epilepsy. Examination of the neonate revealed hypotonia and impaired neonatal reflexes. Management and Outcome: Investigations revealed a negative septic screen, normal blood sugar, calcium, and magnesium levels. Magnetic resonance imaging of the brain was normal, and the electroencephalogram showed generalized epilepsy. Seizures persisted despite 4 days of treatment with intravenous phenobarbitone, levetiracetam, and phenytoin. Pyridoxine was added on day 5 of hospitalization, following which there was reduction in seizure frequency over 24 hours and complete cessation over the subsequent 48 hours. Genetic testing revealed a homozygous missense variant of uncertain significance in the ALDH7A1 gene as well as a heterozygous nonsense variant of uncertain significance in the RHOBTB2 gene, both genes showing phenotypic corroboration. Conclusion: Though the addition of pyridoxine may be beneficial in refractory seizures in neonates, genetic analysis may be considered to elicit underlying mutations, especially with a background of consanguinity and positive family history. Our case is unique, showing the coexistence of ALDH7A1 and RHOBTB2 gene variants in a case of neonatal seizures.