A number sign (#) is used with this entry because of evidence that early-onset vitamin B6-dependent epilepsy-1 (EPEO1) is caused by homozygous or compound heterozygous mutation in the PROSC gene (PLPBP; 604436) on chromosome 8p11.

Early-onset vitamin B6-dependent epilepsy-1 (EPEO1) is an autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period or first months of life. The seizures show favorable response to treatment with activated vitamin B6 (pyridoxal 5-prime-phosphate; PLP) and/or pyridoxine. However, most patients show delayed psychomotor development (Darin et al., 2016).

Genetic Heterogeneity of Early-Onset Epilepsy

EPEO2 (618832) is caused by mutation in the SETD1A gene (611052) on chromosome 16p11. EPEO3 (620465) is caused by mutation in the ATP6V0C gene (108745) on chromosome 16p13. EPEO4 (266100) is caused by mutation in the ALDH7A1 gene (107323) on chromosome 5q23. EPEO5 (615400) is caused by mutation in the CNTN2 gene (190197) on chromosome 1q32.

Darin et al. (2016) reported 3 patients from a consanguineous Syrian family and 4 unrelated additional patients with infantile-onset seizures. Three of the patients showed abnormal intrauterine movements, and 4 showed signs of fetal distress. One infant from the Syrian family died at 4.5 months of age, and the other patients ranged in age from 3 to 16 years. All presented with seizures on the first day of life, except 1 patient who developed seizures at 1 month of age. Seizure manifestations included myoclonus, clonus, hypertonia, grimacing, apnea, respiratory distress, chewing, twitching, generalized tonic-clonic seizures, and stiffness. EEG tended to show a burst suppression pattern, often with reduced background activity. All patients had an immediate response to treatment with pyridoxine. After initial presentation, all children continued to have less frequent seizures and needed to be treated with multiple anticonvulsants. Four patients had their B6 treatment changed from pyridoxine to PLP, and all showed an improvement in seizure control. Several patients showed recurrence of seizures upon withdrawal of B6 treatment. The patients showed delayed psychomotor development with delayed language of variable severity and acquired microcephaly, although the 16-year-old was able to attend normal school. Brain imaging of most patients showed global underdevelopment of the brain, brain atrophy, enlarged ventricles, broad gyri, shallow sulci, reduced white matter, thin corpus callosum, and cysts, although 3 patients had normal brain imaging. Additional features included neonatal metabolic acidosis with increased lactate in 4 patients, anemia in 2 patients, and gastrointestinal dysfunction, including abdominal distention, vomiting, and necrotizing enterocolitis, in 3 patients. Four patients had minor dysmorphic features. Laboratory studies were consistent with abnormalities in B6 metabolism: 2 patients had low CSF PLP concentrations, and 3 had decreased activities of B6-dependent enzymes.

The transmission pattern of EPEO1 in the families reported by Darin et al. (2016) was consistent with autosomal recessive inheritance.

In 7 patients from 5 unrelated families with EPEO1, Darin et al. (2016) identified homozygous or compound heterozygous mutations in the PROSC gene (see, e.g., 604436.0001-604436.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing. Mutations in the 4 other patients were found by Sanger sequencing of the PROSC gene in 29 children with B6-responsive epilepsy. Patient plasma PLP levels in those receiving B6 treatment were increased compared to controls, and PLP levels in cultured patient fibroblasts were also increased. Complementation studies in PROSC-deficient E. coli showed that several of the mutations could not restore growth, indicating a loss-of-function effect. Darin et al. (2016) noted that PLP is a highly reactive aldehyde and may interact nonspecifically with intracellular proteins and small molecules, resulting in a toxic effect. The genetic findings were consistent with a defect in intracellular homeostatic regulation of PLP.