Abstracts

Rationale: Whole-exome sequencing (WES) is perceived as an essential technique to reveal the genetic etiology of early-onset epileptic encephalopathies (EOEEs). Vitamin-B6-dependent epilepsies, which cause EOEEs in most cases if not treated properly, are curable disorders resulting from impaired cellular pyridoxal phosphate homeostasis. Mutations in specific genes, such as ALDH7A1 and PNPO, are responsible for vitamin-B6-dependent epilepsies. Recently, biallelic PROSC mutations were identified as a novel etiology of vitamin-B6-dependent epilepsies; however, phenotypes of PROSC mutations are not entirely understood. We identified non-synonymous PROSC mutations in four unrelated patients with EOEEs and reported their variable phenotypes. Methods: We performed WES in a cohort of patients with EOEEs. Patients with brain malformations were excluded from the study. Blood samples were collected from patients along with informed consents from their parents. In addition, clinical data, including EEG findings and brain MRI, were collected. This study was approved by the IRB for Ethical Issues at Yokohama City University School of Medicine and Showa University School of Medicine. Results: WES revealed a compound heterozygous and three homozygous missense PROSC mutations in four unrelated male patients. One patient had a history of consanguineous marriage, and only one patient was diagnosed with vitamin-B6 epilepsy before the genetic analysis. Remaining three patients were diagnosed with mesial temporal lobe epilepsy, Ohtahara syndrome (OS), and unclassified EOEE, respectively. The onset of seizures was from 4 h after birth to 3 months of age, and the seizure types were generalized tonic-clonic seizures (GTCS), myoclonic seizures, focal motor seizures, complex partial seizures, and breath-holding attacks. Focal or multifocal discharges on EEG were characteristic for two patients. One patient with OS demonstrated suppression-burst on EEG. Seizures disappeared after the administration of pyridoxal phosphate or pyridoxine in two patients. All patients exhibited developmental delay and neurological symptoms, such as intellectual disability and autistic behavior. Conclusions: Till date, only 15 patients with PROSC mutations, including our patients, have been reported. In previous studies, early onset of seizures within 7 days of life was characteristic for patients with PROSC mutation, except for two patients; however, three of our patients demonstrated the first seizure after 7 days of life. GTCS and myoclonic seizures are the primary types of seizures in patients with PROSC mutation, whereas focal seizures are observed in some patients. In addition, the suppression-burst pattern is observed in patients with PROSC mutation in whom the onset of seizures is within 24 h of life. Although PLP or pyridoxine is an effective treatment for seizures, the developmental delay can be observed even if PLP or pyridoxine is administered in the early period. Funding: Grants-in-Aid for Scientific Research (C) from JSPS; Practical Research Project for Rare/Intractable Diseases from AMED; the Health and Labour Sciences Research Grant from MHLW.