A Patient with Pyridoxine-Dependent Epilepsy Who Was Treated with Triple Therapy

Pyridoxine-dependent epilepsy (PDE) is a type of developmental and epileptic encephalopathy manifesting as seizures that are resistant to anti-seizure medication (ASM) but responsive to pharmacologic doses of pyridoxine [1]. PDE caused by bi-allelic mutations in the aldehyde dehydrogenase 7 family member A1 (ALDH7A1) gene on chromosome 5q32.2 is designated PDE-ALDH7A1 [1,2]. Mutations at this locus are associated with decreased activity of α-aminoadipic semialdehyde (α-AASA) dehydrogenase in lysine metabolism [3]. PDE-ALDH7A1 is a rare disease with an estimated incidence of 1:65,000 to 1:250,000 live births [2]. Refractory neonatal seizures are the most common presentation; however, 25% to 30% of patients were found to present with seizures outside of the neonatal period, and varying intellectual disabilities and developmental delays were found in 75% of patients [4]. We report the case of a 9-year-old boy with intractable seizures related to homozygous ALDH7A1 mutations, who improved after triple therapy. The patient had neonatal seizures on his 12th day of life. He was started on multiple ASMs, including phenobarbital, phenytoin, levetiracetam, topiramate, vigabatrin, and clonazepam; however, his seizures and the related epileptiform discharges on electroencephalography (EEG) persisted. He received empiric high-dose vitamin therapy, which included pyridoxine, inconsistently. For the next 7 years, he was admitted repeatedly for recurrent status epilepticus whenever his medications were discontinued. When the patient was 7 years old, his father stopped giving him the prescribed vigabatrin and pyridoxine. Ten days after therapy interruption, he was admitted to the intensive care unit (ICU) for seizures, vomiting, and poor general condition. Doctors resumed vigabatrin and pyridoxine. However, the recurrence of vomiting prevented oral intake of these medications, and he had seizures again. He was readmitted to the ICU and was administered pyridoxine at 50 mg/day (2 mg/kg body weight), after which the seizures stopped. Prompted by this clinical information, wholeexome sequencing was performed in the proband, mother, and father for an accurate diagnosis. Compound heterozygous mutations were identified in the ALDH7A1 genes: NM_001182.4:c. 210C> A (p.Cys70Ter) and c.871+5G >A. The variants confirmed by Sanger sequencing were classified as pathogenic according to the guidelines of the American College of Medical Genetics and Genomics [5]. A segregation study showed both parents as carriers of the variants (Fig. 1). We diagnosed the patient with PDE and increased the pyridoxine dose to 300 mg/day (10 mg/kg). Since pyridoxine supplementation, he became sei-