ABSTRACT
Objective:To analyze the clinical phenotype and genotype characteristics of children with pyridoxine-dependent epilepsy (PDE) and provide evidence for diagnosis.Methods:Clinical data of 3 children with PDE enrolled in the Department of Neurology of Hunan Children′s Hospital from July 2016 to December 2020 were collected, and whole-exome sequencing (WES) was used for analysis. Pathogenic variants were analyzed and screened using bioinformatics tools combined with clinical phenotype. Sanger sequencing was used to analyze the source of mutations in children′s core family members.Results:Cases 1 (female) and 2 (male) were siblings, both of whom had convulsions within 24 hours after birth. WES results showed that the siblings carried compound heterozygous mutations of c.796C>T (p.R266 *) and c.1553G>C (p.R518T) in the ALDH7A1 gene, coming from the father and mother of the siblings respectively. Both of the mutations have been reported as pathogenic. Case 3, female, developed convulsions at the age of 1. WES results revealed that she carried compound heterozygous mutations of c.1094-109T>A and c.7C>T (p.R3C) in the ALDH7A1 gene, coming from her father and mother respectively. After searching HGMDPro, PubMed, 1000 Genomes, and dbSNP databases, both of the 2 mutations of c.1094-109T>A and c.7C>T (p.R3C) were not reported. The pathogenicity predictions of the 2 mutations were carried out by different biological information analysis software. The results showed that both of the mutations were harmful. All the 3 children had no epileptic seizures after treatment with increased doses of vitamin B6. Conclusions:When infants have unexplained convulsions, especially in the neonatal stage, PDE caused by ALDH7A1 gene mutation should be considered. Pyridoxine precision treatment has a good effect. The 2 de novo mutations of c.1094-109T>A and c.7C>T (p.R3C) enrich the mutation spectrum in the ALDH7A1 gene. WES has the auxiliary significance in the diagnosis of epilepsy.
ABSTRACT
【Objective】 To analyze the clinical features and gene mutation characteristics of four children with pyridoxine-dependent epilepsy (PDE) in order to provide evidence for early diagnosis of this rare disease. 【Methods】 The clinical data of four cases of PDE were collected from January 2016 to June 2019 in The Second Affiliated Hospital of Xi’an Jiaotong University. We collected data of the laboratory examination, electroencephalogram, and magnetic resonance imaging (MRI). Peripheral venous blood was collected from children and parents, genomic DNA was extracted from white blood cells, and primers were designed to amplify the aldehyde dehydrogenase 7 family member A1(ALDH7A1) on the long arm of chromosome 5 using PCR; exon and the junction of exon and intron were also amplified to determine whether there is a gene mutation. 【Results】 All the 4 cases had a full-term birth and no history of birth asphyxia. ① Clinical features: onset time from 8 days after birth to 6 months after birth. Type of seizure: 1 case with myoclonus onset, then converted to spasm; 1 case for generalized seizures; 2 cases for partial seizures, then converted to generalized seizures; 3 cases were prone to epileptic seizures; 1 case was significantly worse after infection; MRI: 3 cases showed no abnormalities, 1 case showed non-specific abnormalities; EEG: One case was fragmentary hypsarrhythmia, 3 cases of multifocal epileptiform discharge; Treatment: a small dose of vitamin B6 could control the seizure, 1 of them was controlled at a tiny dose, and 3 cases were controlled by a small dose. ② Genetic analysis results: There were 4 cases of ALDH7A1 gene mutation, of which 3 cases were known gene mutations and 1 case was new mutation. 【Conclusion】 PDE has an early onset, often in the neonatal or small infancy, is prone to epilepticus and has an increased severity after infection. There is no specificity in seizure type, EEG or MRI. The analysis of ALDH7A1 gene and vitamin B6 load test can help to confirm the diagnosis, small dose of Vitamin B6 can control the seizures so as to provide reference for the dose of vitamin B6. However, the number of cases is small, and a large sample size is still needed for verification.