High phenotypic intra-familial variability of pyridoxine-dependent epilepsy

Abstract

Objective: The present study aims to further characterize the phenotypic spectrum of antiquitin (ALDH7A1 gene) deficiency and underlines a high phenotypic intra-familial variability of this condition. ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). Phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy through brain malformation and neurodevelopmental delay, to multisystem neonatal disorder. Results: We present the case of two siblings, children of first-cousin parents, found to harbour a homozygous ALDH7A1 mutation. A boy (7th pregnancy) was born at term. At 3 hours of life he presented drug- resistant seizures. EEG showed a suppression burst pattern and several multifocal critical patterns. Brain MRI was normal. Targeted next-generation sequencing panels for epileptic encephalopathy disclosed a homozygous missense mutation in the gene encoding for ALDH7A1 (antiquitin) responsible for pyridoxine-dependent epilepsy. Supplementation with pyridoxine and lysine- restricted diet led to complete seizure control and to improvement of psychomotor development in the next months. The same mutation was searched and found in a stocked sample of DNA from peripheral blood of the older sister dead 3 years before. His daughter (3rd pregnancy) presented severe brain malformation diagnosed at fetal ultrasound. At birth, MRI showed microcephaly associated to diffuse cortical thinning, agenesis of the corpus callosum and cerebellar hypoplasia. She presented refractory seizures on day two. EEG showed a suppression burst pattern with multifocal epileptiform discharges. CGH-array was negative. Health conditions got worst and she died at 6 months of life. Both parents were tested and found to be heterozygous carriers. Mother had 2 miscarriages and an abortion for anencephaly. Two other children (one boy and one girl) were healthy. Conclusions: Our data show a high phenotypic intra-familial variability of pyridoxine-dependent epilepsy and a possible association of ALDH7A1 gene mutations to severe brain malformations.