Pyridoxine-Dependent Epilepsy in a Patient Homozygous for ALDH7A1 c.1093+1G>A

Abstract

Introduction: Neonatal seizures represent a neurological emergency and can be the initial manifestation of a rare and severe neurological disorder such as pyridoxine-dependent epilepsy, caused by a compound pathogenic variant in the ALDH7A1 gene, located on chromosome 5q23. This disorder is characterized by being difficult to control and only responsive to pyridoxine hydrochloride.

Objective: To describe a clinical case of a patient with a homozygous pathogenic variant in the ALDH7A1 gene c.1093+1G>A.

Methodology: Presentation of a case of a newborn with refractory seizures that responded to pyridoxine.

Case Description and Discussion: The index case is presented, with no history of consanguinity, and a family history of a deceased sibling who experienced status epilepticus at 4 months of age with no clear etiology. The patient was born at term. Within the first hours of life, the patient experienced generalized clonic seizure episodes that did not respond to anticonvulsants until pyridoxine was initiated, which became the sole therapy. Next-generation sequencing (NGS) reported a homozygous pathogenic variant in the ALDH7A1 gene c.1093+1G>A, which affected the splicing consensus region with a potential alteration of mRNA transcript and the development of an abnormal protein, responsible for seizures and developmental delay, as seen in this patient. Additionally, the patient exhibited thinning of the corpus callosum on brain MRI, a finding described in children with neonatal seizures, which are associated with high morbidity and mortality and should prompt consideration of a genetic cause in cases of refractory seizures.

Conclusions: Neonatal seizures require a comprehensive approach. History, clinical records, and response to anticonvulsant treatment are key in guiding specific diagnosis and management to reduce their impact and morbidity.