Novel Homozygous Missense Mutation in ALDH7A1 Causes Neonatal Pyridoxine-Dependent Epilepsy

Background: Pyridoxine dependent epilepsy (PDE; OMIM#266100) is a neonatal form of epilepsy, caused by dysfunction of the enzyme α-aminoadipic semialdehyde dehydrogenase (ALDH7A1 or Antiquitin). This enzyme converts α-aminoadipic semialdehyde (α-AASA) into α-aminoadipate (AAA), a critical step in the lysine metabolism of the brain. ALDH7A1 dysfunction causes an accumulation of α-AASA and δ1-piperideine-6-carboxylic acid (P6C), which are in equilibrium with each other. P6C binds and inactivates pyridoxal 5′-phosphate (PLP), the active form of pyridoxine. Individuals affected by ALDH7A1 deficiency show prenatal and postnatal seizures, which respond to oral pyridoxine but not to other pediatric antiepileptic drugs.

Methods: Neurological, electrophysiological, neuro-radiological, and genetic analyses were performed in a male infant with postnatal epilepsy to reveal the molecular cause of the disorder and to start the most appropriate therapy.

Results: We discovered a novel missense mutation (c.566G>A, p.Gly189Glu) in homozygous state residing in the NAD+ binding domain coding region of exon 6 and affecting a highly conserved amino acid residue. The seizures stopped under postnatal pyridoxine therapy; nevertheless, a longer follow-up is needed to evaluate the intellectual development of the child, who is additionally treated with oral L-arginine since the 13th month of life. Developmental delay with or without structural cortex abnormalities was reported in several patients. A brain MRI scan revealed hyperintense white matter in the right cerebellum compatible with cerebellar gliosis.

Conclusion: Taken together, our studies enlarge the group of missense pathogenic mutations of ALDH7A1 gene and reveal a novel cerebellar finding within the PDE patients’ cohort.