3 years ago

Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency.

Kevin Mongeon, Devon Johnstone, Yann Roussel, Nathalie Lepage, Tuan Vu Bui, Clara D M van Karnebeek, Pranesh Chakraborty, Izabella A Pena, Hellen Weinschutz Mendes, Alex MacKenzie, David A Dyment, Marjolein Bosma, Kate Daniel, Marc Ekker, Vishal Saxena, Kym M Boycott, Nanda Verhoeven-Duif
Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene ALDH7A1 leading to recurrent neonatal seizures which are uniquely alleviated by high doses of pyridoxine or pyridoxal 5'-phosphate (vitamin B6 vitamers). Despite treatment, neurodevelopmental disabilities are still observed in most PDE patients underlining the need for adjunct therapies. Over 60 years after the initial description of PDE, we report the first animal model for this disease: an aldh7a1-null zebrafish (Danio rerio) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 dpf). Epileptiform electrographic activity was observed uniquely in mutants as a series of population bursts in tectal recordings. Remarkably, as is the case in human PDE, the seizures show an almost immediate sensitivity to pyridoxine and pyridoxal 5'-phosphate (PLP) with a resulting extension of the lifespan. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of aldh7a1 knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency and low GABA levels were observed in the aldh7a1(-/-) larvae, which may play a significant role in the seizure phenotype and PDE pathogenesis. This novel model provides valuable insights into PDE pathophysiology; further research may offer new opportunities for drug discovery to control seizure activity and improve neurodevelopmental outcomes for PDE.

Publisher URL: http://doi.org/10.1534/genetics.117.300137

DOI: 10.1534/genetics.117.300137

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