Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency

• Published in: Genetics (Austin) 2017-12, Vol.207 (4), p.1501-1518
• Main Authors: Pena, Izabella A, Roussel, Yann, Daniel, Kate, Mongeon, Kevin, Johnstone, Devon, Weinschutz Mendes, Hellen, Bosma, Marjolein, Saxena, Vishal, Lepage, Nathalie, Chakraborty, Pranesh, Dyment, David A, van Karnebeek, Clara D M, Verhoeven-Duif, Nanda, Bui, Tuan Vu, Boycott, Kym M, Ekker, Marc, MacKenzie, Alex
• Format: Article
• Language: English
• Subjects: Aldehyde Dehydrogenase - deficiency; Aldehyde Dehydrogenase - genetics; Animals; Bioindicators; Biomarkers; CRISPR; Danio rerio; Degradation; Disabilities; Disease Models, Animal; Embryos; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - physiopathology; gamma-Aminobutyric Acid - genetics; gamma-Aminobutyric Acid - metabolism; Gene Knockout Techniques; Genetic engineering; Genetics; Humans; Investigations; Larvae; Life span; Lysine; Lysine - deficiency; Lysine - metabolism; Mass spectrometry; Mass spectroscopy; Metabolism; Mutants; Mutation; Neonates; Neurodevelopmental disorders; Pathogenesis; Phosphatase; Phosphates; Pyridoxine; Pyridoxine - metabolism; Rare diseases; Scientific imaging; Seizing; Seizures; Seizures - genetics; Seizures - metabolism; Seizures - physiopathology; Supplements; Vitamin B 6 - genetics; Vitamin B 6 - metabolism; Vitamin B6; Zebrafish; Zebrafish - genetics; γ-Aminobutyric acid
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1534/genetics.117.300137

Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene 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 ( ) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 days postfertilization). 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, with a resulting extension of the life span. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency, and low γ-aminobutyric acid levels were observed in the 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.