Current knowledge for pyridoxine-dependent epilepsy: a 2016 update

ABSTRACT

Pyridoxine-dependent epilepsy (PDE) is a rare genetic condition characterized by intractable and recurrent neonatal seizures that are uniquely alleviated by high doses of pyridoxine (vitamin B6). This recessive disease is caused by mutations in ALDH7A1, a gene encoding Antiquitin, an enzyme central to lysine degradation. This results in the pathogenic accumulation of the lysine intermediates Aminoadipate Semialdehyde (AASA) and its cyclic equilibrium form Piperideine-6-carboxylate (P6C) in body fluids; P6C reacts with pyridoxal-5ʹ-phosphate (PLP, the active form of vitamin B6) causing its inactivation and leading to pyridoxine-dependent seizures. While PDE is responsive to pharmacological dosages of pyridoxine, despite lifelong supplementation, neurodevelopment delays are observed in >75% of PDE cases. Thus, adjunct treatment strategies are emerging to both improve seizure control and moderate the delays in cognition. These adjunctive therapies, lysine restriction and arginine supplementation, separately or in combination (with pyridoxine thus termed ‘triple therapy’), have shown promising results and are recommended in all PDE patients. Other new therapeutic strategies currently in preclinical phase of study include antisense therapy and substrate reduction therapy. We present here a comprehensive review of current treatment options as well as PDE phenotype, differential diagnosis, current management and views upon the future of PDE research.

KEYWORDS:

• Pyridoxine-dependent epilepsy
• recurrent seizures
• vitamin B6
• pyridoxine
• pyridoxal phosphate
• lysine restriction
• arginine supplementation
• antiquitin
• aldh7a1
• aminoadipate semialdehyde synthase
• treatment

Acknowledgements

The authors would like to thank the support provided by the Care for Rare (http://care4rare.ca/), Genome Canada, International PDE Consortium, the Children’s Hospital of Eastern Ontario (CHEO) Research Institute, BC Children’s Hospital Foundation, Rare Diseases Foundation (Vancouver, Canada) and the Canadian Institute of Health Research (CIHR). The funders had no role in this study, decision to publish and preparation of the manuscript. The authors would also like to thank the PDE patient and families who are both the reason and inspiration for our work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

IAP has a postdoctoral fellowship funded by Care for Rare project (http://care4rare.ca/); CvK’s salary is partly funded by the Michael Smith Foundation for Health Research Scholar Award; Our work is funded by the Children’s Hopsital of Eastern Ontario (CHEO) Reseach Institute, BC Children’s Hospital Foundation, Rare Diseases Foundation (Vancouver, Canada), Genome Canada and the Canadian Institute of Health Research (CIHR).