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Pyridoxine Dependent Epilepsy

The potentials of a novel add-on therapy for PDE

Lysine restriction has been shown by a proof-principle-study to reduce neurotoxic metabolites and improve, seizure control, behavior and/or psychomotor development. But more evidence is required before diet comes mainstay therapy.

Introduction

Pyridoxine-dependent epilepsy (PDE) is a rare yet causally treatable metabolic epilepsy (incidence 1:20.000 to 1:200.000, depending on screening / diagnostic approach and geographic location). The disease is characterized by intractable seizures that do not respond to conventional antiepileptic medications, but are often controlled by daily high doses of vitamin B6 (pyridoxine). Even with early diagnosis and B6 treatment, however, outcomes are often poor; 80% of these children still suffer developmental delay and intellectual disability.

PDE has recently been elucidated as a cerebral organic aciduria and ongoing neurotoxicity despite vitamin B6 dosages may explain these poor outcomes. Antiquitin (ATQ) or the ALDH7A gene (see Gene Reviews or OMIM for details), encodes an enzyme in the lysine degradation pathway named α-amino adipic semi-aldehyde dehydrogenase. Deficiency of this enzyme leads to accumulation of chemical substances -called AASA, P6C and pipecolic acid- that are neurotoxic causing developmental and cognitive deficits.

Understanding the pathophysiology of PDE provides 2 major advances:

improved diagnostics through screening intractable epilepsy patients with specific and sensitive biomarkers (e.g. urinary AASA) is now possible;
a new target for therapeutic intervention has become apparent: the lysine degradation pathway.

Just as a modified diet or substrate inhibition significantly improves the outcomes for children diagnosed with Phenylketonuria (PKU) and Glutaric Aciduria type I, a similar approach for PDE -targeting the lysine pathway in this case- offers the promise of similar dramatic improvements in outcome.
Indeed, our proof-of-principle study (van Karnebeek, Hartmann et al; manuscript in preparation) shows very promising results.

Please join the PDE Consortium

by entering your patients into the PDE Registry, via the link below...

Access PDE Registry

... so that we can collaboratively improve outcomes for affected patients worldwide, through the diet study and other research endeavors.

Read more on the registry.

Download PDE Review & Guidelines 2011

by Stockler et al

PDE Review & Guidelines

It's our mission to:

ensure that every child with PDE is diagnosed and treated early

improve treatment such that every affected child’s outcome is optimized

The 2nd PDE consortium meeting

will take place in Birmingham during the SSIEM 2012 meeting

This initiative is part of a larger project titled the ‘Treatable Intellectual Disability Endeavour in British Columbia’ (TIDE-BC). It is the aim of this project to create a Best Care Practice to enhance diagnosis and treatment of rare diseases such as PDE and the 80 other treatable inborn errors of metabolism which cause intellectual disability and/or epilepsy. While current practice is traditionally focused upon testing for frequent causes, our initiative is built upon the idea that we should prioritize the identification of treatable diseases, even if rare. This strategy provides the opportunity to profoundly improve outcome of the affected individuals. For more information on the TIDE BC project, please visit our website.