Intellectual Disability Associated With Pyridoxine-Responsive Epilepsies: The Need to Protect Cognitive Development.

Bjørnar Hassel,Sigrun Hope,Ane Gretesdatter Rogne

doi:10.3389/fpsyt.2019.00116

Abstract

Pyridoxine (vitamin B6)-responsive epilepsies are severe forms of epilepsy that manifest as seizures immediately after birth, sometimes in utero, sometimes months, or years after birth. Seizures may be treated efficiently by life-long supplementation with pyridoxine or its biologically active form, pyridoxal phosphate, but even so patients may become intellectually disabled, for which there currently is no effective treatment. The condition may be caused by mutations in several genes (TNSALP, PIGV, PIGL, PIGO, PNPO, PROSC, ALDH7A1, MOCS2, or ALDH4A1). Mutations in ALDH7A1, MOCS2, and ALDH4A1 entail build-up of reactive aldehydes (α-aminoadipic semialdehyde, γ-glutamic semialdehyde) that may react non-enzymatically with macromolecules of brain cells. Such reactions may alter the function of macromolecules, and they may produce “advanced glycation end products” (AGEs). AGEs trigger inflammation in the brain. This understanding points to aldehyde-quenching, anti-AGE, or anti-inflammatory therapies as possible strategies to protect cognitive development and prevent intellectual disability in affected children. Studies on how aldehydes traverse cell membranes and how they affect brain function could further the development of therapies for patients with pyridoxine-responsive epilepsies.

Highlights

Pyridoxine-Responsive Epilepsy: Clinical Manifestations and Underlying Molecular CausesPyridoxine-responsive epilepsy is a severe form of epilepsy that manifests as generalized seizures immediately after birth, sometimes in utero
It seems that a lack of pyridoxal 5′-phosphate (PLP) in the brain is the cause of epilepsy in all the above-mentioned conditions: in TNSALP mutations and in mutations causing dysfunctional GPI anchoring of tissue non-specific alkaline phosphatase the transfer of PLP in the form of pyridoxal into the brain is suboptimal; in PNPO mutations, PLP is not produced normally in the liver; in ALDH7A1, MOCS2, and ALDH4A1 mutations, PLP is inactivated by accumulating reactive metabolites
Pyridoxine-responsive epilepsies are often compounded by neurodevelopmental disorders, most importantly intellectual disability

Summary

INTRODUCTION

Pyridoxine-Responsive Epilepsy: Clinical Manifestations and Underlying Molecular Causes. PROSC mutations entail low CSF levels of PLP, possibly because PLP is consumed through spontaneous reactions with other cell constituents, and the epilepsy that accompanies the condition is pyridoxine-responsive It seems that a lack of PLP in the brain is the cause of epilepsy in all the above-mentioned conditions: in TNSALP mutations and in mutations causing dysfunctional GPI anchoring of tissue non-specific alkaline phosphatase the transfer of PLP in the form of pyridoxal into the brain is suboptimal; in PNPO mutations, PLP is not produced normally in the liver; in ALDH7A1, MOCS2, and ALDH4A1 mutations, PLP is inactivated by accumulating reactive metabolites. From toxicological and metabolic studies [42, 61] it is clear that various aldehydes do cross cell membranes, but the transfer mechanism remains unknown and escapes therapeutic manipulation

A PATHOGENIC LACK OF DOWNSTREAM PRODUCTS DURING ENZYME DYSFUNCTION?

CONCLUSION