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Identification of a novel biomarker for pyridoxine-dependent epilepsy: Implications for newborn screening.
J Inherit Metab Dis. 2019 Jan 21;:
Authors: Wempe MF, Kumar A, Kumar V, Choi YJ, Swanson MA, Friederich MW, Hyland K, Yue WW, Van Hove JLK, Coughlin CR
Abstract
Pyridoxine-dependent epilepsy (PDE) is often characterized as an early onset epileptic encephalopathy with dramatic clinical improvement following pyridoxine supplementation. Unfortunately, not all patients present with classic neonatal seizures or respond to an initial pyridoxine trial, which can result in the under diagnosis of this treatable disorder. Restriction of lysine intake and transport is associated with improved neurologic outcomes, although treatment should be started in the first year of life to be effective. Because of the documented diagnostic delay and benefit of early treatment, we aimed to develop a newborn screening method for PDE. Previous studies have demonstrated the accumulation of Δ1 -piperideine-6-carboxylate and α-aminoadipic semialdehyde in individuals with PDE, although these metabolites are unstable at room temperature limiting their utility for newborn screening. As a result, we sought to identify a biomarker that could be applied to current newborn screening paradigms. We identified a novel metabolite, 6-oxo-pipecolate, which accumulates in substantial amounts in blood, plasma, urine and cerebral spinal fluid of individuals with PDE. Using a stable isotope labeled internal standard, we developed a non-derivatized liquid chromatography tandem mass spectrometry-based method to quantify 6-oxo-pipecolate. This method replicates the analytical techniques used in many laboratories and could be used with few modifications in newborn screening programs. Furthermore, 6-oxo-pipecolate was measurable in urine for four months even when stored at room temperature. Herein, we report a novel biomarker for PDE that is stable at room temperature and can be quantified using current newborn screening techniques. This article is protected by copyright. All rights reserved.
PMID: 30663059 [PubMed - as supplied by publisher]
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,