Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics

Kuhara, Tomiko; Akiyama, Tomoyuki; Ohse, Morimasa; Koike, Takayoshi; Shibasaki, Jun; Imai, Katsumi; Cooper, Arthur J. L.

doi:10.1016/j.ab.2020.113739

Cited by 21 publications

(13 citation statements)

References 32 publications

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“…For example, in a study by Wang et al, they report high levels of proline and glutamate and low levels of fatty acids in serum, which is consistent with the dysfunction of oxidative metabolism and fatty acid degeneration, leading to the increased inflammatory effect and energy deficiency found in our study [29]. Furthermore, in a study examining urine, the authors confirm our results by implicating the dysfunction of mitochondrial oxidation pathways' intermediates, such as glutamate, lysine and proline precursors, leading to cell death and neurotoxicity [64]. The record of metabolic dysfunction at the point of injury in epileptic sufferers is both corroborated and expanded upon by this first reported study of ENOS in postmortem brain tissue from Brodmann Area 8/46.…”

Section: Discussionsupporting

confidence: 92%

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

et al. 2020

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Epilepsy not-otherwise-specified (ENOS) is one of the most common causes of chronic disorders impacting human health, with complex multifactorial etiology and clinical presentation. Understanding the metabolic processes associated with the disorder may aid in the discovery of preventive and therapeutic measures. Post-mortem brain samples were harvested from the frontal cortex (BA8/46) of people diagnosed with ENOS cases (n = 15) and age- and sex-matched control subjects (n = 15). We employed a targeted metabolomics approach using a combination of proton nuclear magnetic resonance (1H-NMR) and direct injection/liquid chromatography tandem mass spectrometry (DI/LC-MS/MS). We accurately identified and quantified 72 metabolites using 1H-NMR and 159 using DI/LC-MS/MS. Among the 212 detected metabolites, 14 showed significant concentration changes between ENOS cases and controls (p < 0.05; q < 0.05). Of these, adenosine monophosphate and O-acetylcholine were the most commonly selected metabolites used to develop predictive models capable of discriminating between ENOS and unaffected controls. Metabolomic set enrichment analysis identified ethanol degradation, butyrate metabolism and the mitochondrial beta-oxidation of fatty acids as the top three significantly perturbed metabolic pathways. We report, for the first time, the metabolomic profiling of postmortem brain tissue form patients who died from epilepsy. These findings can potentially expand upon the complex etiopathogenesis and help identify key predictive biomarkers of ENOS.

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Section: Discussionsupporting

confidence: 92%

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

et al. 2020

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“…The 6-oxoPIP levels in urine found in our study were comparable to those previously reported by Kuhara et al (31). The difference in concentration between 6-oxoPIP and 2-OPP was also observed in plasma, though to a lesser extent as seen in urine (mean 6-oxoPIP 7.5 μM versus mean 2-OPP 3.1 μM in plasma), with 6-oxoPIP levels in plasma being comparable to those reported by Wempe et al (30).…”

Section: Untargeted Metabolomics/ngms Identifies Novel Biomarkers In Body Fluids Of Pde-aldh7a1 Patientssupporting

confidence: 92%

“…For biomarker C, a reference standard of 6-oxoPIP was commercially available, and by comparison of its IR spectrum to the IR spectrum measured for the signal observed in patient body fluids, we were able to confirm the identity of biomarker C as 6-oxoPIP (Fig 2C). During the preparation of this manuscript, 6-oxoPIP has been reported by two independent studies as a novel PDE-ALDH7A1 biomarker (30,31). However, its suitability for detection in DBS using a direct-infusion MS method, which is commonly used for newborn screening, was not evaluated in these studies, as Wempe et al (30) To further examine the suitability of 2-OPP and 6-oxoPIP as possible biomarkers for PDE-ALDH7A1, we developed quantitative targeted assays for these markers, using LC-tandem MS for analysis in plasma, urine, and CSF.…”

Section: Untargeted Metabolomics/ngms Identifies Novel Biomarkers In Body Fluids Of Pde-aldh7a1 Patientsmentioning

confidence: 99%

Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy

Engelke

Outersterp

Merx

et al. 2021

Journal of Clinical Investigation

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Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5'phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Combining the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we were able to discover a novel biomarker for PDE-ALDH7A1, 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP), and confirmed 6oxopiperidine-2-carboxylic acid (6-oxoPIP) as biomarker. We demonstrated the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we showed that 2-OPP accumulates in brain tissue of patients and aldh7a1 knock-out mice, and induced epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.

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Section: Feature M/z Rt (Min) Fold Changementioning

confidence: 99%

Identification of novel biomarkers for pyridoxine-dependent epilepsy using untargeted metabolomics and infrared ion spectroscopy - biochemical insights and clinical implications

Merx

et al. 2021

Preprint

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Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5’-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Using a combination of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we have been able to discover novel biomarkers for PDE-ALDH7A1: 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) and 6-oxopiperidine-2-carboxylic acid (6-oxoPIP). We demonstrate the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we show that 2-OPP accumulates in brain tissue of patients and Aldh7a1 knock-out mice, and induces epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.

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Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics

Cited by 21 publications

References 32 publications

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy

Identification of novel biomarkers for pyridoxine-dependent epilepsy using untargeted metabolomics and infrared ion spectroscopy - biochemical insights and clinical implications

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