Metabolomics analysis of antiquitin deficiency in cultured human cells and plasma: relevance to pyridoxine-dependent epilepsy.

Crowther, Lisa M; Poms, Martin; Zandl-Lang, Martina; Abela, Lucia; Hartmann, Hans; Seiler, Michelle; Mathis, Déborah; Plecko, Barbara (2023). Metabolomics analysis of antiquitin deficiency in cultured human cells and plasma: relevance to pyridoxine-dependent epilepsy. Journal of inherited metabolic disease, 46(1), pp. 129-142. Wiley 10.1002/jimd.12569

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AIM

Deficiency of antiquitin (α-aminoadipic semialdehyde dehydrogenase ), an enzyme involved in lysine degradation and encoded by ALDH7A1, is the major cause of vitamin B6 -dependent epilepsy (PDE-ALDH7A1). Despite seizure control with high dose pyridoxine (PN), developmental delay still occurs in approximately 70% of patients. We aimed to investigate metabolic perturbations due to possible previously unidentified roles of antiquitin, which may contribute to developmental delay, as well as metabolic effects of high dose pyridoxine supplementation reflecting the high doses used for seizure control in patients with PDE-ALDH7A1.

METHODS

Untargeted metabolomics by high resolution mass spectrometry (HRMS) was used to analyse plasma of patients with PDE-ALDH7A1 and two independently generated lines of cultured ReNcell CX human neuronal progenitor cells (NPCs) with CRISPR/Cas mediated antiquitin deficiency. Accumulation of lysine pathway metabolites in antiquitin-deficient NPCs and Western-blot analysisconfirmed knockdown of ALDH7A1.

RESULTS

Metabolomics analysis of antiquitin-deficient NPCs in conditions of lysine restriction and PN supplementation identified changes in metabolites related to the transmethylation and transsulfuration pathways and osmolytes, indicating a possible unrecognized role of antiquitin outside the lysine degradation pathway. Analysis of plasma samples of PN treated patients with PDE-ALDH7A1 and antiquitin-deficient NPCs cultured in conditions comparable to the patient plasma samples demonstrated perturbation of metabolites of the gamma-glutamyl cycle, suggesting potential oxidative stress-related effects in PN-treated patients with PDE-ALDH7A1.

CONCLUSIONS

We postulate that a model of human NPCs with CRISPR/Cas mediated antiquitin deficiency is well suited to characterise previously unreported roles of antiquitin, relevant to this most prevalent form of pyridoxine-dependent epilepsy. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Mathis, Déborah

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1573-2665

Publisher:

Wiley

Language:

English

Submitter:

Pubmed Import

Date Deposited:

14 Oct 2022 12:26

Last Modified:

18 Jan 2023 00:13

Publisher DOI:

10.1002/jimd.12569

PubMed ID:

36225138

Uncontrolled Keywords:

NPCs PDE-ALDH7A1 antiquitin deficiency lysine catabolism metabolomics pyridoxine

BORIS DOI:

10.48350/173745

URI:

https://boris.unibe.ch/id/eprint/173745

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