Khalil, Youssef;
Footitt, Emma;
Vootukuri, Reddy;
Wempe, Michael F;
Coughlin, Curtis R;
Batzios, Spyros;
Wilson, Matthew P;
... Mills, Philippa B; + view all
(2024)
Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency.
Journal of Inherited Metabolic Disease
10.1002/jimd.12783.
(In press).
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Abstract
ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.
| Type: | Article |
|---|---|
| Title: | Assessment of urinary 6-oxo-pipecolic acid as a biomarker for ALDH7A1 deficiency |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/jimd.12783 |
| Publisher version: | https://doi.org/10.1002/jimd.12783 |
| Language: | English |
| Additional information: | © 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | 6‐oxo‐pipecolic acid, ALDH7A1 deficiency, aminoadipic semialdehyde, piperideine‐6‐carboxylate, pyridoxine‐dependent epilepsy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10195015 |
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