| Title: |
Advancing Neonatal Screening for Pyridoxine-Dependent Epilepsy-ALDH7A1 Through Combined Analysis of 2-OPP, 6-Oxo-Pipecolate and Pipecolate in a Butylated FIA-MS/MS Workflow |
| Authors: |
Donge, Mylène; Marie, Sandrine; Pochet, Amandine; Marcelis, Lionel; Luis, Geraldine; Boemer, François; Prouteau, Clément; Mesli, Samir; Cuykx, Matthias; Nguyen-Khoa, Thao; Guénet, David; Empain, Aurélie; Barth, Magalie; Dauriat, Benjamin; Laroche-Raynaud, Cécile; De Laet, Corinne; Verloo, Patrick; Jonckheere, An I.; Schiff, Manuel; Nassogne, Marie-Cécile; Dewulf, Joseph P. |
| Contributors: |
UCL - (SLuc) Service de biochimie médicale; UCL - (SLuc) Institut des maladies rares; UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology |
| Source: |
International Journal of Neonatal Screening, Vol. 11, no.3, p. 59 (2025) |
| Publisher Information: |
MDPI AG |
| Publication Year: |
2025 |
| Collection: |
DIAL@USL-B (Université Saint-Louis, Bruxelles) |
| Subject Terms: |
pyridoxine-dependent epilepsy; ALDH7A1; 2-OPP; 6-oxo-pipecolate; pipecolate; FIA-MS/MS; newborn screening; dried blood spots; 2S; 6S-/2S; 6R-oxopropylpiperidine-2-carboxylate |
| Description: |
Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with seizures unresponsive to conventional anticonvulsant medications but responsive to high-dose of pyridoxine (vitamin B6). Adjunctive lysine restriction and arginine supplementation have also shown potential in improving neurodevelopmental outcomes. Given the significant benefit of early intervention, PDE-ALDH7A1 is a strong candidate for newborn screening (NBS). However, traditional biomarkers are biochemically unstable at room temperature (α-AASA and piperideine-6-carboxylate) or lack sufficient specificity (pipecolate), limiting their utility for biomarker-based NBS. The recent identification of two novel and stable biomarkers, 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylate (2-OPP) and 6-oxo-pipecolate (oxo-PIP), offers renewed potential for biochemical NBS. We evaluated the feasibility of incorporating 2-OPP, oxo-PIP, and pipecolate into routine butylated FIA-MS/MS workflows used for biochemical NBS. A total of 9402 dried blood spots (DBS), including nine confirmed PDE-ALDH7A1 patients and 9393 anonymized controls were analyzed using a single multiplex assay. 2-OPP emerged as the most sensitive biomarker, identifying all PDE-ALDH7A1 patients with 100% sensitivity and a positive predictive value (PPV) of 18.4% using a threshold above the 99.5th percentile. Combining elevated 2-OPP (above the 99.5th percentile) with either pipecolate or oxo-PIP (above the 85.0th percentile) as secondary marker detected within the same multiplex FIA-MS/MS assay further improved the PPVs to 60% and 45%, respectively, while maintaining compatibility with butanol-derivatized method. Notably, increasing the 2-OPP threshold above the 99.89th percentile, in combination with either pipecolate or ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
boreal:304307; https://hdl.handle.net/2078.1/304307 |
| DOI: |
10.3390/ijns11030059 |
| Availability: |
https://hdl.handle.net/2078.1/304307; https://doi.org/10.3390/ijns11030059 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.97200516 |
| Database: |
BASE |