Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder
© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd..
ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO2. At the cellular level, deficiency of this NADP+-dependent reaction results in marked reduction in NADPH/NADP+ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP+ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:105 |
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| Enthalten in: |
Clinical genetics - 105(2024), 5 vom: 30. Apr., Seite 488-498 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
You, Mikyoung [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.04.2024 Date Revised 09.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cge.14479 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder |
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| 520 | |a ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO2. At the cellular level, deficiency of this NADP+-dependent reaction results in marked reduction in NADPH/NADP+ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP+ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a metabolomics | |
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| 650 | 4 | |a neurodevelopmental disorder | |
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| 700 | 1 | |a Fogle, Halle M |e verfasserin |4 aut | |
| 700 | 1 | |a Rushing, Blake R |e verfasserin |4 aut | |
| 700 | 1 | |a AlMalki, Reem H |e verfasserin |4 aut | |
| 700 | 1 | |a Jaafar, Amal |e verfasserin |4 aut | |
| 700 | 1 | |a Hashem, Mais |e verfasserin |4 aut | |
| 700 | 1 | |a Abdulwahab, Firdous |e verfasserin |4 aut | |
| 700 | 1 | |a Abdel Rahman, Anas M |e verfasserin |4 aut | |
| 700 | 1 | |a Krupenko, Natalia I |e verfasserin |4 aut | |
| 700 | 1 | |a Alkuraya, Fowzan S |e verfasserin |4 aut | |
| 700 | 1 | |a Krupenko, Sergey A |e verfasserin |4 aut | |
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