German, Hannah M;
Zaki, Maha S;
Usmani, Muhammad A;
Karagoz, Irem;
Efthymiou, Stephanie;
Abdel-Hamid, Mohamed S;
Arabiyat, Haya Abdelhafez;
... Maroofian, Reza; + view all
(2025)
Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements.
Genetics in Medicine
, Article 101587. 10.1016/j.gim.2025.101587.
(In press).
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Abstract
Purpose: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle (MAS), a key regulator of intracellular redox homeostasis. Recently, five patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy. // Methods: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency. // Results: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed two severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation. // Conclusion: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of DEE, and propose novel biomarkers for diagnosis and treatment.
| Type: | Article |
|---|---|
| Title: | Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2025.101587 |
| Publisher version: | https://doi.org/10.1016/j.gim.2025.101587 |
| Language: | English |
| Additional information: | Under a Creative Commons license, https://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Malate-aspartate shuttle, GOT2, neurodevelopmental disorder, epilepsy, mitochondrial disorders |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10214902 |
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