Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements
Year: 2025
Type: article
Study design: Observational Study
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, a key regulator of intracellular redox homeostasis. Recently, 5 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 2 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 developmental epileptic encephalopathy, and propose novel biomarkers for diagnosis and treatment.
Source: Genetics in Medicine
Authors: Hannah M. German, Maha S. Zaki, Muhammad A. Usmani, Irem Karagoz, Stephanie Efthymiou, Mohamed S. Abdel-Hamid, Haya Abdelhafez Arabiyat, Amama Ghaffar, Mohsin Shahzad, Hans van Bokhoven, Zubair M. Ahmed, Omid Yaghini, Neda Hosseini, Maede Majidinezhad, Shahryar Alavi, Marjolein Bosma, Melissa H. Broeks, Dilşad Türkdoğan, Mohnish Suri, Laiz Laura de Godoy, Nanda M. Verhoeven-Duif, Sheikh Riazuddin, Joseph G. Gleeson, Cesar Alves, Judith J.M. Jans, Saima Riazuddin, Henry Houlden, Reza Maroofian
Institutions: Utrecht University, University Medical Center Utrecht, National Research Centre, University of Maryland, Baltimore, Kohsar University Murree, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, UCL Queen Square Institute of Neurology, University College London, Ministry of Health, University of the Punjab, Centre of Excellence in Molecular Biology, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Isfahan University of Medical Sciences, Marmara University, Nottingham University Hospitals NHS Trust, University of Pennsylvania, Allama Iqbal Medical College, University of Health Sciences Lahore, University of California San Diego, Rady Children's Institute for Genomic Medicine, Boston Children's Hospital, Harvard University
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,110
OpenAlex ID: W4414563928