Genetics in medicine : official journal of the American College of Medical Genetics · 2025
Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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German Hannah M, Zaki Maha S, Usmani Muhammad A, Karagoz Irem, Efthymiou Stephanie, Abdel-Hamid Mohamed S, Arabiyat Haya Abdelhafez, Ghaffar Amama, Shahzad Mohsin, van Bokhoven Hans, Ahmed Zubair M, Yaghini Omid, Hosseini Neda, Majidinezhad Maede, Alavi Shahryar, Bosma Marjolein, Broeks Melissa H, Türkdoğan Dilşad, Suri Mohnish, Laura de Godoy Laiz, Verhoeven-Duif Nanda M, Riazuddin Sheikh, Gleeson Joseph G, Alves Cesar, Jans Judith J M, Riazuddin Saima, Houlden Henry, Maroofian Reza
Аннотация
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.
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.