Evidence map›Paper›PMID 41001736›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2025

Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.

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 and 18 more

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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Hannah M GermanSection Metabolic Diagnostics, Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Muhammad A UsmaniDepartment of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD; Department of Biotechnology, Kohsar University Murree, Pakistan; Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
Irem KaragozDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Stephanie EfthymiouDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Mohamed S Abdel-HamidMedical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Haya Abdelhafez ArabiyatMinistry of Health, Al-Hussein Salt New Hospital, As-Salt, Jordon.
Amama GhaffarDepartment of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD; Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Mohsin ShahzadDepartment of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
Hans van BokhovenDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
Zubair M AhmedDepartment of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD; Department of Molecular Biology and Biochemistry, School of Medicine, University of Maryland, Baltimore, MD.
Omid YaghiniChild Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
Neda HosseiniDepartment of Pediatric Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
Maede MajidinezhadDepartment of Pediatric Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
Shahryar AlaviDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; Palindrome, Isfahan, Iran.
Marjolein BosmaSection Metabolic Diagnostics, Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Melissa H BroeksSection Metabolic Diagnostics, Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Dilşad TürkdoğanMarmara University, Medical Faculty, Department of Pediatric Neurology, Istanbul, Türkiye.
Mohnish SuriClinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
Laiz Laura de GodoyDepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Nanda M Verhoeven-DuifSection Metabolic Diagnostics, Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Sheikh RiazuddinDepartment of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
Joseph G GleesonDepartment of Neurosciences, University of California, San Diego, La Jolla, CA; Rady Children's Institute for Genomic Medicine, San Diego, CA.
Cesar AlvesDepartment of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Judith J M JansSection Metabolic Diagnostics, Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
Saima RiazuddinDepartment of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD; Department of Molecular Biology and Biochemistry, School of Medicine, University of Maryland, Baltimore, MD.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Reza MaroofianDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: r.maroofian@ucl.ac.uk.

Funding

Genetics and Functional Studies of Autosomal Recessive Neurological DisordersR01NS107428 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI Saima Riazuddin · 2018 to 2026
$4.7M
Molecular Characterization of Pontocerebellar HypoplasiaR01NS098004 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JOSEPH G GLEESON · 2016 to 2026
$4.6M
NINDS NIH HHS R01 NS098004NINDS NIH HHS R01 NS107428
6 · The paper itself

Abstract

purposeGlutamic-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.

methodsWe 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.

resultsMost 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.

conclusionThese 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.

Indexed as

Aspartate AminotransferasesEpilepsyMovement DisordersNeurodevelopmental DisordersAdolescentChildChild, PreschoolFemaleGenotypeHumansInfantIntellectual DisabilityMaleMicrocephalyMutationPhenotypeAspartate AminotransferasesEpilepsyGOT2Malate-aspartate shuttleMitochondrial disordersNeurodevelopmental disorder

Identifiers

PMID41001736
PMCPMC13108455

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