Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants

Saskia B Wortmann; Rene G Feichtinger; Lucia Abela; Loes A van Gemert; Mélodie Aubart; Claire-Marine Dufeu-Berat; Nathalie Boddaert; Rene de Coo; Lara Stühn; Jasmijn Hebbink; Wolfram Heinritz; Julia Hildebrandt; Nastassja Himmelreich; Christoph Korenke; Anna Lehman; Thomas Leyland; Christine Makowski; Rafael Jenaro Martinez Marin; Pauline Marzin; Chris Mühlhausen; Marlène Rio; Agnes Rotig; Charles-Joris Roux; Manuel Schiff; Tobias B Haack; Steffen Syrbe; Stas A Zylicz; Christian Thiel; Maria Veiga da Cunha; Emile van Schaftingen; Matias Wagner; Johannes A Mayr; Ron A Wevers; Eugen Boltshauser; Michel A Willemsen

doi:10.1212/NXG.0000000000200146

Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants

Neurol Genet. 2024 Apr 5;10(2):e200146. doi: 10.1212/NXG.0000000000200146. eCollection 2024 Apr.

Authors

Saskia B Wortmann¹, Rene G Feichtinger¹, Lucia Abela¹, Loes A van Gemert¹, Mélodie Aubart¹, Claire-Marine Dufeu-Berat¹, Nathalie Boddaert¹, Rene de Coo¹, Lara Stühn¹, Jasmijn Hebbink¹, Wolfram Heinritz¹, Julia Hildebrandt¹, Nastassja Himmelreich¹, Christoph Korenke¹, Anna Lehman¹, Thomas Leyland¹, Christine Makowski¹, Rafael Jenaro Martinez Marin¹, Pauline Marzin¹, Chris Mühlhausen¹, Marlène Rio¹, Agnes Rotig¹, Charles-Joris Roux¹, Manuel Schiff¹, Tobias B Haack¹, Steffen Syrbe¹, Stas A Zylicz¹, Christian Thiel¹, Maria Veiga da Cunha¹, Emile van Schaftingen¹, Matias Wagner¹, Johannes A Mayr¹, Ron A Wevers¹, Eugen Boltshauser¹, Michel A Willemsen¹

Affiliation

¹ From the University Children's Hospital Salzburg (S.B.W., R.G.F., J.A.M.), Austria; Amalia Children's Hospital (S.B.W., L.A.G., J. Hebbink, M.A.W.), Department of Pediatrics (Pediatric Neurology), Nijmegen, The Netherlands; Division of Child Neurology (L.A., E.B.), University Children's Hospital Zurich, Switzerland; Pediatric Neurology Department (M.A.), Necker-Enfants Malades University Hospital, Paris Cité University, APHP; Reference Centre for Mitochondrial Disorders (CARAMMEL) (C.-M.D.-B., M.S.), Hôpital Necker-Enfants-Malades, APHP, Université Paris Cité, Imagine Institute, Genetics of Mitochondrial Disorders, INSERM UMR 1163; 6Paediatric Radiology Department (N.B.), AP-HP, Hôpital Necker Enfants Malades, Université Paris Cité, Institut Imagine INSERM U1163France; Department of Toxicogenomics (R.C.), Research School of Mental Health and Neuroscience, Maastricht University, The Netherlands; Institute of Medical Genetics and Applied Genomics (L.S., T.B.H.), University of Tübingen; Praxis für Humangenetik (W.H.); Carl-Thiem-Klinikum Cottbus (W.H.); Center for Human Genetics Tübingen (J. Hildebrandt, N.H.); CeGaT GmbH (J. Hildebrandt, N.H.), Tübingen; Department Pediatrics (N.H., C.T.), Centre for Child and Adolescent Medicine, University of Heidelberg; Department of Neuropediatrics (C.K.), University Children's Hospital, Klinikum Oldenburg, Germany; University of British Columbia (A.L.), Vancouver, Canada; Royal Belfast Hospital for Sick Children (T.L.), Belfast, Northern Ireland; University Hospital (C. Makowski), LMU Munich, Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Munich, Germany; Department of Neurology (R.J.M.M.), Hospital Universitario La Paz, Madrid, Spain; Reference Center for Intellectual Disabilities of Rare causes (P.M., M.R.), Federation de médecine Génomique des maladies Rares, APHP, Hôpital Necker-Enfants Malades, Paris, France; University Medical Centre Göttingen (C. Mühlhausen), Department of Pediatrics and Adolescent Medicine, Göttingen, Germany; Université Paris Cité (A.R.), Imagine Institute, Genetics of Mitochondrial Disorders, INSERM UMR 1163; Paediatric Radiology Department (C.-J.R), AP-HP, Hôpital Necker Enfants Malades, Université Paris Cité, Institut Imagine INSERM U1163, Paris France; Division of Pediatric Epileptology (S.S.), Centre for Child and Adolescent Medicine, University of Heidelberg, Germany; Department of Neurology (S.A.Z.), LangeLand Hospital, Zoetermeer, The Netherlands; Metabolic Research Group (M.V.C., E.S.), de Duve Institute and UCLouvain, Brussels, Belgium; Technical University of Munich (M. Wagner), School of Medicine, Institute of Human Genetics, Munich, Germany; and Department of Human Genetics (R.A.W.), Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands.

Abstract

Background and objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals.

Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype.

Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile.

Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.