A novel neurodegenerative spectrum disorder in patients with MLKL deficiency

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  • Soren L. Faergeman, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Hayley Evans, University of Oxford, Oxford, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Kathrine E. Attfield, University of Oxford, Oxford, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Christiane Desel, University of Oxford, Oxford, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Subita Balaram Kuttikkatte, University of Oxford, Oxford, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Mette Sommerlund
  • Lise Torp Jensen
  • Jorgen Frokiaer
  • Manuel A. Friese, University Medical Center Hamburg-Eppendorf
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  • Paul M. Matthews, Imperial College London
  • ,
  • Christian Luchtenborg, Heidelberg University 
  • ,
  • Britta Brügger, Heidelberg University 
  • ,
  • Annette Bang Oturai, University of Copenhagen
  • ,
  • Calliope A. Dendrou, Wellcome Trust Centre for Human Genetics
  • ,
  • Lars Fugger

Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.

Original languageEnglish
Article number303
JournalCell Death and Disease
Volume11
ISSN2041-4889
DOIs
Publication statusPublished - May 2020

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