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Ezer S, Daana M, Park JH, et al. Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity. Brain. 2021;doi: 10.1093/brain/awab416.
Ezer, S., Daana, M., Park, J. H., Yanovsky-Dagan, S., Nordström, U., Basal, A., Edvardson, S., Saada, A., Otto, M., Meiner, V., Marklund, S. L., Andersen, P. M., & Harel, T. (2021). Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity. Brain : a journal of neurology, . https://doi.org/10.1093/brain/awab416
Ezer, Shlomit, et al. "Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity." Brain : a journal of neurology vol. (2021). doi: https://doi.org/10.1093/brain/awab416
Ezer S, Daana M, Park JH, Yanovsky-Dagan S, Nordström U, Basal A, Edvardson S, Saada A, Otto M, Meiner V, Marklund SL, Andersen PM, Harel T. Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity. Brain. 2021 Nov 11; doi: 10.1093/brain/awab416. Epub 2021 Nov 11. PMID: 34788402.
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Brain. 2021 Nov 11; doi: 10.1093/brain/awab416. Epub 2021 Nov 11.

Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.

Brain : a journal of neurology

Shlomit Ezer, Muhannad Daana, Julien H Park, Shira Yanovsky-Dagan, Ulrika Nordström, Adily Basal, Simon Edvardson, Ann Saada, Markus Otto, Vardiella Meiner, Stefan L Marklund, Peter Munch Andersen, Tamar Harel

Affiliations

  1. Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel 9112001.
  2. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel 9112001.
  3. Child Development Centers, Clalit Health Care Services, Jerusalem District, Israel.
  4. Department of Clinical Science, Neurosciences, Umeå University, 901 87 Umeå, Sweden.
  5. Department of General Pediatrics, University of Münster, 48149 Münster, Germany.
  6. Pediatric Neurology Unit, Hadassah Medical Organization, Jerusalem, Israel 9112001.
  7. Department of Neurology, University Clinic, 89081 Ulm, Germany.
  8. Department of Neurology, University Clinic, 06120 Halle (Saale), Germany.
  9. Department of Medical Biosciences, Clinical Chemistry, Umeå University, 907 36 Umeå, Sweden.

PMID: 34788402 DOI: 10.1093/brain/awab416

Abstract

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Keywords: SOD1; amyotrophic lateral sclerosis; exome sequencing; superoxide dismutase

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