2. Academic Validation
  3. An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids

An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids

  • Acta Neuropathol Commun. 2019 Nov 27;7(1):188. doi: 10.1186/s40478-019-0843-y.
Christina Sundal 1,  Susana Carmona 2,  Maria Yhr 3,  Odd Almström 1,  Maria Ljungberg 4,  John Hardy 5,  Carola Hedberg-Oldfors 3,  Åsa Fred 6,  José Brás 2 7,  Anders Oldfors 3,  Oluf Andersen 8,  Rita Guerreiro 9 10
Affiliations

Affiliations

  • 1 Department of Clinical Neurology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 11, 3rd floor, Sahlgrenska University Hospital, 413 45, Göteborg, Sweden.
  • 2 Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. N.E, Grand Rapids, MI, 49503-2518, USA.
  • 3 Department of Laboratory Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
  • 4 Department of Radiation Physics, Institute of Clinical Sciences, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
  • 5 Department of Neurodegenerative Disease, Reta Lila Weston Laboratories, Queen Square Genomics, UCL Dementia Research Institute, London, UK.
  • 6 Department of Pathology, Hospital of Halland, Halmstad, Sweden.
  • 7 Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
  • 8 Department of Clinical Neurology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gröna Stråket 11, 3rd floor, Sahlgrenska University Hospital, 413 45, Göteborg, Sweden. [email protected].
  • 9 Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. N.E, Grand Rapids, MI, 49503-2518, USA. [email protected].
  • 10 Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA. [email protected].
PMID: 31775912 DOI: 10.1186/s40478-019-0843-y
Abstract

Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.

Keywords

AARS; Alanyl tRNA synthetase; HDLS; Swedish type hereditary diffuse Leukoencephalopathy with spheroids.

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