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

Journal article
Authors Christina Sundal
Susana Carmona
Maria Yhr
Odd Almström
Maria Ljungberg
John Hardy
Carola Oldfors Hedberg
Åsa Fred
José Bras
Anders Oldfors
Oluf Andersen
Rita Guerreiro
Published in Acta Neuropathologica Communications
Volume 7
Pages 188
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Department of Laboratory Medicine
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Pages 188
Language en
Keywords Swedish type hereditary diffuse Leukoencephalopathy with spheroids, HDLS, Alanyl tRNA synthetase, AARS
Subject categories Clinical Medicine


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 asystematic and recent assessment of several family members. We also report the results from exome sequencing analysesindicating 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.

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