Alanyl-tRNA Synthetase 2-Related Dementia with Selective Bilateral Frontal Cystic Leukoencephalopathy

Carle, Guilhem; Morin, Alexandre; Noiray, Camille; Roy-Joly, Perrine; Cohen, Laurence; Lévy, Richard; Samaan, Simon; Nadjar, Yann

doi:10.3988/jcn.2018.14.3.420

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…Mutations in other tRNA synthetases have also been associated with leukoencephalopathy. Several cases of adult-onset leukodystrophy were recently shown to be caused by bi-allelic mutations in AARS2 , the gene encoding the mitochondrial alanyl-tRNA synthetase, expanding the spectrum of adult onset neuroaxonal degeneration disorders [6, 7, 20, 28]. The clinical phenotypes of CSF1R and AARS2 related ALSPs showed minor differences [15], sharing major clinical, imaging, and pathologic features, such as cognitive and motor symptoms [20].…”

Section: Discussionmentioning

confidence: 99%

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

Sundal

Carmona

Yhr

et al. 2019

acta neuropathol commun

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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.

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