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

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.

Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

“…3 , 4 With the discovery of causative genes, 5 , 6 these two clinic‐pathologically similar conditions (i.e., POLD and HDLS) now can be clearly distinguished. 7 For patients diagnosed with POLD and some literature cases pathologically mislabeled as HDLS, the new nomenclature is “colony‐stimulating factor 1 receptor gene ( CSF1R )‐related leukoencephalopathy.” On the other hand, the patients diagnosed with HDLS including the original Swedish family reported in 1984 are belonged to “alanyl‐transfer tRNA synthetase 2 gene ( AARS2 )‐related leukoencephalopathy.” 7 , 8 CSF1R ‐related leukoencephalopathy has become increasingly recognized, and it is estimated to account for 10% of adult‐onset leukodystrophy in the Caucasian populations. 9 , 10…”

Neuroimaging phenotypes of CSF1R‐related leukoencephalopathy: Systematic review, meta‐analysis, and imaging recommendations

“…Due to the varying terminology over time and advances in genetic analyses, there is value in integrating the literature on neuroimaging manifestations of the now genetically defined group of CSF1R ‐related leukoencephalopathy [9]. To date, 96 CSF1R mutations have been described in around 200 families [2].…”

First Polish case of CSF1R-related leukoencephalopathy

“…HDLS was first describe by Axelsson et al in 1984 [8] in a Swedish family with clinical and pathologic similarities to POLD families. Recently, this family was found to carry mutations in AARS2 gene [9]. Even before this genetic discovery, we found that families mislabeled as HDLS were indeed POLD families the diagnosis easier and faster as demonstrated in the case presented by Żur-Wyrozumska et al [1].…”