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

Christina Sundal,Oluf Andersen,John Hardy,Rita Guerreiro,Odd Almström,Maria Yhr,Maria Ljungberg,Åsa Fred,Susana Carmona,Anders Oldfors,José Brás,Carola Hedberg-Oldfors

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.

Highlights

Adult onset leukodystrophies are a heterogenous group of genetic disorders associated with myelin pathology [13, 21]
In 1984, we described a severe adult onset leukoencephalopathy occurring in a dominant segregation pattern in a large western Swedish family, with histopathology assessment performed in four autopsies available from two generations
Of 8 Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS) cases in generations II-III, 5 were documented by relevant diagnostic codes or hospital records from regional psychiatric or geriatric institutions, with HDLS confirmed by histopathology in one (II:8)

Summary

Introduction

Adult onset leukodystrophies are a heterogenous group of genetic disorders associated with myelin pathology [13, 21]. An adolescence-to adult onset leukoencephalopathy with axonal spheroids and glial lipofuscin-like pigment was described [38], later termed Pigmentary Orthochromatic Leukodystrophy (POLD). The genetic study of several US families with at least one neuropathologically confirmed HDLS case, and the expansion of this study to an international consortium, led to the identification of disease causative mutations in the gene coding for the colony stimulating factor 1. More recently mutations in this gene have been associated with the development of POLD and the diagnostic term Adult-onset Leukoencephalopathy with Spheroids and Pigmented glia (ALSP) was coined as a unifying identifier for POLD and HDLS, justified by their essentially common neuropathology [1]. Not all cases of leukoencephalopathy with neuroaxonal spheroids from an international biobank material carried CSF1R mutations [9], and until now no locus has been associated with the original Swedish HDLS [4] (HDLS-S)

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