Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Abstract

IMPORTANCE Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder.OBJECTIVE To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. DESIGN, SETTINGS, AND PARTICIPANTSIn this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing.

Two Korean siblings with recently described ovarioleukodystrophy related to AARS2 mutations

“…Our family, the first Korean cases of ovarioleukodystrophy related to AARS2 mutations, have the compound heterozygous mutations p.Tyr321* and p.Met151Thr which have not yet been reported. The phenotypes of the siblings are in line with those described earlier: no cardiomyopathy, primary ovarian failure in the fourth decade of life, and progressive neurodegeneration resulting in spastic gait disturbance, ataxia and cognitive deterioration [2][3][4][5].…”

“…In 2014, a novel ovarioleukodystrophy related to AARS2 mutation (MIM #612035) was described by Dallabona et al in six unrelated patients without signs of cardiomyopathy [2]. Here, two novel compound mutations in a Korean family associated with the ovarioleukodystrophy phenotype are reported [2][3][4][5].…”

“…Exome sequencing revealed two novel AARS2 gene mutations: a nonsense c.963C>A, p.Tyr321* and a missense c.452T>C, p.Met151Thr. No record of these mutations was present in TIARA databases for Korean variants [6], the 1000 Genomes Project Database, ExAC or dbSNP [2][3][4][5]7]. Both mutations were predicted to be pathogenic by in silico analysis using SIFT, PolyPhen-2 and Mutation Taster (Table S2).…”

Clinical and genetic characterization of leukoencephalopathies in adults

“…The clinical details and mutations detected are reported in more detail elsewhere (Lynch et al , 2016). Briefly, the phenotype consisted of adult onset leukoencephalopathy with a variable combination of dementia, upper motor neuron signs, ataxia and ovarian failure in females.…”

Biallelic mutations in mitochondrial tryptophanyl‐tRNA synthetase cause Levodopa‐responsive infantile‐onset Parkinsonism

“…Numerous publications have documented significant phenotypic variability caused by defects in mtARS genes . Patients harboring biallelic mutation in AARS2 , for example, may present with intrauterine or perinatal cardiomyopathy, adolescent onset ovario leukodystrophy or late‐onset neurodegeneration in patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) . The explanation for the broad range of manifestations is unclear.…”