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A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report

Year: 2024

Type: article

Abstract: Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the AARS2 gene. We describe a patient with late-onset AARS2 -related leukoencephalopathy, a milder phenotype and a novel disease-causing variant. The patient was characterized during routine clinical practice. A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the AARS2 gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C > T (p.(Arg199Cys)), and one novel variant c.730G > A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression. This case underlines that adult-onset leukodystrophy caused by variants in AARS2 may have a wide range of phenotypes and patterns of progression. The new variant c.730G > A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern. Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified.

Source: Molecular Genetics and Metabolism Reports

DOI: 10.1016/j.ymgmr.2024.101157