Novel (ovario) leukodystrophy related to AARS2 mutations.

TitleNovel (ovario) leukodystrophy related to AARS2 mutations.
Publication TypeJournal Article
Year of Publication2014
AuthorsDallabona, C, Diodato, D, Kevelam, SH, Haack, TB, Wong, L-J, Salomons, GS, Baruffini, E, Melchionda, L, Mariotti, C, Strom, TM, Meitinger, T, Prokisch, H, Chapman, K, Colley, A, Rocha, H, Ounap, K, Schiffmann, R, Salsano, E, Savoiardo, M, Hamilton, EM, Abbink, TEM, Wolf, NI, Ferrero, I, Lamperti, C, Zeviani, M, Vanderver, A, Ghezzi, D, van der Knaap, MS
Date Published2014 Jun 10
KeywordsAdolescent, Adult, Alanine-tRNA Ligase, Ataxia, Atrophy, Cognition Disorders, Exons, Female, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Muscle Spasticity, Mutation, Phenotype, Primary Ovarian Insufficiency, Young Adult

OBJECTIVES: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype.METHODS: Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated.RESULTS: Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhood- to adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy.CONCLUSIONS: Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported.

Alternate JournalNeurology
Citation Key10.1212/WNL.0000000000000497
PubMed ID24808023
PubMed Central IDPMC4118500
Grant ListGGP11011 / / Telethon / Italy
GPP10005 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom