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Dallabona, C.* ; Diodato, D.* ; Kevelam, S.H.* ; Haack, T.B. ; Wong, L.J.* ; Salomons, G.S.* ; Baruffini, E.* ; Melchionda, L.* ; Mariotti, C.* ; Strom, T.M. ; Meitinger, T. ; Prokisch, H. ; Chapman, K.* ; Colley, A.* ; Rocha, H.* ; Ounap, K.* ; Schiffmann, R.* ; Salsano, E.* ; Savoiardo, M.* ; Hamilton, E.M.* ; Abbink, T.E.M.* ; Wolf, N.I.* ; Ferrero, I.* ; Lamperti, C.* ; Zeviani, M.* ; Vanderver, A.* ; Ghezzi, D.* ; van der Knaap, M.S.*

Novel (ovario) leukodystrophy related to AARS2 mutations.

Neurology 82, 2063-2071 (2014)
Publ. Version/Full Text Volltext DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Transfer-rna Synthetases; Spinal-cord Involvement; Brain-stem; Hypertrophic Cardiomyopathy; Lactic-acidosis; Muscle Weakness; Mitochondrial; Leukoencephalopathy; Deficiency; Dysgenesis
ISSN (print) / ISBN 0028-3878
e-ISSN 1526-632X
Journal Neurology
Quellenangaben Volume: 82, Issue: 23, Pages: 2063-2071 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Philadelphia
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)