PuSH - Publikationsserver des Helmholtz Zentrums München

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)
Verlagsversion Volltext DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Neurology
Quellenangaben Band: 82, Heft: 23, Seiten: 2063-2071 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Philadelphia
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)