Novel (ovario) leukodystrophy related to AARS2 mutations

作者：Dallabona Cristina; Diodato Daria; Kevelam Sietske H; Haack Tobias B; Wong Lee Jun; Salomons Gajja S; Baruffini Enrico; Melchionda Laura; Mariotti Caterina; Strom Tim M; Meitinger Thomas; Prokisch Holger; Chapman Kim; Colley Alison; Rocha Helena; Ounap Katrin; Schiffmann Raphael; Salsano Ettore; Savoiardo Mario; Hamilton Eline M; Abbink Truus E M; Wolf Nicole I; Ferrero Ileana; Lamperti Costanza; Zeviani Massimo; Vanderver Adeline; Ghezzi Daniele

来源：Neurology, 2014, 82(23): 2063-2071.

DOI：10.1212/WNL.0000000000000497

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2014-6-10