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; van der Knaap, Marjo S     «

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; van der Knaap, Marjo...     »

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.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.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.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.     «

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.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 leukoencephalop...     »