Details

Autor(en) / Beteiligte

• 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

Titel

Novel (ovario) leukodystrophy related to AARS2 mutations

Ist Teil von

• Neurology, 2014-06, Vol.82 (23), p.2063

Ort / Verlag

United States

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.