Novel (ovario) leukodystrophy related to AARS2 mutations

Abstract

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 childhoodto 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.

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

“…Most YARS2 defects result in a more moderate MLASA2 than seen in the patient mentioned above (Riley et al 2013;Shahni et al 2013); however another lethal infantile case has recently been reported (Nakajima et al 2014). In the case of AARS2, two missense variants have been associated with a lethal infantile cardiomyopathy (Gotz et al 2011), while another 11 variants have resulted in leukoencephalopathy and premature ovarian failure (Dallabona et al 2014). A range of compound heterozygous variants in EARS2 result in leukoencephalopathy with thalamus and brainstem involvement and high lactate (Steenweg et al 2013).…”

“…However, in other cases, different mutations in the same gene result in distinct phenotypes. For example, AARS2 mutations result in either infantile cardiomyopathy (OMIM 614096) (Gotz et al 2011) or leukoencephalopathy with premature ovarian failure (POF; OMIM 615889) (Dallabona et al 2014). In this study we expand the clinical spectrum associated with LARS2 variants to include a patient with hydrops, lactic acidosis, sideroblastic anemia, and infantile multisystem failure.…”

Genetics of mitochondrial dysfunction and infertility

“…Recessive variants in AARS2 were associated with leukoencephalopathy and POI in six subjects (MIM 615889) (68). Subjects had childhood onset of neurological deterioration including ataxia, spasticity, cognitive decline and white matter abnormalities.…”

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

“…2 0 1 2 ) ; E A R S 2 (OMIM#614924) (Steenweg et al 2012) and AARS2 (OMIM#615889) (Dallabona et al 2014). Although the biochemical signatures and neuroimaging of combined respiratory chain deficiency can be distinctive, it remains difficult to infer the genetic origin from often heterogeneous phenotypes.…”