Leukoencephalopathy, Progressive, with Ovarian Failure via the AARS2 Gene

AARS2-related Leukoencephalopathy is one of the most common adult onset leukoencephalopathies and is characterized by progressive leukoencephalopathy with ovarian failure (Dallabona et al. 2014. PubMed ID: 24808023; Lynch et al. 2017. PubMed ID: 28334938; Lynch et al. 2018. PubMed ID: 30467211; Lakshmanan et al. 2017. PubMed ID: 28243630; Srivastava et al. 2019. PubMed ID: 31099476). Early symptoms may include developmental delay in childhood. Onset of the disorder is usually in young adulthood. The major features include cerebellar ataxia with nystagmus, dysarthria, tremor, upper motor neuron signs. In certain cases, patients present other neurological symptom such as cognitive deterioration, dementia and psychosis. Brain MRI shows slightly asymmetric abnormal T2 hyperintense signal in the frontoparietal and periventricular white matter, with white matter rarefaction, involvement of the corpus callosum and pyramidal tracts and punctate areas of restricted diffusion. Males and females are about equally affected. Ovarian failure was present in all known female cases. AARS2-related Leukoencephalopathy is a rare disease with prevalence of roughly 1 per 100,000.

In addition, pathogenic variants in AARS2 are also causative for combined oxidative phosphorylation deficiency 8 . Major symptoms include severe infantile hypertrophic mitochondrial cardiomyopathy, pulmonary hypoplasia, and early-onset brain disease. Other features include failure to thrive. If both the heart and brain are involved, the prognosis is poor (Dallabona et al. 2014. PubMed ID: 24808023; Kamps et al. 2018. PubMed ID: 29440775).

As both leukoencephalopathy and combined oxidative phosphorylation deficiency can be caused by defects in a number of genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, prediction of recurrence risk, as well as future family plans.

AARS2-related disorders are inherited in an autosomal recessive manner. Pathogenic variants in AARS2 include missense, nonsense, splicing, and small deletion/duplications (mostly frameshift). No large deletions and duplications have been reported in the AARS2 locus (Dallabona et al. 2014. PubMed ID: 24808023; Lynch et al. 2017. PubMed ID: 28334938; Lynch et al. 2018. PubMed ID: 30467211; Lakshmanan et al. 2017. PubMed ID: 28243630; Human Gene Mutation Database). No de novo pathogenic variants have been documented in this gene. The vast majority of variants are missense. The most frequently reported pathogenic variant in AARS2, p.Arg592Trp, is located in the alanyl-tRNA synthetase core domain with allele frequency of 0.04% in the non-Finnish European population (gnomAD database).  

AARS2 encodes a mitochondrial aminoacyl tRNA synthetase, which is responsible for the charging of tRNA-Ala with alanine during mitochondrial translation. A mouse model demonstrated that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms (Hilander et al. 2018. PubMed ID: 29228266). AARS2 has been cited as a conditional essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). 

Clinical sensitivity of AARS2 gene in a large cohort of patients with Leukoencephalopathy, progressive, with ovarian failure relevant phenotypes is unavailable in the literature because most of studies are case reports. Analytical sensitivity is expected to be high as all reported pathogenic variants are detectable by sequencing. AARS2-related Leukoencephalopathy is one of the most common adult onset leukoencephalopathies.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the AARS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).