AARS2
Alanyl—tRNA synthetase, mitochondrial, also known as alanine—tRNA ligase (AlaRS) or alanyl—tRNA synthetase 2 (AARS2), is an enzyme that in humans is encoded by the AARS2 gene.[5][6] Clinical relevanceGene changes in the AARS2 gene result in infantile mitochondrial cardiomyopathies.[7] Progressive leukoencephalopathy with Ovarian Failure (LKENP). FunctionThe AARS2 gene provides instructions for producing alanyl-tRNA synthetase 2, which is localized to mitochondria. This enzyme plays a critical role in the fidelity of mitochondrial protein translation by charging tRNAs with the correct amino acid (alanine). Proper mitochondrial protein synthesis is essential for the assembly and function of the oxidative phosphorylation system, which drives ATP production. Dysregulation of this process can disrupt cellular energy homeostasis and lead to a cascade of pathophysiological effects. Pathogenic Variants and Associated DisordersLeukoencephalopathyAARS2-related leukodystrophy causes dementia, upper motor neuron signs and ataxia. Ovarian FailureA subset of patients with AARS2 gene changes has been reported to exhibit premature ovarian insufficiency (POI), indicating a potential link between mitochondrial dysfunction and reproductive health. POI is often an early or predominant manifestation in affected women. Cardiac and Multisystem DisordersEmerging reports describe AARS2 variants in patients with cardiomyopathy, including dilated cardiomyopathy, alongside neurological and systemic manifestations. These findings underscore the pleiotropic effects of AARS2 mutations on multiple organ systems. GeneticsThe AARS2 gene is located on chromosome 6 (6p21.1) and comprises 20 exons. Mutations reported include missense, nonsense, and splice-site variants, as well as deletions. Pathogenic mutations often lead to impaired enzyme function, resulting in defective mitochondrial protein synthesis. The inheritance pattern is autosomal recessive, requiring both alleles to carry mutations for the disorder to manifest. DiagnosisClinical PresentationPatients may present with a combination of neurological symptoms, including ataxia, spasticity, and cognitive decline. In cases of LBSL, characteristic MRI findings are critical for diagnosis. Genetic TestingDiagnostic confirmation involves genetic testing to identify pathogenic variants in AARS2. Whole exome sequencing (WES) or targeted gene panels for mitochondrial disorders are commonly used. Biochemical TestsElevated lactate levels in the cerebrospinal fluid or through magnetic resonance spectroscopy (MRS) can provide supportive evidence of mitochondrial dysfunction. ManagementCurrently, there are no specific treatments targeting AARS2-related disorders. Management is primarily supportive and symptom-based: Neurological Symptoms: Physical therapy, occupational therapy, and medications for spasticity (e.g., baclofen) may improve quality of life. Premature Ovarian Insufficiency: Hormone replacement therapy (HRT) and fertility counseling are recommended for affected women. Cardiac Symptoms: Routine cardiac monitoring and management by a cardiologist are essential in patients with cardiomyopathy. Research DirectionsMechanistic StudiesOngoing research aims to understand the molecular mechanisms linking AARS2 mutations to mitochondrial dysfunction. Insights into these pathways could reveal novel therapeutic targets. Therapeutic DevelopmentGene therapy, small-molecule chaperones, and mitochondrial-targeted antioxidants are potential avenues under investigation to address mitochondrial disorders, including those involving AARS2. Resources for Patients and FamiliesPatient Advocacy GroupsCureARS - a non-profit organization dedicated to spreading awareness, connecting & providing support to affected families and funding research for the ultra-rare Mitochondrial ARS genes. United Mitochondrial Disease Foundation (UMDF) The Lily Foundation (United Kingdom) - A charity supporting patients and families affected by mitochondrial diseases. Alex TLC (United Kingdom) - Advocacy and support for individuals with leukodystrophies, including a dedicated page on AARS2-related conditions. AEPMI - Asociación Española de Pacientes con Enfermedades Mitocondriales (Spain) - Spanish organization providing resources and support for mitochondrial disease patients. Genetic CounselingFamilies affected by AARS2-related disorders are encouraged to seek genetic counseling for reproductive planning and understanding inheritance patterns. Clinical TrialsA search on ClinicalTrials.gov can provide updates on ongoing research and experimental treatments for mitochondrial diseases. Support NetworksOnline communities and forums for mitochondrial disease patients and caregivers offer emotional support and shared experiences. Referencesvan Berge L, et al. (2014). "AARS2 mutations: A common cause of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)." Brain. Isohanni P, et al. (2019). "Novel phenotypes associated with AARS2 mutations." Journal of Inherited Metabolic Disease. Sofou K, et al. (2015). "AARS2-related mitochondrial cardiomyopathy: Expanding the clinical spectrum." European Journal of Medical Genetics. Online Mendelian Inheritance in Man (OMIM). AARS2. OMIM Entry. References
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