2024 Oct 31. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024.
ABSTRACT
CLINICAL CHARACTERISTICS: AARS2-related disorder includes two distinct phenotypes, infantile-onset cardiomyopathy and neurodegeneration with or without leukoencephalopathy. AARS2-related infantile-onset cardiomyopathy is characterized by hypertrophic cardiomyopathy, hypotonia, skeletal myopathy, and often lung hypoplasia. Some individuals have nonimmune hydrops and/or seizures. AARS2-related neurodegeneration with or without leukoencephalopathy is characterized by movement disorders, cognitive decline, ovarian failure in females, and psychiatric manifestations. Additional neurologic manifestations (seizures, developmental delay, neuropathy, and/or myopathy) and ocular manifestations can also be present.
DIAGNOSIS/TESTING: The diagnosis of AARS2-related disorder is established in a proband with suggestive findings and biallelic pathogenic variants in AARS2 identified by molecular genetic testing.
MANAGEMENT: Treatment of manifestations: In AARS2-related infantile-onset cardiomyopathy, standard treatment for hypertrophic cardiomyopathy, respiratory failure, and seizures; feeding therapy with tube feedings as required.
In AARS2-related neurodegeneration with or without leukoencephalopathy, levodopa or other dopaminergic therapies for parkinsonism; botulinum toxin for spasticity; additional management of motor dysfunction per orthopedist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist; cognitive behavioral therapy; psychoeducational interventions; treatment of hypogonadism in females per endocrinologist and/or gynecologist; psychotherapy and neuropsychological rehabilitation for neuropsychiatric manifestations; standard treatments for ocular manifestations and seizures.
Surveillance: In AARS2-related infantile-onset cardiomyopathy, cardiology evaluation including EKG and echocardiogram with frequency per cardiologist; assessment of growth and feeding at each visit; assessment of respiratory function as needed; neurologic evaluation, brain MRI, and EEG as needed.
In AARS2-related neurodegeneration with or without leukoencephalopathy, neurologic assessment for movement disorders, changes in tone, and seizures every six months or as needed; assessment of mobility and self-help skills at each visit; assessment of cognitive function every six to 12 months; assessment for features of premature ovarian failure with frequency per endocrinologist and/or gynecologist; psychiatric assessment every six to 12 months; ophthalmology evaluation with frequency per ophthalmologist.
Agents/circumstances to avoid: Sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously.
GENETIC COUNSELING: AARS2-related disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AARS2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AARS2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.