- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: 4/2/2025
Years published: 2025
NORD gratefully acknowledges Zbigniew K. Wszolek, MD, Consultant, Department of Neurology, Mayo Clinic Florida, Haworth Family Professor in Neurodegenerative Diseases, Professor of Neurology and Tomasz Chmiela, MD, Research Fellow, Department of Neurology Mayo Clinic Florida and Neurologist, Department of Neurology, Faculty of Medical Science, Medical University of Silesia, for the preparation of this report.
Advertisement
Summary
Alanyl-transfer RNA (tRNA) synthetase 2 (AARS2)-related disorder (AARS2-RD) is a rare and progressive illness. In infants, it can cause heart muscle dysfunction, leading to severe cardio-respiratory failure. In older people, it can cause the brain’s white matter to deteriorate, affecting personality, thinking and muscle function, and lead to dementia and motor disability. Females with AARS2-RD develop a premature ovarian failure. Eventually, affected individuals may enter a vegetative state.
AARS2-RD is caused by changes (variants) in the AARS2 gene. To cause symptoms, two disease-causing variants of the AARS2 gene must be inherited, one from each parent. This means AARS2-RD is inherited in an autosomal recessive manner.
Diagnosing this condition can be challenging because its symptoms are like those of other disorders. Genetic testing is required to confirm the diagnosis.
There is no cure, and treatment focuses on managing symptoms.
Introduction
AARS2-RD is one of the leukodystrophy disorders. Previously it was classified as adult-onset leukoencephalopathy with axonal spheroids (ALSP). Nowadays, this terminology is being phased out because variants in different genes can cause ALSP. It’s now preferred to classify the disease based on the specific genes involved. Furthermore, diseases associated with these genes often have symptoms beyond ALSP and can occur in childhood.1,2
There are four clinical types of ALSP, caused by variants in different genes: CSF1R-related ALSP, AARS2-RD formerly known as ovario leukoencephalopathy, Swedish type hereditary diffuse leukoencephalopathy with spheroids (HDLS-S due to pathogenic variants in ARAS/AARS1 gene), and AARS/AARS2/CSF1R-negative disorder due to unknown genetic variant/variants.
AARS2- related disorder is classified in two subtypes based on clinical symptoms and time when symptoms start.1
AARS2 is inherited in an autosomal recessive pattern.1
Symptoms in AARS2-RD can begin at different ages. In early childhood, it causes severe cardiomyopathy which means the heart muscle does not work properly. In adulthood, it leads to neurological symptoms and early ovarian failure in females.
In AARS2-related Infantile onset cardiomyopathy the following symptoms are often present.3-5
These symptoms are usually very severe and cause a quick decline in health because the heart or lungs aren’t working properly. Death occurs most commonly in the first year of life, but there are also reports of death in the womb (fetal death). Laboratory findings show lactic acidosis, a condition where lactic acid build up in the bloodstream.
AARS2-related adult-onset leukoencephalopathy symptoms often start with mild psychological or cognitive changes as well as moving difficulties. Symptoms vary widely but ultimately lead to total incapacitation. The age of onset can range from childhood (rarely) to adulthood. Symptoms include.6-11
AARS2-RD is caused by changes (variants) in the AARS2 gene. The AARS2 gene provides instructions for making an enzyme called alanyl-tRNA synthetase 2, which is crucial for protein production in mitochondria.10,12 When mitochondria don’t function properly, energy production is disrupted, potentially damaging energy-dependent tissues like muscles (including the heart) and neurons, leading to cardiomyopathy and neurological symptoms. While there are some links between specific variants and symptoms, the exact reason why some patients develop early-onset cardiomyopathy and others develop later-onset leukoencephalopathy is still unknown.
For the disease to occur, two variants must be inherited, one from each parent, thus it is inherited in autosomal recessive manner.1 Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The exact number of people with AARS2-RD is unknown, but fewer than 100 cases have been reported worldwide.1,3,7 Because its symptoms are like other conditions, it often goes undiagnosed. Additionally, early onset can lead to death before birth, and the disease’s rapid progression can limit the time available for proper diagnosis.
The diagnosis of AARS2-RD should be made by a neurologist or by a neonatologist in cases of infantile onset cardiomyopathy. Due to the similarity of symptoms with other disorders, genetic testing is essential to confirm the diagnosis. The presence of disease-causing variants in the AARS2 gene inherited from both parents confirms the diagnosis.13,14
Suspicion of adult-onset AARS2-RD may be raised based on family history, along with clinical symptoms such as cognitive impairment, movement disorders, or early menopause in females. In cases of infantile onset cardiomyopathy, symptoms involving cardio-pulmonary failure are present at a very early age. To date, no clinical diagnostic criteria for AARS2-RD have been established.1,13,14
Brain scans can show a specific pattern of deterioration associated with AARS2-RD that includes.13-16
In infantile-onset cardiomyopathy, alterations in the structure of peripheral muscles can be observed.17-18 Additionally, elevated levels of lactic acid are often present in the blood of affected people.3,18
For people diagnosed with AARS2-related infantile-onset cardiomyopathy or adult-onset AARS2-RD, doctors recommend a series of evaluations to understand the severity of the disease and plan care. These include heart checks, growth and nutrition assessments, breathing tests, neurologic exams and, in some people, hormone and eye evaluations. Mental health and behavior assessments are also important. Genetic counseling helps families understand the condition and its inheritance.
There is no FDA approved disease modifying treatment for AARS2-RD. Symptomatic treatment is available.1 This type of therapy does not reverse changes in the brain but can be helpful in managing some symptoms and improving quality of life.
In infantile onset cardiomyopathy, treatments to support breathing or heart function are available and may involve heart medications, feeding support (including feeding tubes if needed), breathing support, physical therapy for movement issues and mental health care. Seizures are treated with standard anti-seizure medications and vision problems are managed by eye specialists. Some medications, like sedatives and antipsychotics, should be used cautiously to avoid worsening symptoms.
Infection that might develop as the disease progresses might be treated with antibiotics.
Psychological symptoms can be improved with anti-depressive medications and behavioral symptoms can be treated with anti-psychotic medications.
Regular follow-ups help track the disease, with heart, brain, mobility and mental health checks scheduled as needed. Families can receive support through counseling, social services and community resources. Genetic counseling for relatives may also be recommended.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/One in 10 Americans lives with rare disease, many of whom fight a daily battle to access the care and support they need. Your gift to the National Organization for Rare Disorders (NORD®) funds life-changing programs and helps us advance policies and research to ensure that everyone gets the care they need AND deserve.