Mitochondrial ARS (Aminoacyl-tRNA Synthetase) Disorders (mtARS) are a group of rare genetic conditions caused by mutations in the genes responsible for the production of aminoacyl-tRNA synthetases (ARS), which are enzymes essential for mitochondrial protein synthesis. These enzymes play a critical role in “charging” tRNA molecules with the correct amino acids, allowing them to participate in the formation of proteins within the mitochondria.
ARS disorders are caused by mutations in mitochondrial ARS genes, inherited in an autosomal recessive pattern. This means both parents must carry a mutation, though they may not show symptoms. These disorders are progressive and primarily affect the brain and high-energy systems like the heart, muscles, and nerves.
All Mitochondrial ARS Disorders affect the brain and may also affect other high-energy systems. All ARS2 genes are progressive and neurodegenerative. It can develop at any age, but most often develops in children.
Several of the ARS genes cause a white matter brain disease, also known as a leukodystrophy. Due to lack of energy in the brain cells, the cells in the white matter can begin to die. Other genes may effect the brain as a whole, known as an encephalopathy.
- Developmental Delays
- Ataxia (imbalance)
- Hypotonia (low muscle tone)
- Poor growth/failure to thrive
- Tremors
- Seizures
- Hearing or Vision Loss
- Issues with eye movement
- Gastrointestinal dysmotility/Constipation
- Swallowing issues/Feeding Tube
- Dementia
- Heart issues
- High Lactic Acid
- Neuropathy (tingling, weakness, or pain – commonly in the hands and feet – caused by damage to nerves leading to the brain)
- Dysautonomia (malfunction of autonomic nervous system, which regulates heart rate, blood pressure, temperature control and more).
- Parkinsonism (movement symptoms): slowed movements, balance issues, stiffness and tremors.
- mtARS disorders can cause issues in any high energy organs, such as the heart, kidney, liver, or digestive tract.
| Gene | Protein | Main Phenotype |
| AARS2 | Mt alanyl-tRNA synthetase | Progressive leukoencephalopathy with Ovarian Failure (LKENP); Cardiomyopathy – Combined Oxidative phosphorylation defect type 8 (COXPD8) |
| CARS2 | Mt cysteinyl-tRNA synthetase | Mitochondrial epileptic encephalopathy – Combined oxidative phosphorylation defect type 27 (COXPD27) |
| DARS2 | Mt aspartyl-tRNA synthetase | Leukoencephalopathy with brain stem and spinal cord involvement – high lactate syndrome (LBSL) |
| EARS2 | Mt glutamyl-tRNA synthetase | Leukoencephalopathy with thalamus and brainstem involvement and high lactate elevation (LTBL) – Combined oxidative phosphorylation defect type 12 (COXPD12) |
| FARS2 | Mt phenylalanyl-tRNA synthetase | Spastic paraplegia 77 (SPG77); Infantile onset epilepsy and encephalopathy – Combined oxidative phosphorylation deficiency-14 (COXPD14) |
| GARS | Mt and cyt glycyl-tRNA synthetase | Systemic mitochondrial disease cardiomyopathy; Autosomal dominant Charcot-Marie Tooth disease type 2D Distal hereditary motor neuropathy type 5 |
| HARS2 | Mt histidyl-tRNA synthetase | Perrault syndrome 2 |
| IARS2 | Mt isoleucyl-tRNA synthetase | Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (CAGSSS) |
| KARS | Mt and cyt lysyl-tRNA synthetase | Charcot-Marie-Tooth disease, recessive intermediate, B; Deafness, autosomal recessive 89; Deafness, congential, and adult-onset leukoencephalopathy; Leukoencephalopathy, progressive, infantile onset, with or without deafness |
| LARS2 | Mt leucyl-tRNA synthetase | Perrault syndrome 4 ; Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome |
| MARS2 | Mt methionlyl-tRNA synthetase | Autosomal recessive spastic ataxia with leukoencephalopathy; Combined oxidative phosphorylation defect type 25 (COXPD25) |
| NARS2 | Mt asparaginyl-tRNA synthetase | Deafness, autosomal recessive 94 (DFNB94); Mitochondrial DNA depletion syndrome 4A (Alpers type (MTDPS4A); Combined oxidative phosphorylation deficiency 24 (COXPD24) |
| PARS2 | Mt prolyl-tRNA synthetase | Developmental and epileptic encephalopathy 75 (DEE75) |
| QARS | Mt and cyt glutaminyl-tRNA synthetase 1 | Microcephaly, progressive, with seizures and cerebral and cerebellar atrophy (MSCCA) |
| RARS2 | Mt arginyl-tRNA synthetase | Pontocerebellar hypoplasia type 6 (PCH6) |
| SARS2 | Mt seryl-tRNA synthetase | Progressive spastic paresis; Hyperuricemia – pulmonary hypertension – renal failure – alkalosis syndrome (HUPRA syndrome) |
| TARS2 | Mt threonyl-tRNA synthetase | Combined oxidative phosphorylation deficeincy-21 (COXPD21) |
| VARS2 | Mt valyl-tRNA synthetase | Combined oxidative phosphorylation deficeincy-20 (COXPD20) |
| WARS2 | Mt tryptophanyl-tRNA synthetase | Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizure; Parkinsonism-dystonia 3, childhood onset |
| YARS2 | Mt tyrosyl-tRNA synthetase | Mitochondrial myopathy and sideroblastic anemia (MLASA) |
Are there any clinical trials for ARS Disorders?
To see what trials you may qualify for, visit our Clinical Trials page – which also included a Clinical Trials Finder Tool. We also highly encourage you to join our patient registry, mitoSHARE, where we are actively recruiting mtARS families.
We are here to help. We suggest you reach out to our Support & Education Team – online, via email at support@umdf.org or phone at (888) 900-6486 – who can suggest a host of resources including doctors, disease specific support meetings, and more. They’ll also connect you with a UMDF ambassador, likely a fellow mtARS patient or family member, who can help support and guide you through your questions.
- Get Support
Connect with our Support & Education Team online, via email at support@umdf.org or phone at (888) 900-6486.
- Check our clinical trials finder
Use our Clinical Trials Finder tool to see if you qualify for any clinical trials.
- Join our patient registry, mitoSHARE
We are actively recruiting ARS families to participate in our patient registry, mitoSHARE. Patient registries like mitoSHARE are an integral part in charting a course toward treatments and cures for mtARS and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical trials. Next generation patient registries like mitoSHARE are an integral part of expanding that number.
- Become an advocate
Ask your representatives to prioritize mitochondrial disease research and support via the UMDF Advocacy Center. We’ll send regular action items where you – and your friends and family – can let Congress know we need their support. Click here to sign up.
- Join the conversation online
– UMDF Social Media Support Groups: Facebook Support Group
– UMDF News & Updates: Facebook | Twitter | Instagram | YouTube
- Get involved
Join the fight by giving your voice, generosity, time, or energy. Click here to see how you can help.
UMDF is helping chart a path toward treatments and eventual cure of mitochondrial diseases like ARS through:
- Research & Funding: UMDF has provided more than $15 million in research funding to find treatments for diseases like ARS. UMDF advocacy has helped secure an additional $55 million in federal funding via the Department of Defense and National Institutes of Health.
- Data: Over two decades ago, UMDF pioneered patient registries for the mitochondrial disease community. Today, our next generation patient registry, mitoSHARE, is helping chart a path toward the treatment and eventual cure of mitochondrial diseases.
- Patient Support: Thousands of families just like you depend upon UMDF for support and education on diseases like mtARS. Attendance at our support meetings annually tops 7,000, including disease specific support meetings for families.
- Clinician Support: To help educate clinicians on diseases like mtARS, we feature monthly Bench to Bedside clinician seminars, host the annual Mitochondrial Medicine Symposium, support the Mitochondrial Care Network, and educate clinicians on our Mito U platform.
For more information on mtARS, please visit:
- While the UMDF science team works to build out this page further, our friends at CureARS have provided content symptoms and ARS-related genes.