General Info for mtARS: Mitochondrial Aminoacyl-tRNA Synthetase Disorders
Overview
Mitochondrial ARS (Aminoacyl-tRNA Synthetase) Disorders (mtARS) are a group of rare genetic disorders. The disorders are caused by mutations in the aminoacyl-tRNA synthetases (ARS) genes, which are responsible for the production of enzymes essential for mitochondrial protein synthesis.
Genetics
Affected Genes
AARS2, CARS2, DARS2, EARS2, FARS2, GARS, HARS2, IARS2, KARS, LARS2, MARS2, NARS2, PARS2, QARS, RARS2, SARS2, TARS2, VARS2, WARS2, YARS2
Inheritance Type(s)
- Autosomal recessive
Cause and Genetics
Mitochondrial ARS Disorders are all genetic conditions, meaning they are passed down in a family. To be affected by the disorder, someone must inherit an ARS mutation from both parents (autosomal recessive inheritance). Someone who only inherits an ARS mutation from a single parent is called a carrier, and they usually do not have any medical symptoms. If both parents are carriers, there is a 1 in 4 chance with each pregnancy that their child will have mtARS. Both males and females can have mtARS.
There are many Mitochondrial ARS genes, and all are named with an -ARS2 naming system with the exception of GARS and KARS:
| 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) |
Signs and Symptoms of mtARS: Mitochondrial Aminoacyl-tRNA Synthetase Disorders
All Mitochondrial ARS Disorders affect the brain and may also affect other high energy systems. All ARS2 genes are progressive and neurodegenerative. mtARS can develop at any age, but it most often develops in children. Signs and symptoms of mtARS can include:
- 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.
- Issues in any high energy organs, such as the heart, kidney, liver, or digestive tract.
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.
Resources
Connecting with others impacted by a rare disease allows for vital information to be shared about day-to-day life, prevents isolation, and gives hope. Please contact MitoAction for peer support opportunities at 888-MITO-411 or email mito411@mitoaction.org.
Other resources we recommend are:
MitoAction does not provide medical advice, diagnosis, treatment, or legal advice. It is essential that all those living with or caring for someone with a Mitochondrial or FAOD disease have an emergency protocol letter. These letters, which are written and signed by a doctor, share details about prescribed treatment during crises and in emergency room settings. Always check with your doctor if you or your child has concerns as everyone may present with symptoms differently. Before beginning any treatment or therapy, please consult with your physician.
Sources:
Last Updated: 11/15/2024
