Mitochondrial ars genes
What Are Mitochondrial ARS Genes?
Mitochondrial (Mt) Aminoacyl tRNA Synthetase (ARS) genes are essential for the cells in the body to make energy within the mitochondria. Inherited mutations in these genes cause ultra-rare types of Mitochondrial Disease (Mito). Mitochondria are essentially the "powerhouse" in our bodies or the "batteries" to sustain life. If the body does not receive the proper energy it needs for cellular function, cells begin to die, eventually leading to organ failure. High energy organs need more energy to function, and these organs may sustain more injury. Mitochondrial ARS genes all affect the brain, but can involve multiple organ systems in the body.
Just as there are different types of cancers, there are many different types of Mitochondrial Disease. There are over 300 genes that cause different types of Mito, and there are 20 Mito ARS genes.
Mitochondrial Disease effects 1 in 4,000.
Mito is considered a rare disease meaning there is a small percentage of the population affected. In the United States, rare disease is defined as any condition affecting less than 200,000 individuals in the country. Every country has their own definition for what conditions are considered rare. There are over 7,000 rare diseases and 95% do not have a treatment option. Rare disease as a whole effects approximately 300 million individuals in the world. About half are children with no treatment options or cure. A large portion of rare disease research is funded by families of affected individuals through Patient Advocacy Groups (PAGs).
1 in 10 Americans are living with a rare disease.
All mitochondrial ARS genes are inherited in an autosomal recessive pattern, meaning the mutations are inherited from two parents who are carriers.
Mitochondrial ARS genes are named with an -ARS2 naming system, with the exception of GARS, KARS & QARS. Other names for the Mitochondrial ARS Genes are: MtARS, Mt-aaRS, ARS2 and Mito ARS.
See below the mitochondrial ARS genes included in this group.
The first case of Mito was discovered in 1962 and there still is no approved treatment option or cure.
Mito can affect multiple parts of the body and each affected individual may have a different number of symptoms and a different level of severity. All Mitochondrial ARS Disorders affect the brain and may also effect other high energy systems. All ARS2 genes are progressive and neurodegenerative. Mito can develop at any age; it most often develops in children.
Hypotonia (low muscle tone)
Poor growth/failure to thrive
Hearing or Vision Loss
Issues with eye movement
Swallowing issues/Feeding Tube
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.
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.
What causes Mitochondrial ARS Disorders?
Mitochondrial ARS Disorders are all genetic conditions. The body functions by following a specific manual of instructions that is encoded in DNA at the cellular level. The mitochondria are the powerhouse of the cell, giving fuel for all cellular functions. DNA tells the body to make mitochondria and instructions on how to keep our mitochondria functioning properly.
Nuclear DNA (nDNA) vs. Mitochondrial DNA (mtDNA)
There are TWO locations that DNA is stored within the cell. Mutations can occur in the nucleus, and this is referred to as nuclear DNA or nDNA. The second location DNA is located is within the mitochondria. Each cell has a organelle called the mitochondria and there are about 100,000 to 600,000 mitochondria in each cell.
nDNA mutations can be either autosomal dominent or autosomal recessive. Autosomal dominent mutations require ONE mutation from ONE parent to be affected (most likely that parent also has the condition). Autosomal recessive disorders require TWO mutations from BOTH parents to be affected by the condition (neither parent may actually be aware that they are carriers and may or may not be affected).
mtDNA mutations are inherited through the mother's side. Men do not pass their mitochondria to their children. mtDNA mutations will have this alteration in a certain percent of mitochondria and the remaining mitochondria will be normal functioning. Depending on the percent (also known as heteroplasmy) this can cause disease.
Sometimes mutations are spontaneous, meaning they happen by chance and neither mother or father have these mutations. This is called de novo mutations.
Mitochondrial disease in general can be caused by mutations in both nDNA and mtDNA. The Mitochondrial ARS Disorders are caused by mutations in nDNA and are ALL inherited in a autosomal recessive pattern by two parents who are carriers.
Each gene is like a sentence in a book, depending on where the change happens, it can change the meaning of the sentence and interpretation of the story as a whole. Any letter within the sentence can be changed. Each affected patient can have a different mutation within the gene. it's rare to find two patients with the same two mutations. If the parents are non-related, most likely the child has two different mutations in the gene (this is known as heterozygous mutations). If the parents are related, there is a higher likelihood of the child having the same two mutations (this is known as homozygous mutations).
Mitochondrial ARS gene listing
Mt alanyl-tRNA synthetase
Progressive leukoencephalopathy with Ovarian Failure (LKENP); Cardiomyopathy - Combined Oxidative phosphorylation defect type 8 (COXPD8)
Mt cysteinyl-tRNA synthetase
Mitochondrial epileptic encephalopathy - Combined oxidative phosphorylation defect type 27 (COXPD27)
Mt aspartyl-tRNA synthetase
Leukoencephalopathy with brain stem and spinal cord involvement – high lactate syndrome (LBSL)
Mt glutamyl-tRNA synthetase
Leukoencephalopathy with thalamus and brainstem involvement and high lactate elevation (LTBL) - Combined oxidative phosphorylation defect type 12 (COXPD12)
Mt phenylalanyl-tRNA synthetase
Spastic paraplegia 77 (SPG77); Infantile onset epilepsy and encephalopathy - Combined oxidative phosphorylation deficiency-14 (COXPD14)
Mt and cyt glycyl-tRNA synthetase
Systemic mitochondrial disease cardiomyopathy; Autosomal dominant Charcot-Marie Tooth disease type 2D Distal hereditary motor neuropathy type 5
Mt histidyl-tRNA synthetase
Perrault syndrome 2
Mt isoleucyl-tRNA synthetase
Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (CAGSSS)
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
Mt leucyl-tRNA synthetase
Perrault syndrome 4 ; Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
Mt methionlyl-tRNA synthetase
Autosomal recessive spastic ataxia with leukoencephalopathy; Combined oxidative phosphorylation defect type 25 (COXPD25)
Mt asparaginyl-tRNA synthetase
Deafness, autosomal recessive 94 (DFNB94); Mitochondrial DNA depletion syndrome 4A (Alpers type (MTDPS4A); Combined oxidative phosphorylation deficiency 24 (COXPD24)
Mt prolyl-tRNA synthetase
Developmental and epileptic encephalopathy 75 (DEE75)
Mt and cyt glutaminyl-tRNA synthetase 1
Microcephaly, progressive, with seizures and cerebral and cerebellar atrophy (MSCCA)
Mt arginyl-tRNA synthetase
Pontocerebellar hypoplasia type 6 (PCH6)
Mt seryl-tRNA synthetase
Progressive spastic paresis; Hyperuricemia – pulmonary hypertension – renal failure – alkalosis syndrome (HUPRA syndrome)
Mt threonyl-tRNA synthetase
Combined oxidative phosphorylation deficeincy-21 (COXPD21)
Mt valyl-tRNA synthetase
Combined oxidative phosphorylation deficeincy-20 (COXPD20)
Mt tryptophanyl-tRNA synthetase
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizure; Parkinsonism-dystonia 3, childhood onset
Mt tyrosyl-tRNA synthetase
Mitochondrial myopathy and sideroblastic anemia (MLASA)
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