Combined Oxidative Phosphorylation Deficiency Caused by Mutation in TARS2

Combined oxidative phosphorylation deficiency caused by mutation in TARS2 is a very rare genetic mitochondrial disease. In medical books it is usually called combined oxidative phosphorylation deficiency-21 (COXPD21). It mainly affects the brain and muscles and often starts in early infancy or early childhood. Children usually have weak trunk muscles (axial hypotonia), stiff arms and legs (limb hypertonia), delayed development, seizures, and raised lactic acid in the blood. []

Combined oxidative phosphorylation deficiency caused by mutation in TARS2 is a genetic mitochondrial disease. In simple words, the TARS2 gene gives instructions to make a protein (mitochondrial threonyl-tRNA synthetase) that helps build some of the tiny “energy machines” (oxidative phosphorylation complexes) inside mitochondria.[2][3] When both copies of TARS2 are faulty, mitochondrial protein production becomes weak, several respiratory chain complexes do not work well together (combined oxidative phosphorylation defect), and cells cannot make enough ATP energy, especially in brain, muscles, kidney, and heart.[4]

Children with TARS2-related disease often show developmental delay, weak muscle tone (hypotonia), movement problems, seizures, abnormal brain MRI findings, feeding problems, poor growth, and sometimes problems in kidney or other organs.[5] The severity can range from very serious early-onset disease to milder forms, and symptoms may change with age. Because the condition is so rare, treatment is usually based on general mitochondrial disease experience and on each child’s specific problems, not on large clinical trials.[6]

This disease happens because both copies of the child’s TARS2 gene are changed (pathogenic variants). This gene makes a mitochondrial enzyme called threonyl-tRNA synthetase 2. When this enzyme does not work well, the mitochondria cannot make energy in a normal way, and several parts of the respiratory chain (oxidative phosphorylation complexes) work poorly. That is why it is called a “combined oxidative phosphorylation deficiency.” []

---

Other names

Doctors and databases use several other names for this condition, for example:

• Combined oxidative phosphorylation deficiency 21

• Combined oxidative phosphorylation defect type 21

• TARS2-related mitochondrial disease

• TARS2 combined oxidative phosphorylation deficiency

• COXPD21

These names all describe the same disease linked to changes in the TARS2 gene. []

---

How TARS2 and mitochondria are involved

The TARS2 gene gives instructions to make a mitochondrial enzyme that attaches the amino acid threonine to its tRNA (threonyl-tRNA synthetase). This step is needed for building mitochondrial proteins that sit inside the respiratory chain complexes. []

When TARS2 is faulty, mitochondrial protein building is slow or incorrect. This leads to low activity of several respiratory chain complexes at the same time, and cells cannot make enough ATP (energy) through oxidative phosphorylation. Organs that need a lot of energy, like the brain, muscles, and sometimes the liver and heart, are the most affected. []

Studies of patients show that some TARS2 variants also disturb a cell growth pathway called mTORC1, which may add to the brain problems and abnormal MRI changes seen in these children. []

---

Types

Doctors often describe patterns rather than strict subtypes, based on age at onset and severity:

• Early-onset severe type
  – Symptoms start in the first months of life. Babies have severe low muscle tone of the trunk, stiff limbs, poor feeding, seizures, and very delayed development. Many have high lactate and serious brain changes on MRI, and some die early. []

• Later-onset milder type
  – Symptoms start after about 6 months of age. Children still have developmental delay and neurological signs, but the course can be milder, and survival can be longer than in the early-onset form. []

• Expanded or atypical phenotypes
  – Newer reports add extra features, such as dystonia, hearing loss, and even neonatal diabetes in some families, showing that the disease can appear in slightly different ways in different people. []

---

Causes

Remember: the main cause is inherited changes (variants) in both copies of the TARS2 gene. The points below break this down into simple steps and risk factors.

1. Biallelic pathogenic TARS2 variants
   The basic cause is having disease-causing variants in both copies of the TARS2 gene (one from each parent). This pattern is called autosomal recessive inheritance. []

2. Missense variants in important enzyme regions
   Many patients have missense variants that change one amino acid in a critical part of the enzyme, reducing its ability to attach threonine to tRNA and harming oxidative phosphorylation. []

3. Nonsense or frameshift variants
   Some variants introduce a stop signal too early or shift the reading frame, making a short, non-functional TARS2 protein that cannot support normal mitochondrial translation. []

4. Splice-site variants
   Variants at splice sites can stop the gene’s RNA from being assembled correctly, so the final enzyme is missing important parts or is unstable, again weakening oxidative phosphorylation. []

5. Loss of threonyl-tRNA synthetase activity
   All these genetic changes reduce TARS2 enzyme activity. When this enzyme is weak or absent, mitochondria cannot correctly load threonine onto tRNA, so many mitochondrial proteins cannot be made in the right way. []

6. Defective mitochondrial protein synthesis
   Because TARS2 works inside mitochondria, its failure directly hurts mitochondrial protein synthesis. This leads to fewer or abnormal protein subunits of respiratory chain complexes. []

7. Combined respiratory chain complex deficiency
   Muscle and other tissues from patients often show reduced activity of multiple oxidative phosphorylation complexes (for example complexes I, III, and IV), giving the “combined oxidative phosphorylation deficiency” name. []

8. Energy failure in high-demand tissues
   Brain, muscles, and sometimes liver and heart need a lot of ATP. When oxidative phosphorylation is weak, these tissues cannot meet their energy needs and start to fail, causing the neurological and systemic symptoms. []

9. Disrupted mTORC1 signalling
   Some TARS2 variants reduce binding to Rag GTPases and may disturb mTORC1 signalling, a pathway that controls cell growth and metabolism, which can worsen brain development problems. []

10. Autosomal recessive inheritance from carrier parents
    Parents usually carry one faulty copy but are healthy. When both are carriers, each pregnancy has a 25% chance of a child with COXPD21, which explains why the disease can appear suddenly in a family with no past history. []

11. Consanguinity (parents related by blood)
    In some families, parents are related (for example cousins), which increases the chance that both carry the same rare TARS2 variant, so the risk of an affected child is higher. []

12. Founder variants in certain populations
    Studies from China have identified particular TARS2 variants, such as c.470C>G, that appear more often in that population and may have a founder effect, meaning they came from a distant common ancestor. []

13. Compound heterozygosity
    Many patients have two different pathogenic variants in TARS2 (one on each chromosome). Together they still cause serious loss of enzyme function and the disease phenotype. []

14. De novo variants (new in the child)
    In rare cases, a disease-causing variant may arise for the first time in the child, but because autosomal recessive disease usually needs two variants, one is often inherited and one may be new. []

15. Lactic acidosis from impaired oxidative metabolism
    When mitochondria cannot oxidize pyruvate well, cells make more lactate. High lactate in blood and sometimes cerebrospinal fluid is therefore a biochemical “cause” of many symptoms like tiredness, vomiting, and breathing problems. []

16. Secondary oxidative stress and mitochondrial damage
    Weak oxidative phosphorylation can increase reactive oxygen species, which further injure mitochondrial membranes and DNA, creating a vicious circle of damage in energy-hungry tissues. []

17. Intercurrent illness and metabolic stress as triggers
    Fever, infection, or fasting do not cause the gene defect, but they increase energy demand and can unmask or worsen symptoms in a child who already has TARS2-related mitochondrial dysfunction. []

18. Possible interaction with other nuclear mitochondrial genes
    Researchers suspect that variants in other nuclear genes involved in mitochondrial function may modify the severity of the TARS2 disease, although this is still being studied. []

19. Developmental vulnerability of the infant brain
    The developing brain is highly dependent on mitochondrial energy, so TARS2 dysfunction during pregnancy and early life may cause structural brain changes seen on MRI, such as cerebral and cerebellar atrophy. []

20. Unknown additional genetic or environmental modifiers
    Only a few dozen patients have been reported worldwide, so scientists believe there are still unknown factors that may make the disease more or less severe in different individuals. []

---

Symptoms

Symptoms can vary, but the following are common and supported by case series and reviews.

1. Axial hypotonia (floppy trunk)
   Babies often have very weak neck and trunk muscles, so their head lags when lifted and they struggle to sit without support. []

2. Limb hypertonia or spasticity
   At the same time, arms and legs can be unusually stiff, with increased reflexes, showing damage to motor pathways in the brain. []

3. Global developmental delay
   Children reach milestones late: they may sit, stand, walk, and talk much later than expected, or sometimes never achieve some milestones. []

4. Intellectual disability or learning difficulties
   Many affected children have problems with thinking, understanding, and learning at school age due to underlying brain involvement. []

5. Psychomotor regression
   Some children lose skills they had already gained, such as walking or speaking, especially after seizures or illness, showing that the nervous system is under ongoing stress. []

6. Epileptic seizures, often difficult to control
   Seizures (convulsions) are very common and sometimes are resistant to usual anti-seizure drugs, adding to developmental and health problems. []

7. Dystonia and other movement disorders
   Some patients have twisting, abnormal postures, tremors, or unsteady movements (ataxia) because of basal ganglia and cerebellar involvement. []

8. Cerebellar signs and poor coordination
   MRI often shows cerebellar atrophy, and clinically children may have wide-based gait, clumsiness, or difficulty with fine hand movements. []

9. Feeding problems and poor sucking
   Babies may tire quickly when feeding, choke or cough with feeds, or show poor weight gain, partly due to weak muscles and neurological issues. []

10. Failure to thrive and low weight gain
    Because of feeding problems and high energy demands from illness, many children do not gain weight as expected and may look small or thin for age. []

11. Raised blood lactate and metabolic acidosis
    High lactate levels in blood and sometimes cerebrospinal fluid are not felt directly by the child but show up in tests and are a key biochemical sign of the disease. []

12. Brain MRI abnormalities
    Many patients have cerebral and cerebellar atrophy and basal ganglia signal changes on MRI scans, matching their neurological symptoms. []

13. Respiratory problems
    Some infants have breathing difficulties or frequent chest infections because of weak respiratory muscles and overall poor health. []

14. Hearing loss
    Several reported individuals have sensorineural hearing impairment, showing that the auditory system can also be damaged in TARS2-related disease. []

15. Neonatal or early-onset diabetes in some cases
    A small number of families have been reported where TARS2 variants were linked with neonatal diabetes plus the usual neurological features, showing a wider systemic effect in rare cases. []

---

Diagnostic tests

Physical examination

1. Full neurological examination
   The doctor checks muscle tone, strength, reflexes, posture, and movement patterns. In COXPD21 they often find low tone in the trunk, high tone in limbs, brisk reflexes, and sometimes abnormal movements, pointing toward a central nervous system problem with possible metabolic cause. []

2. Growth and nutritional assessment
   Measuring weight, length/height, and head size over time helps to show failure to thrive or microcephaly, which are common in severe mitochondrial disorders. []

3. Observation of feeding and breathing
   Watching how the baby feeds and breathes, and checking for choking, poor sucking, or fast breathing, gives clues about muscle weakness and energy failure. []

4. General systems examination
   The clinician also looks for enlarged liver, heart murmurs, or other organ problems, because mitochondrial diseases can affect many organs, not only the brain and muscles. []

---

Manual / bedside tests

5. Developmental screening tools
   Simple tools and games are used at the bedside to see how the child moves, plays, and communicates. These tests show delays in gross motor, fine motor, language, and social skills, which are typical in COXPD21. []

6. Bedside muscle strength and endurance tests
   For older children, the doctor may ask the child to stand from a squat, walk on heels or toes, or repeatedly lift arms to see how quickly muscles tire, which helps to judge the degree of muscle involvement. []

7. Eye movement and coordination checks
   Simple finger-following tests and finger-to-nose tasks can show ataxia or abnormal eye movements, matching cerebellar and basal ganglia changes seen in imaging. []

Laboratory and pathological tests

8. Serum lactate and pyruvate
   Blood tests often show raised lactate (and sometimes abnormal lactate/pyruvate ratio), which is a key marker suggesting mitochondrial respiratory chain dysfunction. []

9. Blood gas analysis and acid–base status
   Arterial or capillary blood gas can show metabolic acidosis related to lactic acid build-up, especially in severely ill infants. []

10. Creatine kinase (CK) and muscle enzymes
    CK may be mildly raised due to muscle involvement. While not specific, an abnormal CK together with high lactate and neurological signs supports a mitochondrial myopathy. []

11. Comprehensive metabolic panel and liver function tests
    Liver enzymes can be elevated, and some patients show fatty change in the liver (hepatic steatosis), which fits with the systemic nature of COXPD21. []

12. Plasma amino acids and urine organic acids
    These tests help to rule out other metabolic diseases and can show patterns suggestive of mitochondrial dysfunction, such as elevated certain organic acids together with lactate. []

13. Mitochondrial respiratory chain enzyme assay in muscle
    A muscle biopsy sample can be used to measure the activity of each respiratory chain complex. In TARS2 disease, several complexes often show reduced activity, confirming a combined oxidative phosphorylation defect. []

14. Histology of muscle biopsy
    Under the microscope, muscle may show features typical of mitochondrial disease, such as ragged-red fibers or other abnormal mitochondrial staining, although findings can vary. []

15. Molecular genetic testing for TARS2
    The final and most specific test is genetic testing, often using a mitochondrial or neuro-metabolic gene panel, whole-exome, or whole-genome sequencing. This can identify pathogenic TARS2 variants and confirm the diagnosis of COXPD21. []

---

Electrodiagnostic studies

16. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity. In many children with TARS2-related disease it shows epileptic discharges or abnormal background rhythms, which help classify and manage seizures. []

17. Electromyography (EMG) and nerve conduction studies
    These tests measure how muscles and nerves respond to electrical signals. They can show patterns suggesting a primary central problem with some muscle involvement, and help rule out other neuromuscular diseases. []

---

Imaging

18. Brain MRI
    MRI of the brain is very important. In COXPD21 it often shows cerebral and cerebellar atrophy and basal ganglia signal changes, which match the clinical features of developmental delay, hypotonia, and movement disorders. []

19. Brain MR spectroscopy (MRS)
    MRS can detect a lactate peak in the brain, showing abnormal energy metabolism and supporting a diagnosis of mitochondrial disease when combined with clinical and other test findings. []

20. Abdominal ultrasound and liver imaging
    Some patients have fatty liver or other liver changes, so ultrasound or other imaging helps to assess hepatic involvement and provides more evidence of a systemic mitochondrial disorder. []

Non-pharmacological treatments (therapies and other approaches)

Below are examples of non-drug treatments commonly used in mitochondrial diseases like TARS2-related deficiency. Actual plans are tailored to each patient.

1. Regular physiotherapy (physical therapy)
Description (purpose): Physiotherapy uses gentle exercises, stretching, and positioning to keep muscles strong, prevent stiffness, and support walking or sitting. The purpose is to improve mobility, balance, and endurance in children with low muscle tone and weakness.[1]
Mechanism: By slowly training muscles and joints, physiotherapy helps maintain muscle fibers, joint range, and coordination, even when mitochondria are weak. Regular movement also supports blood flow and may improve overall energy handling in the body.[2]

2. Occupational therapy
Description (purpose): Occupational therapists help the child manage daily activities such as dressing, feeding, writing, and play. The purpose is to build independence and to adapt tasks so they match the child’s strength and energy level.[1]
Mechanism: They break complex tasks into smaller steps, use special tools (adaptive utensils, splints), and teach energy-saving strategies so the child can use limited mitochondrial energy more efficiently through the day.[2]

3. Speech, swallowing, and feeding therapy
Description (purpose): Speech-language therapists help with speech delays, swallowing difficulties, and feeding issues, which are common in TARS2-related brain and muscle involvement.[1]
Mechanism: Exercises for tongue, lips, and throat, plus safe-swallow techniques and changes in food texture, reduce choking risk, improve nutrition, and may support communication and learning.[2]

4. Individualized nutrition and high-energy diet
Description (purpose): A dietitian plans meals that provide enough calories, protein, and micronutrients to meet increased energy needs and prevent weight loss or failure to thrive. The purpose is to avoid “energy crisis” in mitochondria by preventing long fasting and under-nutrition.[1]
Mechanism: Frequent small meals, complex carbohydrates, healthy fats, and adequate protein help keep a steady supply of fuel to mitochondria, which may reduce episodes of fatigue, lactic acidosis, or metabolic decompensation.[2]

5. Seizure first-aid and safety plan
Description (purpose): Because seizures are common in TARS2 disease, families learn how to act during a seizure, when to give rescue medicine (if prescribed), and when to call emergency services.[1]
Mechanism: Having a clear plan reduces risk of injury, brain damage from prolonged seizures, and panic in caregivers, which indirectly protects the child’s brain and overall health.[2]

6. Respiratory physiotherapy and airway clearance
Description (purpose): If the child has weak breathing muscles or recurrent chest infections, respiratory therapists may teach coughing techniques, use chest physiotherapy, or mechanical devices to clear mucus.[1]
Mechanism: Clearing secretions reduces risk of pneumonia and hypoxia (low oxygen), protecting already vulnerable mitochondria in brain and muscles from extra stress.[2]

7. Vision and hearing rehabilitation
Description (purpose): Because some patients have hearing loss or visual problems, early use of hearing aids, glasses, or other aids helps communication and development.[1]
Mechanism: By improving sensory input, the brain can use its limited energy on learning, movement, and social interaction, rather than struggling to decode weak signals.[2]

8. Assistive devices and adaptive equipment
Description (purpose): Walkers, wheelchairs, standing frames, special seating, and orthotic braces help the child move safely and sit upright without extreme effort.[1]
Mechanism: These devices share the physical load with weak muscles, prevent contractures and scoliosis, and save energy so the child can focus on play, learning, and communication.[2]

9. Psychological and social support for family
Description (purpose): Living with a severe rare disease is emotionally hard. Counseling, support groups, and respite care help parents and siblings cope with stress, sadness, or anxiety.[1]
Mechanism: Emotional support does not change mitochondria directly, but it improves family resilience, adherence to complex treatment plans, and overall quality of life for the child.[2]

10. Genetic counseling
Description (purpose): Genetic counselors explain how TARS2 mutations are inherited, the risk to future pregnancies, and options like prenatal diagnosis or preimplantation genetic testing.[1]
Mechanism: Understanding the genetic cause helps families make informed choices and also helps doctors screen siblings and other relatives early, before symptoms become severe.[2]

11. Vaccination and infection-prevention planning
Description (purpose): Standard childhood vaccines and sometimes extra vaccines (like influenza or pneumococcal vaccines) help reduce infections that can trigger metabolic crises.[1]
Mechanism: Fewer infections mean fewer episodes of high fever, poor feeding, and dehydration, which otherwise increase energy demands and may worsen lactic acidosis and organ stress.[2]

12. Avoidance of fasting and high-stress situations
Description (purpose): Doctors usually advise avoiding prolonged fasting, extreme heat, uncontrolled fever, or very hard exercise in mitochondrial disease.[1]
Mechanism: These stressors quickly increase energy demand or reduce energy supply. Avoiding them protects fragile mitochondria from being pushed beyond their capacity, which may lower risk of acute decompensation.[2]

(In clinical practice, more non-drug strategies may be added, but these are some of the most common.)

---

Drug treatments

There is no medicine that directly “fixes” the TARS2 gene today. Doctors use drugs to control seizures, manage organ problems, and support mitochondrial metabolism, based on evidence from other mitochondrial and neurological diseases.[1] Below are examples, not a complete list. Doses always depend on age, weight, kidney function, and individual response, and must be set by a specialist.

1. Levetiracetam (KEPPRA) – anti-seizure medicine
Description and purpose: Levetiracetam is an FDA-approved anti-epileptic drug used for many seizure types. In TARS2 disease, it is often chosen because it does not strongly harm mitochondria and is generally well tolerated.[1]
Class and mechanism: It is an antiepileptic that binds to synaptic vesicle protein SV2A and helps stabilize abnormal electrical activity in the brain, lowering seizure frequency.
Typical dosing/time: The label suggests twice-daily dosing, with doses increased stepwise; specialists adjust dose carefully, especially in kidney disease.
Side effects: Sleepiness, dizziness, irritability, behavior change, and rarely mood problems or allergic reactions; kidney function needs monitoring.[1]

2. Other mitochondrial-friendly anti-seizure drugs (for example, lamotrigine, clobazam)
Description and purpose: When seizures remain uncontrolled, doctors may add other anti-epileptic drugs that are considered relatively safer for mitochondria and avoid drugs like valproic acid that may worsen mitochondrial disease.[1]
Mechanism: These medicines act on sodium channels, GABA receptors, or other brain targets to reduce abnormal firing.
Side effects: Depend on the exact drug and can include rash, sleepiness, or liver effects, so careful monitoring is needed.

3. Levocarnitine (CARNITOR) – metabolic support
Description and purpose: Levocarnitine is an FDA-approved drug for primary systemic carnitine deficiency and for certain kidney-related carnitine problems. In mitochondrial disease, it is sometimes used off-label to support fatty-acid transport into mitochondria and to reduce toxic acyl-compounds.[1]
Class and mechanism: It is a carrier molecule that helps move long-chain fatty acids into mitochondria for beta-oxidation, which can support ATP production when mitochondrial function is partially preserved.[2]
Typical dosing/time: Oral or IV doses are usually divided two to three times per day; exact dose depends on level of deficiency.
Side effects: Nausea, vomiting, diarrhea, and a fishy body odor are reported; rare muscle weakness in certain patients, so doctors monitor response carefully.[1]

4. Vitamins and cofactors as “drugs” (for example riboflavin, thiamine)
Description and purpose: High-dose B-vitamins such as riboflavin (vitamin B2) and thiamine (vitamin B1) are often used as part of a “mitochondrial cocktail” to support enzyme function in the respiratory chain.[1]
Mechanism: These vitamins act as cofactors for several complexes of the respiratory chain and for other enzymes in energy metabolism, which may improve ATP production when enzymes are partially defective.
Side effects: Usually mild (upset stomach, urine color changes), but very high doses should still be supervised by a doctor.

5. Medications for cardiomyopathy or heart rhythm problems
Description and purpose: If TARS2 disease affects the heart, doctors may use ACE inhibitors, beta-blockers, diuretics, or anti-arrhythmic drugs similar to standard heart-failure care.[1]
Mechanism: These drugs reduce strain on the heart muscle, control blood pressure, remove extra fluid, and stabilize rhythm, which can indirectly protect energy-stressed heart cells.
Side effects: Low blood pressure, dizziness, kidney function changes, electrolyte shifts; so cardiologists monitor closely.

6. Medications for kidney disease and blood pressure
Description and purpose: A recent report showed chronic kidney disease as a main feature in one TARS2 patient; treatments included blood-pressure control and kidney-protective strategies.[1]
Mechanism: ACE inhibitors or ARBs reduce pressure inside kidney filters and slow kidney damage; diuretics manage fluid balance.
Side effects: Similar to cardiac use, including risk of high potassium or worsening kidney function if not carefully monitored.

7. Anti-nausea and reflux medicines
Description and purpose: Many children with mitochondrial disease have reflux, vomiting, or feeding refusal. Proton pump inhibitors (such as omeprazole) or H2-blockers and anti-nausea drugs (such as ondansetron) may help symptoms and protect nutrition.[1]
Mechanism: They reduce stomach acid or act on brain and gut receptors to limit nausea, which helps the child keep down the high-energy diet needed for mitochondrial health.
Side effects: Headache, constipation or diarrhea, and, with long-term acid suppression, possible changes in mineral absorption; doctors balance benefits and risks.

8. Emerging mitochondrial-targeted drugs (example: elamipretide / FORZINITY)
Description and purpose: Elamipretide, marketed as FORZINITY, is a mitochondrial cardiolipin-binding peptide approved by the U.S. Food and Drug Administration (FDA) to improve muscle strength in Barth syndrome, another ultra-rare mitochondrial disease.[1]
Mechanism: It binds to cardiolipin in the inner mitochondrial membrane, helping maintain membrane structure, reduce oxidative damage, and support electron transport and ATP production. It is not approved specifically for TARS2 disease, but it shows a direction for future mitochondrial-directed therapies and might be considered only in research settings.[1]

---

Dietary molecular supplements

These supplements are often called a “mitochondrial cocktail.” Evidence is mixed and mostly from small studies, but they are widely used in mitochondrial clinics under supervision.[1] Always discuss doses with a specialist.

1. Coenzyme Q10 (ubiquinone/ubiquinol)
Description and function: Coenzyme Q10 is a fat-soluble compound that moves electrons along the respiratory chain complexes inside mitochondria and works as an antioxidant. It is often one of the first supplements tried in mitochondrial disease.[1]
Mechanism: By improving electron transfer and reducing free-radical damage, it may support ATP production and protect mitochondrial membranes. Doses are usually divided with meals to improve absorption; side effects are mostly mild stomach upset.

2. Riboflavin (vitamin B2)
Description and function: Riboflavin is a water-soluble vitamin used as a cofactor by several enzymes in complexes I and II of the respiratory chain and in other oxidative reactions. High-dose riboflavin has helped some patients with complex I defects.[1]
Mechanism: It increases the availability of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which can enhance residual electron transport. Excess riboflavin is excreted in urine, which may turn bright yellow, a harmless effect.

3. L-carnitine (also classed as a drug when prescribed)
Description and function: L-carnitine, discussed above, can be considered both a nutrient and a drug. It helps shuttle long-chain fatty acids into mitochondria and remove acyl-waste products.[1]
Mechanism: In mitochondrial disease, this may improve fat metabolism and reduce secondary carnitine deficiency. Doses are typically spread across the day to reduce stomach problems.

4. Alpha-lipoic acid
Description and function: Alpha-lipoic acid is an antioxidant and cofactor in mitochondrial dehydrogenase complexes. It can recycle other antioxidants, such as vitamins C and E, and may support glucose metabolism.[1]
Mechanism: By reducing oxidative stress and supporting enzyme activity, it may protect mitochondria from damage caused by reactive oxygen species and help maintain ATP production.

5. B-complex vitamins (including B1, B6, B12, niacin)
Description and function: A full B-complex ensures that all vitamin-dependent enzymes in energy and nerve metabolism have adequate cofactors. Deficiency of any B-vitamin can worsen neuropathy, anemia, or fatigue.[1]
Mechanism: Each B-vitamin participates in different steps of carbohydrate, fat, and protein metabolism, helping to feed substrates into the Krebs cycle and respiratory chain.

6. Vitamin D and calcium (bone and immune support)
Description and function: Children with severe disability may have low sun exposure and higher risk of low bone density, so vitamin D and calcium are important.[1]
Mechanism: Vitamin D helps absorb calcium from the gut and supports bone mineralization and immune function, reducing fracture risk and possibly infections.

7. Arginine or citrulline (in selected cases)
Description and function: In some mitochondrial disorders with stroke-like episodes, arginine is used to support nitric oxide production and improve blood flow; experience is limited in TARS2 disease.[1]
Mechanism: Arginine is a substrate for nitric oxide synthase, helping dilate blood vessels and potentially improving tissue oxygen and nutrient delivery.

---

Immunity-booster, regenerative, and stem-cell-related approaches

Right now, there are no standard stem-cell or gene-editing medicines approved specifically for TARS2-related combined oxidative phosphorylation deficiency.[1] Research is ongoing in mitochondrial translation disorders and in general mitochondrial medicine.

• Optimizing routine vaccines and infection control is still the most powerful and practical “immune-boosting” strategy, together with good nutrition and sleep.[2]

• Intravenous immunoglobulin (IVIG) may be used in patients who truly have antibody deficiencies or recurrent serious infections, but this is uncommon and must be decided by an immunologist.[3]

• Elamipretide (FORZINITY), discussed earlier, is a mitochondria-targeted peptide now approved for Barth syndrome and being studied for other mitochondrial dysfunctions; any use in TARS2 disease would currently be off-label or research-based only.[4]

• Hematopoietic stem-cell transplantation and gene therapy are being researched in some mitochondrial and metabolic diseases, but there is no routine protocol yet for TARS2 combined oxidative phosphorylation deficiency.[5]

Because these areas are experimental, families who are interested usually join natural-history studies or clinical trials through mitochondrial centers or rare-disease networks.

---

Surgeries and procedures

Surgery decisions are highly individual. In TARS2 disease, surgery is usually done to manage complications, not to treat the gene defect itself.[1]

1. Gastrostomy tube (G-tube) placement
Procedure: A small feeding tube is placed through the skin into the stomach, often by endoscopy or minor surgery.
Why it is done: For children with severe feeding problems, unsafe swallowing, or very high energy needs, a G-tube allows safe, reliable delivery of nutrition and medicines, preventing malnutrition and aspiration.

2. Fundoplication or anti-reflux procedures
Procedure: The top of the stomach is wrapped around the lower esophagus to strengthen the valve and reduce reflux.
Why it is done: In children with severe reflux and aspiration that do not improve with medicines, this surgery can protect the lungs and improve comfort and weight gain.

3. Orthopedic surgery (for contractures or scoliosis)
Procedure: Tendon lengthening, spinal rods, or other operations correct deformities.
Why it is done: Long-term muscle weakness can cause contractures and spinal curvature. Surgery may improve sitting balance, reduce pain, and make care easier.

4. Cardiac devices (pacemaker, defibrillator) in selected cases
Procedure: A small device is implanted under the skin with leads to the heart to support rhythm or prevent sudden cardiac death.
Why it is done: If TARS2 disease causes serious arrhythmias or conduction block, devices may protect the heart, similar to management in other cardiomyopathies.

5. Kidney transplant (rare, severe kidney failure)
Procedure: Replacing a failing kidney with a donor kidney.
Why it is done: In very rare cases where TARS2-related disease leads to end-stage kidney disease, transplant may be considered, but risks must be weighed carefully because the underlying mitochondrial problem remains.[1]

---

Prevention and lifestyle tips

We cannot yet prevent the gene mutation itself, but we can reduce avoidable stresses on mitochondria and plan future pregnancies.

• Avoid long fasting; use frequent meals and snacks.

• Treat fevers and infections early with medical advice.

• Keep up-to-date with routine and recommended vaccines.

• Avoid clearly mitochondrial-toxic drugs when alternatives exist (for example valproic acid in many mitochondrial diseases).[1]

• Maintain good hydration, especially during illness or hot weather.

• Encourage gentle, regular physical activity within the child’s limits, but avoid exhausting exercise.

• Protect from extreme heat or cold, which increase energy demand.

• Ensure good sleep habits to support energy and immune function.

• Attend regular follow-up in a mitochondrial or metabolic clinic.

• Use genetic counseling to discuss recurrence risks and reproductive options.[2]

---

When to see a doctor urgently

Families should seek urgent medical help if the child with TARS2 disease has:

• New or worsening seizures, especially if lasting more than a few minutes or repeating without full recovery.

• Sudden loss of consciousness, very bad headache, or new weakness on one side of the body.

• Fast or difficult breathing, blue lips, or repeated vomiting.

• Very poor feeding, no urine for many hours, or signs of dehydration.

• Fast heart rate, swelling of legs, or trouble breathing when lying flat (possible heart failure).

• Any sudden regression in skills (for example loss of sitting, talking, or walking).

Regular (non-emergency) review is needed for growth, development, heart and kidney function, nutrition, and update of the mitochondrial treatment plan.[1]

---

Diet: what to eat and what to avoid (general ideas)

Diet must be individualized, especially if there are kidney, liver, or swallowing problems. These are broad examples only.[1]

Good to eat (under dietitian guidance)

• Frequent small meals with complex carbohydrates (whole grains, fruits, vegetables) to provide steady energy.

• Adequate protein from lean meats, eggs, dairy, legumes, or medically prescribed formulas to support muscle repair.

• Healthy fats (olive oil, nut butters, avocado) as concentrated calorie sources.

• Enough fluids (water, oral rehydration solutions) to prevent dehydration.

• Foods rich in vitamins and minerals, including leafy greens and colorful vegetables.

Better to limit or avoid (if doctor agrees)

• Very long periods without food, especially overnight fasts.

• Crash diets, extreme low-carb or high-protein diets without medical supervision.

• Highly processed foods with lots of trans-fats or added sugar that give “empty calories.”

• Energy drinks or high-caffeine drinks that can stress the heart and disturb sleep.

• Herbal or bodybuilding supplements without safety data in mitochondrial disease.

---

Frequently asked questions (FAQs)

1. Is TARS2-related combined oxidative phosphorylation deficiency always fatal in early childhood?
No. Many reported patients have severe early-onset disease, but outcomes vary. Some children live longer with supportive care, and new cases continue to expand the known spectrum.[1]

2. Can standard epilepsy medicines be used safely?
Some, like levetiracetam, are widely used and generally considered more mitochondrial-friendly, while others (especially valproic acid) may be risky in certain mitochondrial disorders, so seizure treatment must be chosen by a specialist.[2]

3. Will coenzyme Q10 or vitamins cure the disease?
They do not cure the genetic problem, but they may help symptoms or energy in some patients. Response is variable, and evidence is modest, so they are usually part of a broader care plan.[3]

4. Are there clinical trials for TARS2 disease?
Trials are rare but may exist under umbrellas for mitochondrial translation defects or combined oxidative phosphorylation deficiencies. Families can ask mitochondrial centers or rare-disease registries about current studies.[4]

5. Can gene therapy fix the TARS2 mutation today?
Not yet. Gene therapy for mitochondrial disorders is still experimental, and most work so far is in animal models or other mitochondrial genes.[5]

6. Is kidney disease common in TARS2 deficiency?
At least one detailed case report shows chronic kidney disease as a main feature, suggesting the kidney can be involved, but it is not yet clear how common this is overall.[6]

7. Why does lactic acid go up in this disease?
When mitochondria cannot make enough ATP through oxidative phosphorylation, cells switch more to anaerobic glycolysis, making extra lactate as a by-product, so blood lactate can rise.[7]

8. Can adults have TARS2-related disease?
Most known cases start in childhood, but some mitochondrial translation disorders are diagnosed later; as genetic testing increases, milder or adult-onset TARS2 cases may be found.[8]

9. Are brothers and sisters at risk?
If both parents carry a faulty TARS2 copy, each child has a 25% chance to be affected, 50% chance to be a carrier, and 25% chance to have two working copies. Genetic counseling explains this in detail.[9]

10. Can lifestyle alone control this disease?
Lifestyle measures such as good nutrition, avoiding fasting, infection control, and regular therapy are very important but cannot replace medical care. Both are needed together.[10]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 19, 2025.