Combined Oxidative Phosphorylation Defect Type 21

Combined oxidative phosphorylation defect type 21 (often written as COXPD21) is a very rare genetic disease that damages the tiny power plants inside our cells, called mitochondria. In this disease, the mitochondria cannot make enough energy because several parts of the oxidative phosphorylation chain (the main energy-making system) do not work properly at the same time. This energy failure mainly affects the brain, muscles, and sometimes other organs, leading to low muscle tone, movement problems, developmental delay, seizures, and sometimes early death.

Combined oxidative phosphorylation defect type 21 (also called COXPD21 or “combined oxidative phosphorylation deficiency 21”) is a very rare mitochondrial disease. In this condition, the tiny “power plants” inside cells (mitochondria) cannot make enough energy (ATP) because several parts of the respiratory chain are not working properly. This energy problem mainly affects the brain, muscles, and other organs that need constant energy. [1]

Most reported children show weak body muscles (axial hypotonia), stiff arms or legs (limb hypertonia), slow development, feeding problems, high lactic acid in blood (hyperlactatemia), and brain changes on MRI (for example small corpus callosum or damage in deep brain areas). [2]

COXPD21 is usually caused by harmful changes (variants) in the TARS2 gene on chromosome 1q21.2. This gene helps build a protein (mitochondrial threonyl-tRNA synthetase) that is important for making mitochondrial proteins needed for energy production. When TARS2 does not work, many respiratory chain complexes in muscle are weak, so cells cannot use oxygen efficiently. [3]

The condition is inherited in an autosomal recessive way. This means both parents usually carry one non-working copy of the gene but are healthy themselves. When a baby receives two non-working copies (one from each parent), COXPD21 can appear. Many babies become sick in the first months of life with severe hypotonia, poor growth, seizures, and sometimes early death. In a few children, symptoms may start later and progress more slowly. [4]

Other names

Doctors and scientists may use different names for the same condition. Some names you may see for this disease include:

• Combined oxidative phosphorylation defect type 21

• Combined oxidative phosphorylation deficiency 21

• COXPD21

• Mitochondrial disease due to TARS2 mutation (TARS2-related combined oxidative phosphorylation deficiency)

All these names describe the same basic problem: a mitochondrial energy-making defect caused by harmful changes (mutations) in the TARS2 gene.

How the disease happens

To understand COXPD21, think of mitochondria as power stations that make “cell fuel” called ATP. They use a step-by-step process called oxidative phosphorylation to turn food into energy. In COXPD21, the gene called TARS2 is changed. This gene normally makes an enzyme (threonyl-tRNA synthetase 2) that helps build mitochondrial proteins that are needed for the respiratory chain complexes (I, III, IV, V). When TARS2 does not work well, these complexes are not built correctly, so the oxidative phosphorylation process fails, and ATP production drops.

Because the brain and muscles need a lot of energy all the time, they suffer the most. This is why children with COXPD21 often have poor muscle tone, movement problems like ataxia or stiffness, feeding difficulties, and developmental delay. If the energy problem is severe, acid builds up in the blood (lactic acidosis), and the child may become very sick early in life.

Types of combined oxidative phosphorylation defect type 21

Doctors describe COXPD21 mainly by age of onset and severity, rather than by many completely different types. Based on published cases and disease definitions, we can think of two main clinical patterns:

1. Early-onset severe type
   In this pattern, symptoms begin in the first months of life. Babies may show very weak muscles (hypotonia), trouble feeding, failure to gain weight, seizures, and serious developmental delay. Many of these children may have a short life span because their organs cannot cope with the energy failure.

2. Later-onset milder type
   In this pattern, symptoms appear after about 6 months of age, sometimes in later infancy or early childhood. Children still have developmental delay and movement problems, but they may live longer, and the course can be milder than in the early-onset group. They may have problems like ataxia (unsteady movements), spasticity (stiff muscles), or learning difficulties, but can sometimes achieve partial independence with support.

These “types” are really points along a spectrum of the same disease, all linked to harmful biallelic (both copies) variants in the TARS2 gene.

Causes

In this disease there is one main root cause (harmful variants in the TARS2 gene), but we can break this into more detailed “causes” or mechanisms that explain how and why it happens.

1. Pathogenic variants in the TARS2 gene
   The direct cause of COXPD21 is harmful changes (pathogenic variants) in both copies of the TARS2 gene, which is located on chromosome 1q21.2. These variants stop the gene from making a normal threonyl-tRNA synthetase enzyme in the mitochondria.

2. Autosomal recessive inheritance
   COXPD21 follows an autosomal recessive pattern. This means a child usually gets one faulty TARS2 gene from each parent. The parents are often healthy carriers because they still have one working copy of the gene, but the child has two faulty copies and becomes sick.

3. Missense mutations affecting the catalytic site
   Some TARS2 variants change a single amino acid in the enzyme’s active (working) site. This can reduce the enzyme’s ability to attach the amino acid threonine onto its tRNA, which is a key step in building mitochondrial proteins.

4. Truncating or nonsense mutations
   Other variants create a “stop” signal too early in the TARS2 gene. This produces a shorter, non-functional protein or may lead to complete loss of the protein. Without enough functioning enzyme, mitochondrial translation fails.

5. Compound heterozygous variants
   Many reported patients have two different harmful variants, one on each copy of TARS2 (compound heterozygous). The combination of these two variants is enough to disrupt enzyme function and cause disease.

6. Homozygous variants in consanguineous families
   In families where the parents are related (consanguineous), the child may inherit the same harmful TARS2 variant from both parents, becoming homozygous. This can increase the risk of COXPD21 in such families.

7. Defective mitochondrial protein synthesis
   TARS2 normally helps build mitochondrial proteins by charging tRNA with threonine. When this fails, many mitochondrial proteins cannot be made correctly, especially those needed for respiratory chain complexes.

8. Combined deficiency of multiple respiratory chain complexes
   Because mitochondrial translation is globally affected, several complexes of the oxidative phosphorylation chain (I, III, IV, V) show reduced activity in muscle or fibroblast studies. This “combined” defect is the hallmark of COXPD21.

9. Severe ATP (energy) shortage in brain cells
   Neurons need constant energy. When ATP levels fall due to mitochondrial failure, brain cells cannot maintain their normal electrical activity, leading to seizures, developmental delay, and sometimes structural brain changes.

10. Energy failure in muscle fibers
    Muscle cells also depend on oxidative phosphorylation. When their mitochondria fail, muscles become weak or floppy, which explains the axial hypotonia and limb hypertonia (mixed tone) seen in many children.

11. Lactic acidosis from anaerobic metabolism
    When mitochondria cannot make enough ATP, cells switch more to glycolysis (anaerobic energy production), which produces lactic acid. This can build up in the blood and cause lactic acidosis, a common lab finding in mitochondrial disease.

12. Possible involvement of cerebellum and motor pathways
    Brain imaging and clinical signs like ataxia suggest that parts of the brain that control balance and coordination (cerebellum and related tracts) are harmed by the energy failure, leading to movement problems.

13. Oxidative stress from faulty respiratory chain
    A damaged respiratory chain may leak more reactive oxygen species (ROS). These “free radicals” can harm cell membranes, DNA, and proteins, further worsening cell function and survival in the brain and muscles.

14. Secondary damage to myelin and white matter
    In some mitochondrial diseases with combined oxidative phosphorylation defects, white matter (myelin) in the brain is damaged, leading to leukoencephalopathy-like changes. This may contribute to developmental and motor problems in COXPD21.

15. Nutritional and metabolic stressors
    Periods of infection, fasting, or other stress can further strain already weak mitochondria, making symptoms like seizures, acidosis, or regression worse. These triggers do not cause the disease but can worsen it.

16. Developmental brain vulnerability in early life
    Because the brain is rapidly developing in infancy, it is especially sensitive to mitochondrial defects. This timing helps explain why many children with COXPD21 show symptoms in the first months or years of life.

17. Possible organ-specific differences in enzyme expression
    Some tissues may express TARS2 or related factors at different levels. Organs with higher demands or lower spare capacity (like brain, liver, and muscles) may be affected earlier and more severely.

18. Genetic background and modifier genes
    Other genes in a person’s genome may slightly change how severe the TARS2 defect becomes. These modifier genes can help explain why some patients have extremely severe disease and others have milder forms, even with similar core mutations.

19. Random events during development (stochastic factors)
    Even with the same TARS2 variants, random differences in early development or in how mitochondria are distributed among cells can influence which brain regions are most affected, changing the exact symptom pattern.

20. Delayed diagnosis and lack of targeted treatment
    Because COXPD21 is very rare and complex, diagnosis is often delayed. During this time, the disease can progress without supportive measures, which can worsen outcomes. Better awareness and earlier genetic testing can help but do not remove the underlying genetic cause.

Symptoms

Not every child has exactly the same symptoms, but many share a common group of problems related to low energy in the brain and muscles.

1. Axial hypotonia (floppy trunk and neck)
   Many babies with COXPD21 have very poor muscle tone in the neck and trunk, so their head may flop, and they may not be able to sit without support. This is called axial hypotonia and is a key sign of mitochondrial brain and muscle involvement.

2. Limb hypertonia or spasticity
   While the trunk may be floppy, the arms and legs can be stiff or tight, a state called hypertonia or spasticity. This mixed pattern reflects complex damage to motor pathways in the brain and spinal cord.

3. Global developmental delay
   Children often reach milestones, such as rolling, sitting, walking, and talking, much later than usual or sometimes not at all. This overall slowing of development is called global developmental delay and reflects reduced brain function due to chronic energy failure.

4. Failure to thrive and poor growth
   Because feeding may be difficult and energy use is abnormal, many infants do not gain weight or grow as expected. They may need special feeding methods or high-calorie diets to support growth.

5. Epileptic seizures
   Seizures are common in severe mitochondrial diseases. In COXPD21, abnormal electrical activity in the energy-starved brain can cause episodes of stiffening, staring, jerking, or loss of awareness that require anti-seizure medicines.

6. Ataxia (unsteady movements)
   Some children, especially in milder or later-onset forms, have ataxia. They may walk with a wide-based, unsteady gait, have trouble with fine hand movements, and easily lose balance, because the cerebellum and motor tracts are affected.

7. Abnormal eye movements and vision problems
   Mitochondrial disease can affect the nerves and brain areas that control eye movement and vision. Children may have nystagmus (rapid, jerky eye movements), poor visual tracking, or decreased vision.

8. Feeding difficulties and swallowing problems
   Weak muscles and poor coordination can make sucking, chewing, and swallowing hard. Babies may cough or choke with feeds or take very long to finish a meal, which can contribute to poor growth and repeated chest infections.

9. Lethargy and low activity levels
   Because their cells cannot make enough energy, affected children often appear tired, sleepy, or less responsive than other children. They may not move spontaneously very much and may seem “floppy and quiet.”

10. Abnormal muscle reflexes
    On neurological exam, doctors may find brisk or reduced deep tendon reflexes, depending on which pathways are more affected. These changes help show that the nervous system is involved.

11. Lactic acidosis-related symptoms (vomiting, fast breathing)
    When lactic acid builds up, children may vomit, breathe fast, and look very sick. Lactic acidosis can also cause irritability, poor feeding, and, in severe cases, altered consciousness.

12. Microcephaly or abnormal head growth (in some cases)
    In some mitochondrial disorders with serious brain involvement, head size may be smaller than expected, or brain imaging may show poor growth of certain brain structures. This has been reported in related COXPD conditions and may also appear in some COXPD21 patients.

13. Learning difficulties and cognitive problems
    Children who survive into later childhood may have learning difficulties, limited speech, or cognitive impairment. They often need special educational support and therapies to help communication and daily skills.

14. Respiratory issues (breathing problems)
    Weak muscles and poor coordination can affect breathing. Some children may need extra support, such as oxygen, non-invasive ventilation, or hospital care during infections.

15. Shortened life span in severe cases
    In the most severe early-onset forms, the combination of brain failure, lactic acidosis, feeding problems, and infections can lead to early death, often in infancy or early childhood. Milder, later-onset forms may allow much longer survival.

Diagnostic tests

Diagnosis of COXPD21 usually needs a mix of clinical examination, metabolic and genetic tests, and sometimes tissue studies and imaging. Because the disease is so rare, final confirmation almost always comes from genetic testing of the TARS2 gene and related panels.

Physical exam–based tests

1. Full general physical examination
   The doctor carefully checks growth (weight, length/height, head size), vital signs, skin, and organs. Findings like failure to thrive, microcephaly, or organ involvement raise suspicion for a systemic condition such as a mitochondrial disease.

2. Neurological examination
   This exam looks at muscle tone, strength, reflexes, coordination, eye movements, and responses. The combination of axial hypotonia, limb hypertonia, abnormal reflexes, and developmental delay strongly suggests a central nervous system disorder such as COXPD21.

3. Developmental assessment
   Clinicians use structured tools or careful questioning to see how the child is doing in motor, language, social, and cognitive skills compared with typical milestones. Significant delays across several areas support the diagnosis of a serious neurodevelopmental condition.

4. Growth chart and nutritional status review
   Measurements over time are plotted on growth charts. Poor weight gain, low body mass, and crossing down percentiles suggest failure to thrive, which fits with chronic metabolic disease and feeding difficulties.

5. Ophthalmologic and vision screening at the bedside
   Simple bedside checks of visual tracking, fixation, pupil responses, and eye movements can reveal problems like nystagmus or poor visual attention, pointing toward neurological involvement from mitochondrial disease.

Manual (bedside) tests

6. Muscle strength and tone testing
   The doctor moves the child’s limbs and asks older children to push or pull against resistance. Mixed hypotonia and hypertonia, plus weakness, help show the pattern of central and sometimes peripheral motor involvement.

7. Reflex testing with a tendon hammer
   Deep tendon reflexes (knee, ankle, etc.) are tested. Very brisk reflexes suggest upper motor neuron involvement, while reduced reflexes may suggest peripheral nerve or muscle problems, helping to localize the lesion.

8. Coordination and ataxia tests
   In children who can cooperate, simple tests like finger-to-nose, heel-to-shin, or asking them to walk heel-to-toe can show ataxia. This supports cerebellar or motor pathway dysfunction often seen in COXPD21.

9. Gait and posture assessment
   Observation of how the child stands, sits, and walks gives clues to balance, spasticity, and weakness. A wide-based, unsteady gait or scissoring pattern can point toward central motor pathway involvement.

10. Bedside feeding and swallowing evaluation
    Clinicians watch how the child sucks, chews, and swallows different textures. Coughing, choking, or long feeding times support the presence of oropharyngeal dysphagia linked to neuromuscular weakness.

Laboratory and pathological tests

11. Blood lactate and pyruvate levels
    Elevated blood lactate, often with an abnormal lactate-to-pyruvate ratio, is a key clue to mitochondrial oxidative phosphorylation failure. Many patients with combined oxidative phosphorylation defects show persistent or episodic lactic acidosis.

12. Blood gas and acid–base analysis
    Arterial or venous blood gas helps detect acidosis (low pH, low bicarbonate) related to lactic acid buildup. These results guide urgent treatment and help document metabolic stress.

13. Basic metabolic panel and liver function tests
    Electrolytes, glucose, kidney function, and liver enzymes are checked to look for organ involvement, hypoglycemia, or other metabolic disturbances that often accompany mitochondrial disease.

14. Plasma amino acid and acylcarnitine profile
    These specialized tests screen for other inborn errors of metabolism that can mimic mitochondrial disease. They may show non-specific changes but are important to rule out other treatable conditions.

15. CSF (cerebrospinal fluid) analysis including lactate
    In some cases, spinal tap is done to measure lactate and other markers in CSF. Elevated CSF lactate further supports mitochondrial dysfunction in the brain.

16. Muscle biopsy with respiratory chain enzyme analysis
    A small piece of muscle may be studied under the microscope and tested for the activity of respiratory chain complexes. COXPD21 typically shows reduced activity in several complexes, confirming a combined oxidative phosphorylation defect.

17. Molecular genetic testing of TARS2
    The most specific test is DNA sequencing of the TARS2 gene, often as part of a mitochondrial or neurogenetic panel. Finding biallelic pathogenic variants in TARS2 confirms the diagnosis of COXPD21.

18. Exome or genome sequencing
    When the cause is unclear, whole-exome or whole-genome sequencing can look at many genes at once, including TARS2 and other COXPD-related genes. This can be especially useful in very rare or unusual cases.

Electrodiagnostic tests

19. Electroencephalogram (EEG)
    EEG measures brain electrical activity. In COXPD21, EEG may show abnormal background slowing and epileptic discharges, helping to diagnose and manage seizures and to show diffuse brain dysfunction.

20. Electromyography (EMG) and nerve conduction studies (NCS)
    These tests measure muscle and nerve electrical activity. They can help distinguish between primary muscle disease, nerve disease, and central causes, and in some mitochondrial disorders they show myopathic or mixed patterns.

Imaging tests (also very important)

Although we have already listed 20 tests above, imaging is usually part of the diagnostic work-up and helps show how much the brain and other organs are affected, even if not counted separately in the 20-test list.

• Brain MRI
  MRI can show brain atrophy, white matter changes, or other structural abnormalities related to mitochondrial disease. These findings support the diagnosis but are not specific to COXPD21.

• Magnetic resonance spectroscopy (MRS)
  MRS can detect a lactate “peak” in the brain, which is a strong sign of mitochondrial energy failure.

• Echocardiography (heart ultrasound) if indicated
  In some combined oxidative phosphorylation defects, cardiomyopathy can occur, so heart ultrasound may be done to check heart function, even though this is not a core feature in all COXPD21 cases.

Non-pharmacological treatments (therapies and other care)

These treatments do not change the gene problem, but they help the child move, breathe, eat, communicate, and feel more comfortable. They are usually planned by a multidisciplinary team familiar with mitochondrial disease. [7]

1. Physiotherapy and movement therapy
   Gentle stretching, positioning, and active exercises keep joints flexible and muscles as strong as possible. The purpose is to reduce contractures, prevent deformities, and improve posture and mobility. It works by regular use of muscles and stimulation of blood flow. [8]

2. Occupational therapy
   An occupational therapist trains the child in daily activities like sitting, holding toys, and later simple self-care. The goal is maximum independence and safety at home. It works by adapting tasks and using aids so the child uses remaining strength efficiently. [9]

3. Speech, feeding, and swallowing therapy
   A speech-language therapist helps with sucking, chewing, swallowing, and, when possible, early communication. Purpose is safe feeding and prevention of choking or aspiration. Mechanism is teaching better mouth and tongue control and safe feeding positions. [10]

4. Respiratory physiotherapy
   Chest physiotherapy, breathing exercises, and sometimes mechanical cough assist help clear mucus and prevent chest infections. Purpose is to improve ventilation and oxygen levels. It works by loosening secretions and helping the child cough them out. [11]

5. Low-intensity, paced aerobic activity
   When safe, very gentle activity (short, supervised movement, supported sitting) can maintain endurance. Purpose is to avoid complete deconditioning. Mechanism is slow training of heart and muscles without over-loading the fragile mitochondria. [12]

6. Energy conservation and pacing education
   Parents learn to plan rest breaks, avoid long fasting, and spread tasks through the day. Purpose is to reduce energy crashes and lactic acid build-up. Mechanism is matching activity levels to the child’s limited energy supply. [13]

7. Orthotic devices and supportive seating
   Splints, special shoes, standing frames, and molded chairs support weak trunk and limbs. Purpose is to maintain alignment, prevent contractures, and make daily care easier. They work by holding joints in functional positions for long periods. [14]

8. Assistive communication devices
   For children who cannot speak, simple picture boards, switches, tablets, or eye-gaze devices allow them to express needs. Purpose is better communication and less frustration. Mechanism is bypassing the motor difficulty and using remaining movements or eye control. [15]

9. Developmental and behavioral therapy
   Play-based programs stimulate touch, sound, vision, and social interaction. Purpose is to support brain development and reduce behavioral distress. Mechanism is regular structured stimulation and positive reinforcement. [16]

10. Special education support
    For survivors beyond infancy, tailored school programs with one-to-one support can help learning at the child’s level. Purpose is inclusion and skill development. Mechanism is adapting curriculum, environment, and expectations to the child’s abilities. [17]

11. Hearing rehabilitation (hearing aids or cochlear implant rehab)
    If hearing loss is present, early fitting of aids and intensive listening therapy can improve awareness of sound. Purpose is better communication and bonding. Mechanism is amplifying sound and training the brain to use what hearing is left. [18]

12. Vision support and low-vision aids
    If vision is affected, simple tools (high-contrast objects, large pictures, good lighting) and low-vision services help the child use remaining sight. Purpose is safer interaction with the environment. Mechanism is making visual information easier to see and process. [19]

13. Nutritional counseling and high-calorie feeding plans
    A dietitian designs frequent small feeds, calorie-dense formulas, and fluid plans. Purpose is to prevent malnutrition and support growth. Mechanism is giving enough calories without long fasting times that worsen lactic acidosis. [20]

14. Gastrostomy-based feeding programs (non-drug aspect)
    If a feeding tube (PEG / G-tube) is placed, the nursing team trains the family to use it safely. Purpose is reliable nutrition and medicine delivery. Mechanism is bypassing weak mouth and throat muscles and using the stomach directly. [21]

15. Sleep hygiene and positioning
    Regular sleep routines, comfortable positioning, and sometimes special mattresses help children sleep better. Purpose is better daytime alertness and less irritability. Mechanism is improving comfort and reducing night-time breathing problems. [22]

16. Infection-prevention routines
    Simple steps like good hand washing, limiting exposure to sick contacts, and quick response to fevers help protect fragile children. Purpose is fewer serious infections that can trigger metabolic crises. Mechanism is reducing germ exposure and catching illness early. [23]

17. Psychological support for family
    Counseling helps parents cope with stress, grief, and complex decisions. Purpose is better mental health and stronger caregiving capacity. Mechanism is emotional support, coping strategies, and sometimes support groups for rare diseases. [24]

18. Genetic counseling for the family
    Genetic counselors explain inheritance, recurrence risk, and options in future pregnancies. Purpose is informed family planning. Mechanism is reviewing test results, drawing pedigrees, and discussing carrier and prenatal testing. [25]

19. Palliative care and symptom-management support
    Palliative care teams focus on comfort, symptom relief, and family values, from early in the disease. Purpose is best possible quality of life, not just end-of-life care. Mechanism is careful symptom control, communication, and psychosocial support. [26]

20. Care coordination by a mitochondrial center
    A specialist center can coordinate neurology, cardiology, nutrition, rehab, and palliative care. Purpose is consistent, evidence-based management. Mechanism is regular team reviews and shared care plans. [27]

Drug treatments (supportive medicines)

There is no specific FDA-approved drug that cures COXPD21. Medicines are used to control seizures, muscle tone problems, reflux, infections, and other complications. Doses must always be chosen by a specialist, often using FDA labels as a starting guide. [28]

Below are examples of 20 supportive drug groups often considered in similar mitochondrial encephalopathies. They are not all required in every child, and many are off-label for this exact diagnosis.

1. Levetiracetam (antiseizure medicine)
   Class: antiepileptic. Purpose: control focal and generalized seizures. Usually given twice a day; dose is based on weight and adjusted slowly following the FDA label. Mechanism: modulates synaptic neurotransmitter release; often well tolerated. Side effects: sleepiness, irritability, behavior changes. [29]

2. Other antiseizure drugs (e.g., topiramate, lamotrigine)
   Class: antiepileptics. Used when seizures are not well controlled with one drug. Mechanism: stabilize brain electrical activity. Side effects: appetite change, sleep problems, rare serious skin rashes. Doctors choose carefully and monitor for side effects. [30]

3. Benzodiazepines (e.g., diazepam, midazolam) for acute seizures
   Class: benzodiazepines. Purpose: stop prolonged seizures or status epilepticus in emergencies. Mechanism: enhances GABA, a calming brain chemical. Side effects: drowsiness, breathing depression if overdosed; risk of dependence with repeated use. [31]

4. Baclofen for spasticity
   Class: muscle relaxant. Purpose: reduce limb stiffness and painful spasms. Usually given several times per day, dose slowly increased. Mechanism: acts on GABA-B receptors in spinal cord. Side effects: sleepiness, weakness, low mood if too high. [32]

5. Diazepam orally for spasticity and anxiety
   Class: benzodiazepine. Sometimes used in low doses to relax muscles and reduce distress. Mechanism: GABA-A receptor agonist. Side effects: sedation, dependence, breathing depression in overdose; must be closely supervised. [33]

6. Proton pump inhibitors (e.g., omeprazole)
   Class: acid-suppressing drugs. Purpose: treat reflux, prevent esophagitis when children have feeding problems. Mechanism: blocks acid pumps in the stomach. Usually once daily before feeds. Side effects: diarrhea, low magnesium with long use. [34]

7. Pro-motility agents (e.g., metoclopramide, carefully used)
   Class: dopamine antagonist. Purpose: improve stomach emptying and reduce vomiting in severe reflux or gastric stasis. Mechanism: increases gut movement and tightens lower esophageal sphincter. Side effects: movement disorders and mood changes, so use is cautious and time-limited. [35]

8. Antibiotics for proven infections
   Class: varies (e.g., beta-lactams, macrolides). Purpose: treat bacterial pneumonia, sepsis, urinary infections. Mechanism: kill or stop growth of bacteria. Doses follow standard pediatric guidelines. Side effects: diarrhea, allergies, resistance risk. [36]

9. Antipyretics and simple analgesics (paracetamol / acetaminophen)
   Class: analgesic-antipyretic. Purpose: reduce fever and pain from procedures or infections. Mechanism: acts on brain temperature center and pain pathways. Given in weight-based doses as needed. Side effects: liver toxicity if overdosed. [37]

10. Laxatives (e.g., polyethylene glycol)
    Class: osmotic laxative. Purpose: relieve constipation from immobility and medicines. Mechanism: draws water into stool to soften it. Side effects: bloating, loose stools if too much. [38]

11. Bronchodilators (if reactive airway disease present)
    Class: beta-agonists (e.g., salbutamol). Purpose: open narrowed airways during wheeze. Mechanism: relaxes airway smooth muscle. Side effects: jitteriness, fast heart rate. [39]

12. Inhaled steroids (when indicated for chronic airway inflammation)
    Class: corticosteroids. Purpose: control airway swelling and reduce frequent wheeze. Mechanism: decreases local inflammation. Side effects: oral thrush, slowed growth with long-term high doses. [40]

13. Antisialogogues (to reduce drooling and aspiration, e.g., glycopyrrolate)
    Class: anticholinergic. Purpose: lessen saliva volume when drooling is severe. Mechanism: blocks acetylcholine at salivary glands. Side effects: dry mouth, constipation, urinary retention. [41]

14. Vitamin and cofactor “cocktail” given as medicines
    Often includes riboflavin, thiamine, alpha-lipoic acid, and others. Purpose: support mitochondrial enzyme function and reduce oxidative stress. Evidence is mixed; benefits vary. Side effects: usually mild stomach upset. [42]

15. Sodium bicarbonate or other buffering agents (in metabolic acidosis)
    Class: systemic alkalinizing agents. Purpose: correct severe lactic acidosis in acute crises. Mechanism: neutralizes excess acid in blood. Side effects: fluid overload, electrolyte shifts; used in intensive care only. [43]

16. Anti-spasticity drugs via pump (intrathecal baclofen in selected cases)
    Class: muscle relaxant delivered to spinal fluid. Purpose: treat severe generalized spasticity when oral therapy fails. Mechanism: high local baclofen effect with lower blood levels. Side effects: pump complications, withdrawal if suddenly stopped. [44]

17. Sedatives for procedures (short-acting benzodiazepines or others)
    Class: sedatives. Purpose: allow MRI, surgeries, or tube procedures safely. Mechanism: reduce anxiety and movement. Side effects: breathing depression; must be done with anesthesiology team. [45]

18. Antidepressants / anxiolytics for older patients and caregivers
    Class: SSRIs, other agents. Purpose: treat significant depression or anxiety in older children, teenagers, or parents. Mechanism: change brain neurotransmitters over weeks. Side effects depend on drug; all need close monitoring. [46]

19. Cardiac medications if heart is involved
    Class: varies (ACE inhibitors, beta blockers, diuretics). Purpose: support heart function in cardiomyopathy or heart failure if present. Mechanism: reduce strain on heart and improve pumping. Side effects: blood pressure changes, electrolyte shifts. [47]

20. Anti-reflux thickening agents or alginates
    Class: physical barrier agents. Purpose: reduce spit-ups and reflux episodes. Mechanism: form a foam or thicker layer on stomach contents. Side effects: mild bloating or constipation. [48]

All drugs must be prescribed and regularly reviewed by specialists; never start, change, or stop medicine without your doctor’s advice. [49]

Dietary molecular supplements

Supplements are often used in mitochondrial diseases to support energy production and reduce oxidative stress, although strong proof of benefit in COXPD21 is limited and research is ongoing. [50]

1. Coenzyme Q10 (ubiquinone / ubiquinol)
   Supports the electron transport chain and works as an antioxidant in mitochondria. Purpose is to improve energy transfer and reduce oxidative damage. Usual dosing is divided through the day, based on weight and specialist advice. Side effects are usually mild, like stomach discomfort. [51]

2. L-carnitine
   Helps move fatty acids into mitochondria to be used as fuel. Purpose is to support energy production and remove toxic acyl compounds. Dose is weight-based in divided doses. Side effects can include fishy body odor and diarrhea. [52]

3. Riboflavin (vitamin B2)
   Works as a cofactor for many mitochondrial enzymes. Purpose is to support electron transport and energy release from food. Dose depends on age and protocol. Side effects are rare; urine may become bright yellow. [53]

4. Thiamine (vitamin B1)
   Important for pyruvate dehydrogenase and other enzymes connecting sugar breakdown to the Krebs cycle. Purpose is to help the body handle carbohydrates and reduce lactic acid formation. Side effects are uncommon at usual doses. [54]

5. Alpha-lipoic acid
   An antioxidant and enzyme cofactor that may reduce oxidative stress. Purpose is protection of cell membranes and mitochondria from free radicals. Usually given orally with food. Possible side effects: nausea, rare low blood sugar. [55]

6. Vitamin C
   Water-soluble antioxidant that supports immune function and helps recycle other antioxidants. Purpose is to limit oxidative damage. Given in divided doses according to age. Side effects: stomach upset at high doses. [56]

7. Vitamin E
   Fat-soluble antioxidant that protects cell membranes from lipid peroxidation. Purpose is to stabilize membranes, including mitochondrial ones. Dose must be carefully chosen to avoid toxicity. Side effects at high levels: bleeding risk. [57]

8. Creatine
   Stores high-energy phosphate in muscles and brain. Purpose is to provide quick energy buffer when ATP is low. Dose is weight-based and often divided. Side effects: weight gain, cramps in some people. [58]

9. Folate and B-complex vitamins
   Support many cellular reactions including DNA repair and methylation. Purpose is general metabolic support. Doses follow age-appropriate ranges. Side effects: usually minimal; rare allergic reactions. [59]

10. Selenium and trace antioxidant minerals (when deficient)
    These are needed for antioxidant enzymes like glutathione peroxidase. Purpose is to optimize natural defense systems. Given only if deficiency is suspected or proven. Too much can be toxic, so careful medical guidance is essential. [60]

Immunity-booster, regenerative and stem-cell–related drugs

Currently, there are no approved stem-cell or gene-editing drugs specifically for COXPD21. Most “regenerative” approaches are still in research stages for mitochondrial diseases. The items below describe concepts sometimes discussed in the literature, not standard care. [61]

1. General antioxidant “cocktail” as mitochondrial support
   Combination of CoQ10, vitamins B, C, E, alpha-lipoic acid, and L-carnitine may help protect mitochondria from oxidative stress. Purpose is supportive, not curative. Mechanism is reduction of free radicals and stabilization of mitochondrial membranes. Evidence is mixed. [62]

2. Immunizations as immune support (standard vaccines)
   Routine vaccines against pneumonia, influenza, and other infections help protect fragile children. Purpose is to reduce severe infections that can trigger metabolic crises. Mechanism is training the immune system safely. These are standard pediatric tools, not special drugs. [63]

3. Experimental stem-cell therapies (research only)
   Some laboratories explore bone-marrow–derived or mesenchymal stem cells to support damaged tissues in mitochondrial disease. Purpose is potential regeneration or support. Mechanism may involve paracrine signals and immune modulation. At present, this is experimental and not routine care. [64]

4. Future gene-therapy strategies for nuclear mitochondrial genes
   Researchers are studying viral vectors or gene-editing tools (such as CRISPR-based methods) to correct nuclear genes like TARS2. Purpose is to fix the root genetic cause. This work is early and not available as treatment yet. [65]

5. Immune-modulating drugs in special situations
   If a child has autoimmune features or post-infectious complications, doctors may occasionally use steroids or other immune modulators. Purpose is to calm harmful immune activity. These medicines carry significant risks and are not specific for COXPD21. [66]

6. Clinical trials of new mitochondrial agents
   Some trials test new drugs that target mitochondrial biogenesis or respiratory chain function. Purpose is to improve energy production broadly. Families may be offered trials only through specialized centers, with strict safety monitoring. [67]

Surgeries and procedures

Surgery does not treat the gene defect, but some procedures can improve nutrition, breathing, or comfort. All operations for mitochondrial disease patients must be planned with anesthesiologists experienced in these disorders. [68]

1. Gastrostomy tube placement (PEG / G-tube)
   A small opening is made into the stomach, and a feeding tube is placed. Purpose: safe, reliable feeding and medicine delivery when oral feeding is not adequate or unsafe.

2. Tracheostomy (in selected patients)
   A surgical opening is made in the windpipe to place a breathing tube. Purpose: long-term airway support and easier connection to ventilators when breathing muscles are very weak.

3. Orthopedic surgery for contractures or hip dislocation
   Tendon lengthening or bone surgery may be done when joints are fixed in bad positions or hips dislocate. Purpose: easier care, sitting, and reduced pain.

4. Spinal surgery for severe scoliosis
   In older children with significant spinal curvature affecting breathing and sitting, corrective spinal fusion may be considered. Purpose: improve posture and lung function.

5. Cochlear implant surgery (if severe sensorineural deafness)
   An electronic device is implanted in the inner ear. Purpose: provide sound perception when hearing aids are not enough, improving communication and interaction.

Prevention strategies

It is not yet possible to completely prevent COXPD21 in a child who already carries the gene changes. However, families and doctors can try to prevent complications and reduce risk in future pregnancies. [69]

1. Avoid long fasting; use frequent feeds.

2. Treat infections quickly and seriously.

3. Keep vaccinations up to date (according to local schedules).

4. Avoid extreme heat or cold that can stress the body.

5. Avoid unnecessary exposure to people with flu or stomach bugs.

6. Do not use known mitochondrial-toxic drugs if safer options exist.

7. Plan surgeries carefully with experienced anesthetic teams.

8. Provide early physiotherapy to prevent severe contractures.

9. Use safe lifting and positioning to avoid injuries.

10. Seek genetic counseling before future pregnancies to discuss carrier testing and prenatal or preimplantation genetic testing options.

When to see a doctor urgently

Families should seek urgent medical care if they notice any of the following warning signs:

• New or worsening seizures, especially if they last more than a few minutes or come in clusters.

• Fast or labored breathing, blue lips, or repeated pauses in breathing.

• Strong sleepiness, poor response, or sudden change in behavior or awareness.

• Repeated vomiting, inability to keep feeds down, or signs of dehydration (very few wet diapers, dry mouth).

• High fever that does not respond to simple medicines, or any fever in a very young or very fragile child.

• Sudden loss of skills, such as no longer holding up the head or not responding to sound or touch as before.

Regular follow-up with neurology, metabolic specialists, cardiology, and rehabilitation teams is also important, even when the child seems stable, because problems can build slowly over time. [70]

What to eat and what to avoid

Diet must be individualized by a metabolic team, but some general ideas are often used in mitochondrial disease care. [71]

What to eat (with medical guidance)

1. Frequent small meals and snacks to avoid long fasting and big blood sugar swings.

2. Balanced diet with complex carbohydrates (e.g., rice, bread, potatoes) to provide steady energy.

3. Adequate proteins (milk, yogurt, lentils, eggs, lean meat as culturally appropriate) to support growth and muscle repair.

4. Healthy fats (oils, nuts, seeds if safe, fatty fish) in amounts recommended by the dietitian to increase calories without large volume.

5. Plenty of fluids to prevent dehydration, especially during fevers or hot weather.

What to avoid or limit (unless the team says otherwise)

6. Long periods without food (such as skipped meals or long overnight fasts).

7. Very high-sugar drinks and sweets that give quick spikes and crashes in blood sugar.

8. Excessively high-protein or fad diets without specialist supervision.

9. Herbal or “energy” supplements bought without medical advice, because some may harm the liver or mitochondria.

10. Alcohol and tobacco exposure for older patients and family members, as these can worsen overall health and mitochondrial stress.

Frequently asked questions (FAQs)

1. Is COXPD21 always fatal in early life?
   No. Many reported children become very sick in infancy and some die early, but others survive longer with careful supportive care. The course can vary, and new supportive methods continue to improve outcomes. [72]

2. Can diet or vitamins cure COXPD21?
   No. Diet and supplements like CoQ10 may support energy production and reduce stress on cells, but they do not remove the underlying TARS2 mutation. They are best seen as supportive tools, not cures. [73]

3. Are there specific drugs approved just for COXPD21?
   At present there are no drugs approved only for COXPD21. Doctors use regular antiseizure, reflux, and supportive medicines according to general pediatric and mitochondrial guidelines. [74]

4. Is valproate safe in mitochondrial disease?
   In several mitochondrial conditions, valproate can increase risk of liver failure and severe side effects, so many experts avoid it or use it with great caution. Families should ask their mitochondrial specialist about safer antiseizure options. [75]

5. Can children with COXPD21 be vaccinated?
   In most cases, routine vaccines are recommended because infections can be very dangerous. The metabolic team may adjust timing in special situations, but vaccines are usually an important protection. [76]

6. Will another child in the family also have COXPD21?
   If both parents are carriers, each pregnancy has a 25% chance the baby will have COXPD21, a 50% chance of being a healthy carrier, and a 25% chance of being unaffected and not a carrier. Genetic counseling explains these numbers in detail. [77]

7. Can prenatal or preimplantation testing be done?
   Yes, if the family’s specific TARS2 variants are known, some centers can offer prenatal diagnosis or preimplantation genetic testing. Availability depends on local laws and resources. [78]

8. Does exercise help or harm?
   Gentle, carefully supervised activity can help prevent total deconditioning and improve comfort. Over-exertion may worsen fatigue and lactic acidosis, so pacing and rest are very important. [79]

9. Why are so many supplements used together?
   Because mitochondrial problems affect many steps of energy production, clinicians sometimes use a “cocktail” of antioxidants and cofactors. Evidence is limited, but some patients and families report better energy or fewer crises. [80]

10. Are stem-cell treatments available in clinics now?
    No standard stem-cell therapy is approved for COXPD21. Offers from unregulated clinics should be treated with extreme caution. Participation in properly supervised research trials is safer and more ethical. [81]

11. Can adults have COXPD21?
    Most reported cases begin in infancy, but some children with milder forms may live into later childhood or beyond. Long-term natural history is still poorly understood because the disease is so rare. [82]

12. Does this condition affect only the brain and muscles?
    No. Because mitochondria are in almost every cell, COXPD21 can also affect liver, hearing, vision, heart, and other organs, depending on the person. [83]

13. Is genetic testing necessary?
    Yes. Confirming TARS2 variants helps clarify the diagnosis, guide family planning, and sometimes connect the family to research. It also avoids unnecessary tests for other conditions. [84]

14. What is the role of MRI and other imaging?
    Brain MRI often shows structural changes, and sometimes heart or abdominal imaging is needed to check other organs. Imaging helps doctors understand how widely the disease has affected the body. [85]

15. Where can families find more support?
    Families can connect with rare-disease and mitochondrial-disease organizations, local parent groups, and online communities. These groups share practical tips and emotional support, and sometimes information about trials and expert centers. [86]

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.