Combined Oxidative Phosphorylation Defect Type 25 (COXPD25)

Combined oxidative phosphorylation defect type 25 (COXPD25) is a very rare genetic mitochondrial disease. It affects how the “power stations” of the cell, called mitochondria, make energy. In this condition there is reduced activity of mitochondrial respiratory chain complex I and complex IV, so cells cannot produce enough ATP, especially in organs that need a lot of energy like brain, muscles, heart and ears.[1][2] COXPD25 is caused by harmful changes (mutations) in a nuclear gene called MARS2, which provides instructions for a mitochondrial enzyme (mitochondrial methionyl-tRNA synthetase). This enzyme is needed for building mitochondrial proteins that are essential for oxidative phosphorylation, so MARS2 mutations disturb many mitochondrial proteins at once.[3][4]

The disease is inherited in an autosomal recessive pattern. This means a child becomes affected only when they receive one faulty MARS2 gene from each parent. Carriers (with only one faulty copy) are usually healthy but have a chance in each pregnancy to have an affected child.[1][3]

Symptoms usually start in the newborn period or early infancy. Common features include low muscle tone (hypotonia), global developmental delay, poor growth, progressive chest wall deformity (pectus carinatum), sensorineural hearing loss, distinctive facial features, and brain changes such as cerebral atrophy and enlargement of the brain ventricles. Seizures and feeding difficulties can also occur.[1][2][5]

Combined oxidative phosphorylation defect type 25 (COXPD25) is a very rare genetic disease of the mitochondria, the tiny “power stations” inside our cells. In this condition, important energy-making machines (complex I and complex IV of the respiratory chain) work less than normal, so the body’s cells cannot make enough energy (ATP). This mainly harms the brain, muscles, hearing, growth, and chest shape in early life. [1]

In most reported children, symptoms start soon after birth. Many have low muscle tone (they feel “floppy”), global developmental delay, poor weight gain, a chest that sticks out in the front (pectus carinatum), hearing loss, and clear changes on brain scans such as brain shrinkage (atrophy) and enlarged fluid spaces (ventricular dilatation). [1]

COXPD25 belongs to a larger group called “combined oxidative phosphorylation deficiencies”. In these diseases, more than one mitochondrial complex is affected at the same time, so the energy problem is usually severe and involves several organs at once. [2]

This article is for education only. It explains the condition in very simple words and is not a substitute for personal medical advice from a qualified doctor. [1]

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Other names

Doctors and scientists use several other names for the same disease. These are helpful when searching the medical literature or genetic test reports. [1]

Some other names include:

• Combined oxidative phosphorylation deficiency 25 [1]

• Combined oxidative phosphorylation defect type 25 [1]

• COXPD25 [1]

• MARS2-related combined oxidative phosphorylation deficiency [2]

• Combined oxidative phosphorylation deficiency caused by mutation in MARS2 [2]

All of these names describe the same underlying disorder, where changes in the MARS2 gene lead to a serious mitochondrial energy problem. [2]

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Types

At this time, COXPD25 is extremely rare, and only a very small number of families have been clearly described in the medical literature. Because of this, doctors do not yet use strict, official “subtypes”. [1]

However, based on reported cases and general knowledge about mitochondrial disease, we can think about clinical patterns or “types of presentation” in a practical way: [2]

1. Classical neonatal-onset COXPD25 – Symptoms start at or soon after birth with low muscle tone, poor growth, chest deformity, and brain changes. [1]

2. Infant-onset COXPD25 with strong neurological features – Symptoms appear in the first months of life with marked developmental delay, feeding problems, and structural brain abnormalities on MRI. [2]

3. MARS2-related mitochondrial disease spectrum – Some people with MARS2 changes show overlap with other conditions such as spastic ataxia, so doctors consider COXPD25 as part of a wider MARS2-related phenotype. [3]

These patterns are not official subtypes, but they help clinicians think about how the disease may look in different patients. [1]

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Causes

The main cause of COXPD25 is a change (mutation) in a single gene. Other “causes” listed here are supporting mechanisms or factors that explain how the gene change leads to disease and what can make symptoms appear or worsen. [1]

1. MARS2 gene mutation – The core cause is harmful changes in MARS2, the gene that gives the instructions to make mitochondrial methionyl-tRNA synthetase, an enzyme needed for building mitochondrial proteins. When this gene does not work correctly, many mitochondrial proteins cannot be made properly. [1]

2. Autosomal recessive inheritance – The disease usually happens when a child receives one faulty MARS2 gene from each parent. Parents are often healthy carriers and do not know they carry a single faulty copy. [2]

3. Loss of normal mitochondrial protein building – MARS2 is part of the system that attaches the amino acid methionine to tRNA in mitochondria. If this step fails, mitochondria cannot build some of their own proteins, especially those used in the respiratory chain. [3]

4. Complex I deficiency – Poor mitochondrial protein production leads to low activity of complex I, one of the main entry points for electrons in the respiratory chain. This limits ATP production and increases the risk of energy failure in cells. [4]

5. Complex IV deficiency – Complex IV (cytochrome c oxidase) is also affected, so the final step of the electron transport chain is slowed. This further reduces ATP production and adds to the energy crisis. [4]

6. Energy failure in brain cells – The brain uses a lot of energy. When oxidative phosphorylation is weak, brain cells cannot keep normal structure and function, leading to cerebral atrophy and enlarged ventricles seen on MRI. [5]

7. Energy failure in muscle cells – Muscle fibers need constant ATP for tone and movement. Low ATP leads to low muscle tone (hypotonia) and delayed motor milestones. [5]

8. Energy failure in growth and bone cells – Growing tissues require high energy. Chronic mitochondrial dysfunction can disturb growth and bone shaping, contributing to poor weight gain and chest wall deformity such as pectus carinatum. [6]

9. Damage in hearing cells – The inner ear hair cells and auditory nerve also need healthy mitochondria. Low ATP and oxidative stress in these cells can lead to sensorineural hearing loss. [7]

10. Build-up of lactic acid – When mitochondria cannot use oxygen effectively, cells switch to less efficient pathways (anaerobic glycolysis). This produces more lactic acid, causing lactic acidosis and related symptoms like vomiting or tiredness. [8]

11. Oxidative stress – Defective respiratory chain function can increase reactive oxygen species (ROS). Over time, ROS can damage lipids, proteins, and DNA inside the cell, further worsening mitochondrial function. [9]

12. Modifier genes – Other mitochondrial or nuclear genes may not cause the disease by themselves but may change how severe or mild the symptoms look in a person with MARS2 mutations. This idea comes from studies of other COXPD disorders. [10]

13. Random (de novo) mutations – In some rare cases, the mutation in MARS2 may appear for the first time in the child (de novo). This is still being studied but is a possible cause pattern in mitochondrial disease. [11]

14. Consanguinity (parents related by blood) – In some families with autosomal recessive mitochondrial disease, parents are related (for example, cousins). This increases the chance that both carry the same rare MARS2 mutation. [12]

15. Fever and infections as triggers – Fever or serious infections do not cause the genetic disease but can reveal or worsen symptoms, because the body suddenly needs more energy that the mitochondria cannot supply. [13]

16. Poor nutritional state – Lack of proper calories, proteins, or vitamins can further reduce the energy available to cells and may aggravate mitochondrial symptoms, though it does not cause the gene defect itself. [14]

17. Environmental toxins affecting mitochondria – Certain drugs or chemicals can be toxic to mitochondria. In someone with MARS2-related weakness, such exposures might worsen the condition, so doctors try to avoid them. [15]

18. Metabolic stress from surgery or fasting – Long fasting, surgery, or anesthesia can stress energy metabolism and may trigger decompensation in children with mitochondrial disease. Careful planning of such events is important. [16]

19. Lack of early diagnosis and supportive care – Late diagnosis does not cause the gene change but may cause worse outcomes because nutrition, infection control, and other supports start later. [17]

20. Limited ability of cells to repair mitochondrial damage – Once mitochondria are very damaged, cells may not fully repair them. This slow loss of healthy mitochondria over time is another mechanism behind progressing symptoms. [18]

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Symptoms

Symptoms can vary between children, even in the same family, but certain features are reported again and again in COXPD25 and in related combined oxidative phosphorylation deficiencies. [1]

1. Hypotonia (floppy muscles) – Babies often feel “floppy” when held. Their head may lag when pulled to sit, and their limbs may feel soft because muscles do not have enough energy to keep normal tone. [1]

2. Global developmental delay – Children reach milestones such as sitting, crawling, walking, and talking later than expected. Both movement skills and learning skills can be delayed because the brain and muscles are affected. [1]

3. Neonatal chest deformity (pectus carinatum) – The breastbone (sternum) may push outward, giving the chest a “pigeon chest” look. In COXPD25, this can start soon after birth and slowly become more obvious with time. [1]

4. Poor growth and failure to thrive – Children may gain weight slowly or even lose weight. They may be shorter and thinner than other children of the same age because of the ongoing energy problem. [1]

5. Feeding problems – Babies may suck weakly, tire quickly during feeds, or have trouble swallowing. Older children may need special feeding plans or tube feeding to maintain nutrition. [2]

6. Sensorineural hearing loss – Many affected children have trouble hearing because the inner ear and auditory nerve are damaged. They may not respond well to sounds or voices, and hearing tests show reduced function. [1]

7. Abnormal facial features (dysmorphism) – Some children may have subtle differences in facial shape, such as a high forehead, low-set ears, or other features described in case reports. These features are not specific but support the diagnosis. [2]

8. Brain atrophy and enlarged ventricles on MRI – Brain scans often show loss of brain tissue (atrophy), enlarged fluid spaces (quadriventricular dilatation), and a thin band that connects the two brain halves (thin corpus callosum). These are signs of long-term energy failure in the brain. [1]

9. Seizures (fits) – Some children with combined oxidative phosphorylation deficiencies have seizures because the energy-starved brain becomes more irritable and unstable. Seizures may be difficult to control in severe cases. [2]

10. Abnormal muscle reflexes – Reflexes may be weaker due to hypotonia, or in some cases brisker due to damage of certain brain pathways. Detailed neurological exam helps describe the pattern. [3]

11. Movement difficulties – Children may show stiffness, clumsy movements, or poor balance as part of their motor delay. In related MARS2 disorders, spasticity and ataxia (unsteady movement) are also reported. [4]

12. Tiredness and low stamina – Because cells cannot make enough ATP, affected children may tire very easily. Simple tasks like sitting up, feeding, or playing may make them exhausted. [2]

13. Breathing problems – Weak respiratory muscles or brain control centers can cause shallow breathing, fast breathing, or periods of poor breathing, especially during infections or sleep. [3]

14. Lactic acidosis signs (vomiting, fast breathing) – When lactic acid builds up in the blood, a child may vomit, breathe quickly, appear weak, and look very unwell. Blood tests show raised lactate levels during these episodes. [3]

15. Learning difficulties and intellectual disability – Over time, many children with serious mitochondrial brain disease develop problems with understanding, speech, and school learning, reflecting the underlying brain injury. [2]

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Diagnostic tests

Diagnosis of COXPD25 is complex. Doctors usually think about this condition when they see a baby or child with early-onset hypotonia, developmental delay, growth problems, hearing loss, chest deformity, and signs of mitochondrial disease on blood tests or biopsies. The final proof usually comes from genetic testing that finds harmful changes in the MARS2 gene. [1]

Physical examination tests

1. General physical exam of the newborn or child – The doctor looks at the whole body, measures weight, length, and head size, and checks for obvious problems such as chest shape or facial differences. This first exam gives important clues that the problem may be global and genetic. [1]

2. Neurological exam for tone and reflexes – The doctor gently moves the arms and legs, checks how floppy or stiff they are, and tests reflexes with a small hammer. In COXPD25, tone is often low and reflexes may be reduced or altered. [2]

3. Growth and nutrition assessment – Plotting weight, length, and head size on growth charts shows if the child is failing to thrive. In COXPD25, many children fall below expected curves, which supports a serious chronic disorder. [3]

4. Hearing-focused bedside exam – Simple tests such as speaking softly near the baby’s ear or using gentle sounds can show if the child reacts to noise. Poor response suggests possible sensorineural hearing loss and guides further audiology tests. [4]

Manual tests

5. Developmental milestone checklists – Doctors or therapists use structured questions and simple tasks (such as rolling, sitting, grasping) to see how far behind the child is compared to typical development. A wide delay across many areas suggests a global neurological problem. [1]

6. Manual muscle strength grading – Using scales like the Medical Research Council (MRC) scale, the examiner checks how strongly the child can push against resistance. Weakness in many muscles supports a systemic neuromuscular disorder. [2]

7. Chest wall inspection and measurement – The doctor looks closely at the chest shape, feels the ribs and sternum, and may measure how far the breastbone protrudes. Progressive pectus carinatum is a striking sign in COXPD25. [3]

8. Functional tests (age-appropriate) – For children who can sit or stand, simple tasks like standing from sitting, walking a few steps, or climbing a small stair are observed. Marked fatigue or inability to perform tasks points toward significant muscle and energy problems. [4]

Lab and pathological tests

9. Blood lactate and pyruvate levels – These tests measure how much lactic and pyruvic acid are in the blood. High lactate, sometimes with a high lactate-to-pyruvate ratio, is a classic sign of mitochondrial oxidative phosphorylation defects. [1]

10. Blood gas and acid–base balance – This test checks pH and carbon dioxide in the blood. Lactic acidosis from mitochondrial disease often shows as a low pH (acidosis) with changes in bicarbonate and carbon dioxide levels. [2]

11. Basic metabolic panel and liver enzymes – Electrolytes, glucose, liver enzymes, and kidney markers help rule out other causes of illness and may show liver stress, which is common in many mitochondrial disorders. [3]

12. Plasma amino acids and acylcarnitine profile – These detailed blood tests look for other metabolic diseases that can mimic mitochondrial problems. A relatively normal profile with high lactate supports a primary oxidative phosphorylation defect. [4]

13. Urine organic acid analysis – This test detects abnormal organic acids in urine. Certain patterns suggest mitochondrial dysfunction or help exclude other inborn errors of metabolism. [5]

14. Creatine kinase (CK) level – CK is an enzyme released from damaged muscle. It may be normal or mildly raised in mitochondrial disease, but it helps distinguish from primary muscle breakdown disorders. [6]

15. Muscle biopsy with respiratory chain enzyme analysis – A small piece of muscle is taken and studied in the lab. Special tests measure the activity of complexes I–IV. In COXPD25, complex I and IV activities are reduced, confirming a combined oxidative phosphorylation defect. [7]

16. Histology and histochemistry of muscle – Under the microscope, muscle may show abnormal mitochondria, ragged-red fibers, or other changes that support mitochondrial myopathy. These findings, together with enzyme results, strengthen the diagnosis. [8]

Electrodiagnostic tests

17. Electroencephalogram (EEG) – EEG records brain electrical activity. In children with seizures or developmental delay, EEG may show abnormal patterns that support the presence of an underlying encephalopathy such as a mitochondrial disorder. [1]

18. Electromyography (EMG) and nerve conduction studies – These tests measure how muscles and nerves respond to small electrical signals. They can help separate primary nerve disease from primary muscle or mitochondrial disease and guide further testing. [2]

Imaging tests

19. Brain MRI – MRI scanning of the brain often shows structural changes such as cerebral atrophy, enlarged ventricles, and a thin corpus callosum in COXPD25. These changes are strong markers of brain energy failure and help distinguish this disorder from other causes of delay. [1]

20. Brain MR spectroscopy, echocardiogram, and chest imaging – MR spectroscopy can show high lactate inside the brain, supporting a mitochondrial defect. Echocardiogram looks for heart muscle problems, which are common in many COXPD forms, and chest X-ray or CT can document pectus carinatum and check lung status. [2]

Non-pharmacological treatments

All non-drug therapies should be guided by a specialist team experienced in mitochondrial disease. They do not cure COXPD25 but can improve comfort, function and quality of life.[5][7][8]

1. Individualized physiotherapy and motor rehabilitation
Regular physiotherapy helps maintain joint range, prevent contractures, reduce stiffness and encourage motor milestones like rolling, sitting and standing. The therapist designs gentle exercises matched to the child’s energy limits, using pacing and rest to avoid over-fatigue, which can worsen mitochondrial stress.[5][26]

2. Occupational therapy for daily skills
Occupational therapists work on hand skills, posture, feeding positions, dressing, and safe play. They also recommend adaptive tools (special cups, spoons, seating systems) to reduce the energy cost of daily activities and support participation at home and school.[5][26]

3. Speech and feeding therapy
Speech-language therapists support early communication and manage swallowing problems. They teach safe swallowing strategies, textures and positions to lower aspiration risk, and later support language and communication aids if speech is delayed.[5][7]

4. Nutritional counselling and energy-balanced diet
A dietitian skilled in mitochondrial disease helps provide enough calories and protein without long fasting gaps. Frequent small meals and bedtime snacks can prevent low blood sugar and metabolic decompensation, and special formulas may be used if growth is poor.[6][13][16]

5. Gastrostomy tube (PEG or button) feeding support (non-oral strategy)
When oral feeding is unsafe or not enough, a feeding tube directly into the stomach allows reliable calories and fluids. This is a supportive technique, not a drug, and can reduce hospital admissions for dehydration and malnutrition.[5][24]

6. Hearing rehabilitation with hearing aids
Because sensorineural hearing loss is common, early fitting of hearing aids helps language development and social interaction. Audiology teams adjust devices over time as hearing can change and sometimes worsen.[1][3][5]

7. Cochlear implantation in selected patients
For severe or profound hearing loss not helped by hearing aids, cochlear implants can directly stimulate the auditory nerve. In carefully chosen mitochondrial patients, implants improve sound awareness and speech perception, though surgical and anesthetic risks must be weighed.[5][7]

8. Chest physiotherapy and airway clearance
Because weak muscles make coughing hard, chest physiotherapy (percussion, assisted coughing, mechanical devices) helps clear mucus, prevent pneumonia and support breathing, especially during infections.[5][24]

9. Non-invasive ventilatory support (e.g., BiPAP)
Some children develop nocturnal hypoventilation or sleep-disordered breathing. Non-invasive ventilation through a mask (CPAP or BiPAP) can support gas exchange, reduce morning headaches and fatigue, and protect heart and brain from chronic low oxygen.[5][7]

10. Orthopedic and posture management (bracing, seating)
Spinal supports, ankle–foot orthoses and custom seating help maintain posture, reduce deformity and make sitting and standing more comfortable. This can also improve breathing mechanics and feeding safety by optimizing trunk alignment.[5][17]

11. Behavioral and developmental interventions
Early intervention programs, special education services and behavioral therapies address learning difficulties, attention problems and adaptive skills. These structured supports can maximize cognitive potential even when underlying brain injury is present.[7][14]

12. Psychological and family support
Chronic rare disease affects the whole family. Access to counselling, support groups and social work services helps caregivers manage stress, navigate services and cope with uncertainty about prognosis.[7][19]

13. Regular vaccination and infection prevention
Routine vaccines, influenza and pneumococcal shots reduce the chance of serious infections that could trigger metabolic crises. Hand hygiene, prompt treatment of fevers and avoiding sick contacts are also important non-drug preventive strategies.[5][12]

14. Avoidance of mitochondrial-toxic drugs
Some medicines, such as valproic acid, certain aminoglycosides and linezolid, can worsen mitochondrial function. Non-pharmacological care includes having an emergency and medication card listing drugs to avoid, so all providers are aware.[7][24]

15. Emergency “sick-day” plans
Families are given a written plan explaining what to do during fever, vomiting or fasting, including early hospital contact, intravenous glucose and careful fluid management. Although this may involve medicines, the plan itself is an important organizational intervention.[5][24]

16. Sunlight and temperature moderation
Extreme heat, cold or prolonged sun exposure can increase metabolic stress. Simple lifestyle measures like avoiding overheating, ensuring hydration and resting in cooler environments can help prevent energy crashes.[7][35]

17. Gentle, paced physical activity
Light, regular movement within the person’s limits may maintain muscle strength and circulation without overloading mitochondria. Structured pacing (activity, then rest) is safer than long, intense exercise sessions.[7][17]

18. Sleep optimization
Good sleep hygiene, regular routines and sometimes sleep studies are important. Poor sleep worsens fatigue, learning and seizure control, so non-drug strategies to improve sleep environment can indirectly support mitochondrial health.[7][14]

19. Genetic counselling for the family
Genetic counselling explains inheritance, carrier testing and options for prenatal or pre-implantation diagnosis. This is a key non-pharmacological service that helps families plan future pregnancies and understand risks.[1][3]

20. Participation in clinical research and registries
Enrolling in rare disease registries or observational studies can give families access to expert monitoring and contributes to scientific knowledge that may lead to future therapies, including gene or cell-based approaches.[3][9]

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Drug treatments

There is no FDA-approved drug specifically for COXPD25. Medicines are used to treat symptoms such as seizures, spasticity, reflux, infections or heart problems, following general mitochondrial and pediatric neurology guidelines.[5][7][11] Information on approval status and safety profiles is available in the official Drugs@FDA database on [accessdata.fda.gov][11].

Doses, schedules and combinations must always be chosen by the treating specialist. Below are examples of drug types commonly used in mitochondrial diseases; they are not a self-treatment guide.

1. Levetiracetam (anti-seizure medicine)
Levetiracetam is widely used to control focal and generalized seizures, including in children with mitochondrial disorders, because it has relatively low mitochondrial toxicity compared with some older anti-seizure drugs. It is an anticonvulsant that modulates synaptic vesicle protein SV2A to stabilize neuronal firing. Dose and timing are individualized and adjusted gradually by the neurologist, following the FDA label and seizure control.[7][11]

2. Lamotrigine (anti-seizure medicine)
Lamotrigine blocks voltage-gated sodium channels and reduces glutamate release, helping prevent seizures and sometimes mood swings. It is often considered in mitochondrial patients because of a relatively favorable safety profile, although skin rash risk requires slow dose escalation and careful monitoring by clinicians.[7][36][11]

3. Clobazam or other benzodiazepines (rescue for seizures)
Benzodiazepines such as clobazam or diazepam enhance GABA-A receptor activity, providing rapid calming of seizure activity or severe myoclonus. They are usually used as add-on or rescue therapy. Dosing must respect sedation and breathing risks, especially in children with muscle weakness.[7][36]

4. Baclofen (anti-spasticity agent)
Baclofen activates GABA-B receptors in the spinal cord to reduce spasticity and stiffness that can develop with long-standing brain injury. In COXPD25 it may make care and positioning easier, but doses must be carefully titrated to avoid excessive weakness and sleepiness.[5][26]

5. Proton-pump inhibitors or H2 blockers (reflux and gastric protection)
Drugs such as omeprazole or ranitidine reduce stomach acid and help treat reflux, gastritis or risk of bleeding, which are common in children with feeding difficulties or chronic illness. They reduce acid secretion by blocking proton pumps or histamine-2 receptors in stomach cells.[5][7]

6. Antibiotics for infections
Appropriate antibiotics are used promptly to treat bacterial pneumonia, ear infections or urinary infections, which can destabilize mitochondrial patients. Drug choice and dosing follow standard pediatric infectious disease guidelines, with care to avoid agents known to harm mitochondria (for example, some aminoglycosides in people at risk for mitochondrial deafness).[5][7]

7. Anti-reflux pro-motility agents (e.g., erythromycin low-dose)
Low-dose macrolides are sometimes used as gastrointestinal pro-motility agents to help stomach emptying and reduce vomiting. They act on motilin receptors to stimulate gut contractions. Because macrolides are antibiotics, specialists balance benefits and risks, including QT prolongation.[5][7]

8. Cardiac medicines (e.g., beta-blockers, ACE inhibitors)
If cardiomyopathy or rhythm problems occur, cardiologists may use beta-blockers or ACE inhibitors to support heart function and reduce workload. These medicines act on heart rate, blood pressure and remodeling pathways, and their use follows standard cardiac guidelines, not COXPD25-specific data.[7][29]

9. Anti-spasticity botulinum toxin injections
In localized severe spasticity interfering with hygiene or positioning, botulinum toxin injections can reduce muscle overactivity by blocking acetylcholine release in neuromuscular junctions. Effects are temporary and dosing is done by specialists about every few months.[26]

10. Analgesics and antipyretics (e.g., paracetamol/acetaminophen)
Simple pain and fever medicines are used to control discomfort and high temperature, which can increase energy use. Doses must respect liver and kidney function, and caregivers should avoid over-the-counter combinations without professional advice.[5][7]

Important note: Some drugs commonly used in other conditions, such as high-dose valproic acid, certain aminoglycosides and linezolid, may be relatively contraindicated in mitochondrial disease due to mitochondrial toxicity, and should only be used if absolutely necessary under expert supervision.[7][24]

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Dietary molecular supplements

Evidence for supplements in mitochondrial disease is mixed, and they are usually used as part of a “mitochondrial cocktail” under specialist care.[6][10][11] They can interact with medicines, so self-supplementation is not recommended.

1. Coenzyme Q10 (ubiquinone)
CoQ10 is a key electron carrier in the respiratory chain and a powerful lipid-soluble antioxidant. Supplementation may support ATP production and reduce oxidative stress in some mitochondrial disorders, although large trials show variable benefit. Doses are individualized and often divided with food to improve absorption.[10][15][18][22]

2. L-carnitine
L-carnitine transports long-chain fatty acids into mitochondria for β-oxidation and helps remove toxic acyl compounds. Low levels are found in some patients with mitochondrial disease, and cautious supplementation may improve fatigue and exercise tolerance when deficiency is documented.[6][16][28]

3. Riboflavin (vitamin B2)
Riboflavin is a precursor of FAD and FMN, cofactors for many mitochondrial enzymes. In some flavoprotein-related mitochondrial disorders, riboflavin can clearly improve symptoms, and it is often used empirically at modest doses in other mitochondrial diseases.[6][20][31]

4. Thiamine (vitamin B1)
Thiamine is required for pyruvate dehydrogenase and other key enzymes of energy metabolism. Supplementation is sometimes used to support mitochondrial function, especially if there is any suggestion of thiamine-responsive syndromes or poor dietary intake.[7][13]

5. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant and cofactor for mitochondrial enzyme complexes. It may help reduce oxidative stress and support energy metabolism in selected mitochondrial and metabolic conditions, though strong evidence in COXPD25 is lacking.[13][18]

6. Creatine monohydrate
Creatine acts as an energy buffer in muscle and brain by storing high-energy phosphate bonds. Some studies in mitochondrial disease suggest improved exercise tolerance and muscle strength, but responses are variable and dosing must consider kidney function.[13]

7. Arginine and citrulline
These amino acids are used to boost nitric oxide production and improve blood vessel function in certain mitochondrial stroke-like syndromes. In COXPD25 they would only be considered if there is a relevant vascular or stroke-like feature, and always under specialist guidance.[13][27]

8. Antioxidant vitamins C and E (carefully selected)
Vitamin E is a lipid-soluble antioxidant that can help protect cell membranes, while vitamin C is water-soluble. Some protocols include them to counteract excess free-radical production, but current expert statements warn that high-dose vitamin C has limited value and is not universally recommended.[10][26]

9. Folinic acid and B-complex vitamins
Folinic acid and other B vitamins support one-carbon metabolism and DNA repair, and are sometimes used in mitochondrial encephalopathies with cerebral folate deficiency. Their use in COXPD25 is individualized based on laboratory findings and clinical suspicion.[13][29]

10. Combination mitochondrial “cocktails”
Many centers use personalized combinations of CoQ10, carnitine, riboflavin and other vitamins, adjusted over time. Studies show that many patients report subjective benefit, but objective evidence is still limited and cocktails should be monitored for side effects and cost–benefit.[6][11][24]

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Immune-booster, regenerative and stem-cell-related medicines

At present, there are no approved immune-booster or stem-cell drugs that specifically treat COXPD25. Research is ongoing, and the following points summarize the current situation.[3][9][21]

1. General immune support through vaccines and nutrition – Instead of special “immune pills”, experts focus on standard vaccinations, good nutrition, adequate sleep and prompt treatment of infections to protect children with mitochondrial disease.[5][19]

2. Antioxidant and mitochondrial-support supplements – CoQ10, carnitine and vitamins sometimes get called “immune boosters”, but their main role is to support energy metabolism and reduce oxidative stress. They are not proven to normalize the immune system in COXPD25.[10][28]

3. Experimental gene and cell-based approaches – Scientists have created induced pluripotent stem cell (iPSC) lines from patients with COXPD25 to study the disease in the lab. These cells may one day allow gene correction or cell therapy, but this is still experimental and not available as standard treatment.[3][9][13]

4. Hematopoietic or mesenchymal stem cell infusions – At the moment, there is no strong evidence that these types of stem cell infusions help primary mitochondrial disorders like COXPD25, and they may carry serious risks. They should only be considered in formal clinical trials.[21][32]

5. Immune-modulating drugs – Standard immunosuppressive or immunomodulatory drugs (such as steroids or biologics) are not used to treat COXPD25 itself, unless there is a second autoimmune disease. They can sometimes worsen muscle weakness and must be used cautiously.[7][29]

6. Future targeted therapies – As understanding of MARS2 function grows, future treatments may aim to stabilize or replace the faulty enzyme, or enhance mitochondrial protein translation. For now, these ideas remain in pre-clinical or very early research stages.[3][9][18]

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Surgeries and procedures

Surgery does not correct the mitochondrial defect but can treat complications or improve function. Decisions are highly individualized and require careful anesthetic planning in mitochondrial patients.[5][7]

1. Gastrostomy tube placement
A gastrostomy tube (PEG or button) is placed through the abdominal wall into the stomach to provide direct feeding access. It is done when oral feeding is unsafe or insufficient, and its main purpose is to improve nutrition, reduce aspiration risk and support growth in COXPD25.[5][24]

2. Cochlear implant surgery
In severe sensorineural hearing loss, cochlear implant surgery places an electrode into the inner ear to stimulate the auditory nerve. This can markedly improve sound perception and language development, especially when done early, but requires a stable medical condition and careful peri-operative monitoring.[1][5]

3. Chest wall surgery for pectus carinatum
In some children with painful or very prominent pectus carinatum, surgical correction or bracing may be considered. The goal is mainly cosmetic and comfort-related; it may also slightly improve breathing mechanics, but careful risk–benefit discussion is needed in mitochondrial patients.[2][5]

4. Orthopedic surgeries for contractures or scoliosis
If contractures or spinal deformities severely limit sitting, standing or hygiene, orthopedic surgery might be considered after trying conservative treatments. The aim is to improve comfort and function, but surgery carries anesthetic stress and recovery challenges in low-energy states.[17]

5. Dental and minor surgical procedures under tailored anesthesia
Even minor procedures can be significant in mitochondrial disease. Anesthesia teams may use special protocols (avoiding prolonged fasting, maintaining glucose and temperature) to reduce metabolic stress. The “procedure” here is careful peri-operative planning rather than a specific operation.[5][7]

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Prevention and risk-reduction tips

Because COXPD25 is genetic, we cannot fully prevent it, but we can reduce complications and help families plan.[1][3][7]

1. Genetic counselling before future pregnancies – Helps parents understand recurrence risk and options like carrier testing, prenatal testing or pre-implantation genetic testing.[1][3]

2. Early diagnosis and referral to a mitochondrial center – Faster diagnosis allows earlier supportive therapies and better planning for emergencies.[5][7]

3. Routine vaccinations and infection control – Keeps children safer from illnesses that can trigger metabolic crises.[5][19]

4. Avoidance of prolonged fasting – Frequent meals and bedtime snacks reduce hypoglycemia risk and metabolic stress.[6][13]

5. Written emergency plan for fevers and vomiting – Families should know when to seek hospital care and what labs and treatments are recommended.[5][24]

6. Avoidance of clearly mitochondrial-toxic drugs where possible – Use safer alternatives when they exist, guided by specialist lists.[7][24]

7. Regular follow-up for heart, hearing and vision – Detects complications early so treatment can start before major damage develops.[5][7]

8. Careful anesthesia protocols – Prevents avoidable stress during surgeries or imaging.[5][7]

9. Balanced lifestyle with rest and pacing – Avoid both extreme inactivity and exhausting over-exercise.[7][17]

10. Connecting with rare disease networks – Gives families up-to-date information about research and care standards.[19]

(All recommendations above must be individualized by clinicians.)

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When to see a doctor

You should seek urgent or immediate medical help if a person with known or suspected COXPD25 has: sudden loss of consciousness, new or prolonged seizures, severe breathing difficulties, repeated vomiting, very poor feeding, marked drop in activity, or signs of infection such as high fever and fast breathing.[5][7][35]

Regular follow-up with a neurologist, metabolic specialist, cardiologist, audiologist, ophthalmologist, physiotherapist and dietitian is recommended even when the child seems stable, because complications can appear gradually.[5][7][29]

If a baby or child shows unexplained low muscle tone, developmental delay, poor growth, unusual chest shape, hearing loss or abnormal brain imaging, doctors should consider a mitochondrial disease and refer to genetics for further testing, including MARS2 analysis when appropriate.[1][18][29]

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What to eat and what to avoid

Diet must be individualized by a metabolic dietitian, but some general patterns are often recommended in primary mitochondrial disease.[6][13][16][35]

1. Eat regular, frequent meals and snacks – Avoid long gaps without food to reduce hypoglycemia and metabolic stress.[6][35]

2. Focus on balanced meals – Include complex carbohydrates, lean protein and healthy fats at each meal to provide steady energy.

3. Ensure enough total calories and protein – Many children with COXPD25 need extra calories to support growth and illness recovery.

4. Include nutrient-dense foods – Fruits, vegetables, whole grains, legumes, nuts and seeds provide vitamins, minerals and antioxidants that support general health.

5. Use special formulas when advised – High-energy or semi-elemental formulas may be used through a bottle or gastrostomy when needed.

6. Avoid crash diets or intentional fasting – Rapid weight loss and ketosis can stress mitochondria.

7. Limit very high-sugar drinks – Sudden large sugar loads can cause swings in blood glucose and are less helpful than balanced meals.

8. Be cautious with herbal supplements and “energy drinks” – Many are not well studied in mitochondrial disease and may interact with medicines.

9. Stay well hydrated – Adequate fluids help circulation, kidney function and temperature control.

10. Ask before changing the diet – Any major diet change (ketogenic, high-fat or others) should be supervised by a mitochondrial team, as benefits and risks differ between disorders.[7][13]

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Frequently asked questions (FAQs)

1. Is combined oxidative phosphorylation defect type 25 curable?
No. At present there is no cure that fixes the underlying MARS2 gene defect. Treatment focuses on supporting organs, preventing complications and improving quality of life. Researchers are exploring gene and cell-based approaches, but these are not yet available in routine care.[3][9][21]

2. How rare is COXPD25?
COXPD25 is extremely rare, with only a small number of families reported worldwide. This is why much of what we know comes from case reports and small series, and why expert centers and registries are so important.[2][3]

3. What is the usual age of onset?
Most reported patients have symptoms beginning in the newborn period or early infancy, including hypotonia, feeding problems and developmental delay. Hearing loss and chest wall deformity may become clearer over time.[1][2][5]

4. Are both boys and girls affected?
Yes. Because COXPD25 is autosomal recessive, boys and girls are affected equally when they inherit two faulty copies of MARS2.[3][18]

5. Can a carrier develop symptoms?
Carriers usually have one healthy and one altered MARS2 gene and do not develop COXPD25. However, they can pass the faulty gene to their children, which is why carrier testing and counselling are important for family planning.[1][3]

6. How is COXPD25 diagnosed?
Diagnosis usually includes clinical evaluation, brain imaging, biochemical tests of mitochondrial function, and genetic testing. MARS2 sequencing or panel testing for mitochondrial disorders confirms the diagnosis in most cases.[3][18][29]

7. Does every child have exactly the same symptoms?
No. Even within the same family, symptoms and severity can vary. Some children may have more severe neurologic problems, others more prominent hearing or skeletal issues, depending on the exact variants and other modifying factors.[1][3]

8. What is the long-term outlook?
Because only a few patients are known, prognosis is not fully clear. Many affected children have significant developmental challenges and need lifelong support. Early, comprehensive care may improve comfort and survival, but exact life expectancy is uncertain and should be discussed with specialists.[1][2][5]

9. Can regular exercise help?
Gentle, well-paced activity can help maintain strength and prevent contractures, but over-exercise can worsen fatigue. A physiotherapist experienced in mitochondrial disease should design a safe program for each person.[5][17]

10. Are mitochondrial supplements mandatory?
No supplement is mandatory. Some people feel better on CoQ10, carnitine or vitamins, while others notice little change. Decisions should be made with a mitochondrial specialist, based on symptoms, lab results and the family’s goals.[6][11][16]

11. Do standard childhood illnesses cause permanent damage?
Common infections like colds and flu can temporarily worsen weakness and feeding problems. With good sick-day management (hydration, glucose, rapid treatment of infections), many children recover to their baseline, but some may lose skills after severe illnesses, so prevention and early treatment are important.[5][24]

12. Can a special diet cure COXPD25?
No diet can cure the underlying genetic defect. However, an energy-balanced, nutrient-rich diet with avoidance of fasting can reduce metabolic stress and support overall health. Any special diet (for example ketogenic) must be supervised by a metabolic team.[6][13][35]

13. What should families tell schools and caregivers?
Schools should know that the child has a rare mitochondrial disease, tires easily, may need extra rest, and may have hearing, vision or learning difficulties. Written plans for medication, emergency responses and physical limitations are very helpful.[5][19]

14. Are clinical trials available?
Because COXPD25 is very rare, there may not be disease-specific trials yet, but patients can sometimes join broader studies on mitochondrial disease, registries or natural history projects. Mitochondrial centers and rare-disease networks can help families find opportunities.[3][19][21]

15. What is the most important message for caregivers?
The most important message is that you are not alone and that good supportive care really matters. Working closely with a multidisciplinary mitochondrial team, protecting nutrition and preventing infections can make a meaningful difference in comfort, development and family quality of life.[5][7][19]

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 20, 2025.