Combined oxidative phosphorylation defect type 26 (COXPD26) is a very rare inherited disease that affects how the “power stations” of the cell, called mitochondria, make energy. In this condition, a fault (mutation) in a gene called TRMT5 damages a step in mitochondrial protein building, so the oxidative phosphorylation (OXPHOS) system cannot work properly. This lowers energy in many organs, especially brain, nerves, muscles, heart, liver, kidneys, and gut.
Combined oxidative phosphorylation defect type 26 (COXPD26) is a very rare genetic mitochondrial disease caused by harmful changes in the TRMT5 gene. This gene helps modify transfer RNA inside mitochondria, which is needed to make energy correctly. When TRMT5 does not work properly, the oxidative phosphorylation system in mitochondria fails, so cells cannot make enough ATP. Children or adults with COXPD26 may have early-onset developmental delay, muscle weakness, poor muscle tone (hypotonia), exercise intolerance, shortness of breath, spasticity (stiff muscles), peripheral neuropathy, feeding problems, seizures, and sometimes heart or liver involvement. There is no cure at the moment, so treatment focuses on careful supportive care, symptom control, and avoiding extra stress on mitochondria.
Because energy is low, children can have problems such as weak muscles, trouble exercising, stiff or floppy muscles, nerve damage, and delays in reaching milestones like sitting, walking, or talking. Some children also have heart muscle thickening, seizures, breathing trouble, feeding problems, or poor growth. Symptoms often start in infancy or early childhood, and the exact picture can differ a lot from one child to another.
COXPD26 is inherited in an autosomal recessive way. This means a child becomes ill when they receive one faulty copy of the TRMT5 gene from each parent. Parents who each carry a single faulty copy usually have no symptoms themselves. Because the disease is so rare, only a small number of families have been reported worldwide.
Other names
Doctors and researchers may use several other names for combined oxidative phosphorylation defect type 26. These names refer to the same or very closely related condition:
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Combined oxidative phosphorylation deficiency 26
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Combined oxidative phosphorylation defect type 26 (COXPD26)
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COXPD26 – combined oxidative phosphorylation defect type 26
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Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (sometimes shortened to PNSED)
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TRMT5-related combined oxidative phosphorylation deficiency
Using these names in medical records or searches can help families and doctors find the correct information and genetic tests.
Types and clinical patterns
Although COXPD26 is one named disease, doctors see different clinical patterns. Because only a few patients are known, these are not strict official subtypes, but they help explain how children may differ:
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A neuromuscular-predominant form, where the main problems are exercise intolerance, shortness of breath with activity, muscle weakness, tremor, and peripheral neuropathy. Thinking and learning may be mostly normal in these children.
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A developmental-delay form, where the main problems are global developmental delay, spastic (stiff) muscles, problems with walking and speech, and sometimes seizures.
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A multisystem severe form, where children also have heart muscle thickening, liver disease, feeding problems, and poor growth, often with many hospital stays.
The same gene, TRMT5, is involved in all of these patterns, so doctors consider them part of a single disease spectrum rather than completely separate diseases.
Causes and contributing factors
In simple terms, the root cause is a harmful change in the TRMT5 gene, but many related factors and mechanisms influence how the disease appears.
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Biallelic TRMT5 gene mutations – Children with COXPD26 have disease-causing changes in both copies of the TRMT5 gene (one from each parent). This breaks the normal function of the encoded enzyme, which is needed for correct mitochondrial tRNA modification.
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Defective mitochondrial tRNA methylation – TRMT5 normally adds a small chemical group (a methyl group) to mitochondrial tRNA. When this step fails, the tRNA cannot help build mitochondrial proteins correctly, which harms the respiratory chain complexes.
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Impaired mitochondrial protein production – Because the tRNA is not properly modified, many proteins that sit in the mitochondrial respiratory chain are made in the wrong way or in lower amounts. This directly reduces energy production in cells.
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Combined oxidative phosphorylation deficiency – Several complexes (not just one) in the electron transport chain can show reduced activity. This is why the disease is called a “combined” oxidative phosphorylation defect and not a single-complex defect.
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Autosomal recessive inheritance – Parents who carry one altered TRMT5 gene copy are healthy carriers. When two carriers have a child, there is a one-in-four chance that the child will inherit both altered copies and develop COXPD26.
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Random (de novo) mutations – In some families, one of the TRMT5 mutations may appear for the first time in the affected child rather than being inherited from a long family line. This can make the diagnosis unexpected.
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Energy-hungry organs – Organs that need a lot of constant energy, such as brain, skeletal muscle, heart, and liver, are more sensitive to mitochondrial problems. This is why COXPD26 strongly affects movement, thinking, heart function, and growth.
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Metabolic stress during infections – Fever, infections, or dehydration can increase energy needs. In children with COXPD26, these stresses can worsen symptoms, such as weakness, breathing trouble, or lactic acidosis, and sometimes trigger hospital admission.
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Poor tolerance of intense exercise – Hard physical activity demands sudden bursts of energy from muscles. Because oxidative phosphorylation is weak, lactic acid builds up and muscles fatigue quickly, causing exercise intolerance and shortness of breath.
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Accumulation of toxic by-products – When mitochondria cannot use nutrients efficiently, products like lactate and certain organic acids increase in blood or urine. These can contribute to tiredness, nausea, and other symptoms.
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Secondary liver damage – In some children with COXPD26, the liver shows scarring (cirrhosis) and problems in processing nutrients and toxins. The exact pathway is not fully known, but it likely relates to chronic energy failure in liver cells.
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Kidney tubular dysfunction – The kidney tubules also need energy to filter and reabsorb salts and minerals. Mitochondrial defects can cause renal tubular problems, leading to loss of important substances in urine and further weakness.
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Disrupted nerve cell function – Peripheral nerves and central nervous system pathways require stable ATP levels for signal transmission. When energy is low, axons and myelin can be damaged, causing neuropathy, tremor, spasticity, and delayed myelination.
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Abnormal brain development or atrophy – Long-term lack of energy in brain tissue can lead to poor development or shrinkage (atrophy) of certain brain areas, which contributes to global developmental delay and movement problems.
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Heart muscle hypertrophy – The heart may respond to energy stress by thickening its muscle walls (hypertrophic cardiomyopathy). This is both a sign of stress and a cause of further fatigue and breathlessness.
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Gastrointestinal dysmotility – Mitochondrial dysfunction in smooth muscles and nerves of the gut can slow movement of food, causing vomiting, constipation, or other digestive problems and making nutrition more difficult.
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Poor growth and feeding difficulties – Children with chronic low energy and frequent illness may not eat well or absorb food efficiently. This leads to failure to thrive and weight faltering, which further reduces strength.
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Genetic background and modifiers – Other genes besides TRMT5 may slightly worsen or soften the disease by changing how cells handle stress and energy. This may explain why symptoms vary between patients with similar TRMT5 mutations.
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Environmental triggers (e.g., toxins, severe malnutrition) – While TRMT5 mutation is the main cause, exposure to certain toxins, severe lack of nutrients, or repeated severe illness may speed up damage in already fragile mitochondria.
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Delayed or missed diagnosis – When diagnosis is late, supportive care may also be delayed. Repeated unmanaged metabolic crises can lead to extra organ damage over time, making the disease course appear more severe.
Symptoms and signs
Symptoms can differ widely, even inside the same family, but the following are common patterns in COXPD26.
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Exercise intolerance – Children tire very quickly during play or walking. They may need frequent rests, avoid running, or complain of heavy legs and shortness of breath after only mild activity. Parents often notice that peers can play much longer without getting exhausted.
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Exertional shortness of breath – Even small amounts of effort can cause fast breathing, chest discomfort, or the feeling of “air hunger.” This happens because muscles and heart cannot produce enough energy, so breathing has to increase to compensate.
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Muscle weakness – Weakness may affect legs more than arms. Children may struggle to climb stairs, stand from the floor, or carry heavy objects. Weakness can be constant or worse during illness or after activity.
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Spasticity (stiff muscles) – Some children develop stiff, tight muscles, especially in the legs. This can cause scissoring of the legs, toe walking, or trouble with smooth movements. It may look similar to cerebral palsy.
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Hypotonia (floppy muscles) – In other cases, especially early in life, muscle tone is low. Infants may feel “floppy” when held, have poor head control, and be late to sit or stand. Over time, floppy muscles may become weak and tired easily.
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Peripheral neuropathy – Damage to the nerves of the arms and legs can cause numbness, tingling, burning pain, or balance problems. Children may trip more often or have difficulty feeling where their feet are on the ground.
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Global developmental delay – Many children reach milestones late. They may sit, stand, or walk much later than peers, and speech can be slow to develop. Learning difficulties may also appear, although some patients have normal intellect.
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Tremor and movement problems – Some children have shaking of the hands or head (tremor) and difficulties with fine motor tasks like writing or buttoning clothes. This reflects both brain and nerve involvement.
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Feeding difficulties and vomiting – Poor sucking in infants, slow feeding, frequent vomiting, or signs of reflux are common. When combined with low energy and gut movement problems, these issues can make it hard to maintain weight.
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Failure to thrive and poor growth – Because of high energy needs, frequent illness, and feeding problems, many children grow more slowly than expected. Their weight and sometimes height may fall below normal growth curves.
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Heart problems (hypertrophic cardiomyopathy) – The heart muscle can become abnormally thick. This may cause chest discomfort, fast heartbeat, fainting, or worsening tiredness, especially during exertion. In severe cases it can be life-threatening.
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Liver disease (cirrhosis or dysfunction) – Some children show signs of liver damage, such as enlarged liver, abnormal blood tests, or cirrhosis. This may cause poor appetite, swelling, or bleeding problems if advanced.
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Renal tubular dysfunction – The kidneys may lose their ability to reabsorb certain salts and minerals. Children can show excessive urination, dehydration, or abnormal blood chemistry, which can worsen weakness and fatigue.
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Abnormal facial features – Some children are reported to have a triangular face, narrow mouth, or other subtle facial differences. These do not cause direct harm but can be extra clues for doctors.
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Seizures and neurologic crises (in some cases) – A few reported patients have had seizures or sudden worsening of neurologic symptoms, especially during metabolic stress. Not every child has seizures, but they are important to watch for.
Diagnostic tests
Physical examination
Doctors start with a detailed clinical exam, then use special lab and imaging tests to support the diagnosis.
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General physical exam and growth assessment – The doctor checks weight, height, and head size and compares these to growth charts. Poor growth, small size, or signs like a triangular face or narrow mouth can raise suspicion of a complex genetic and mitochondrial disorder.
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Neurologic examination – Reflexes, muscle tone (stiff or floppy), coordination, and balance are tested. Findings like spasticity, hypotonia, hyperreflexia, hyporeflexia, tremor, or signs of peripheral neuropathy help show that both brain and peripheral nerves are affected.
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Cardiovascular examination – The doctor listens for heart murmurs or unusual heart sounds, feels pulses, and looks for signs of heart failure (such as leg swelling or enlarged liver). These checks may suggest hypertrophic cardiomyopathy and guide further testing.
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Respiratory examination – Breathing rate, chest movement, and sounds in the lungs are checked. Signs of breathing difficulty at rest or with minor activity may point to involvement of respiratory muscles or heart problems.
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Abdominal examination – The doctor feels for enlargement of the liver or spleen and looks for tenderness or bloating. An enlarged or nodular liver may point toward chronic liver involvement as part of COXPD26.
Manual and bedside tests
These tests are simple assessments done at the bedside or in clinic, without complex machines.
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Manual muscle strength testing – The doctor asks the child to push or pull against resistance with arms and legs. This helps grade muscle strength and shows typical patterns, such as weaker hips and shoulders, that suggest a neuromuscular problem.
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Gait and posture assessment – Walking and running are observed. Toe-walking, scissoring, frequent falls, or wide-based gait can point to spasticity, weakness, or balance problems related to mitochondrial disease.
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Tone and reflex scales – Doctors may use simple scales to rate muscle tone and reflex strength. Strong or weak reflexes and very stiff or very floppy muscles help localize where in the nervous system the problem lies.
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Developmental screening tests – Simple checklists or play-based tests measure skills such as sitting, walking, fine motor control, and language. Delays across many areas support the idea of a global neurodevelopmental disorder like COXPD26.
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Functional exercise tests (e.g., timed walk) – Short timed walks or stair-climbing tasks can show how quickly fatigue and shortness of breath appear, providing practical evidence of exercise intolerance.
Laboratory and pathological tests
These tests measure chemicals in blood and urine or look at tissue under the microscope. They support the suspicion of a mitochondrial oxidative phosphorylation disorder.
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Serum lactate and pyruvate – High levels of lactate (and sometimes pyruvate) at rest or after exercise suggest that cells are relying too much on anaerobic pathways because mitochondria cannot keep up with energy demand.
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Creatine kinase (CK) and muscle enzymes – CK may be mildly or moderately elevated, showing muscle stress or damage. This is common in mitochondrial myopathies and encourages further investigation of muscle and mitochondrial function.
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Liver and kidney function tests – Blood tests can show raised liver enzymes, signs of cirrhosis, or abnormal kidney handling of salts. These results show that COXPD26 can affect organs beyond brain and muscle.
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Blood glucose and HbA1c – Some patients show glucose intolerance or raised HbA1c, reflecting changes in how the body handles sugar when mitochondrial energy production is impaired.
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Plasma amino acids, acylcarnitine profile, and urine organic acids – These metabolic tests can reveal patterns that suggest mitochondrial dysfunction, such as elevated certain organic acids or changes in amino acid levels, and help rule out other metabolic diseases.
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Muscle biopsy with respiratory chain enzyme analysis – A small piece of muscle is examined. In COXPD26, it may show myopathic changes, cytochrome c oxidase-negative fibers, and reduced activity in several respiratory chain complexes, confirming a combined OXPHOS defect.
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Histology and electron microscopy of muscle – Under high-power microscopes, doctors may see abnormal mitochondria in number, shape, or internal structure. These findings give direct visual proof that mitochondria are not healthy.
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Targeted TRMT5 gene sequencing – DNA testing focuses on the TRMT5 gene to look for disease-causing variants. Finding two harmful variants (one on each copy) strongly confirms the diagnosis of COXPD26.
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Broad exome or genome sequencing panels – Some patients are diagnosed using large gene panels or clinical exome sequencing for mitochondrial or neurodevelopmental diseases, which include TRMT5 among many other genes. This is useful when the diagnosis is not obvious.
Electrodiagnostic tests
These tests examine electrical activity in nerves, muscles, and the heart.
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Nerve conduction studies (NCS) – Electrodes placed on the skin send small electrical pulses along nerves. Slowed or weak signals confirm peripheral neuropathy, which is common in COXPD26 and related TRMT5 disorders.
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Electromyography (EMG) – A fine needle records electrical activity inside muscles. EMG can show patterns suggesting myopathy (muscle disease) or neuropathy, supporting the idea of a mitochondrial neuromuscular disorder.
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Electrocardiogram (ECG) – ECG measures the heart’s electrical rhythm. It can show conduction problems or strain patterns suggesting hypertrophic cardiomyopathy or other cardiac involvement.
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Holter monitoring or exercise ECG (when appropriate) – Continuous ECG recording over 24 hours or during mild exercise may reveal rhythm disturbances or ischemia-like changes that are not seen on a short resting ECG.
Dmaging tests
Imaging helps doctors see structural changes in the brain, heart, and other organs affected by COXPD26.
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Brain MRI – Magnetic resonance imaging of the brain can show brain atrophy (shrinkage), delayed myelination, or other structural abnormalities. These findings fit with the developmental delay and movement problems seen in many children.
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Spinal MRI (in selected cases) – When spastic paraparesis (stiffness in both legs) is prominent, MRI of the spinal cord can rule out other causes and may show subtle signal changes related to mitochondrial damage.
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Echocardiography (heart ultrasound) – This test uses sound waves to look at heart structure and movement. It can show thickened heart muscle, reduced pumping function, or other features of hypertrophic cardiomyopathy.
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Abdominal ultrasound – Ultrasound of the abdomen can detect enlarged liver, signs of cirrhosis, or kidney abnormalities. This helps document the multisystem nature of COXPD26.
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Skeletal imaging (X-ray or DXA) when indicated – In children with poor growth, deformities, or frequent falls, imaging may be used to assess bones and spine, mainly to rule out other conditions. While not specific for COXPD26, it helps complete the overall evaluation.
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Advanced metabolic imaging (research settings) – In some specialized centers, research tools such as advanced MRI or spectroscopy may be used to study energy metabolism in tissues. These are not routine tests but illustrate how deeply mitochondrial diseases can be investigated.
Non-pharmacological (non-drug) treatments
1. Individualized aerobic exercise program
Gentle, regular aerobic exercise such as walking, cycling, or pool therapy, designed by a physiotherapist, can help muscles use oxygen more efficiently and may improve mitochondrial function. Exercise can increase the number and efficiency of mitochondria in muscle cells, improve endurance, and reduce deconditioning. It must be started slowly and increased carefully to avoid over-fatigue or lactic acid build-up.
2. Resistance and strength training
Light resistance exercises using bands or small weights can help maintain muscle strength, joint stability, and posture. In mitochondrial disease, the goal is not bodybuilding, but preventing muscle wasting and contractures. Short, supervised sessions with enough rest can improve functional independence, walking distance, and ability to perform daily activities by stimulating muscle fibers without excessive energy strain.
3. Physiotherapy for tone, balance, and contractures
Physiotherapy uses stretching, positioning, and balance training to reduce spasticity, prevent joint stiffness, and improve coordination. For COXPD26, where spasticity and neuropathy are common, regular stretching and range-of-motion work help keep joints flexible and reduce pain. The mechanism is mechanical: gentle repetitive movement maintains muscle length, joint lubrication, and nerve input, which supports better mobility.
4. Occupational therapy for daily living skills
Occupational therapists teach practical strategies and tools to manage dressing, feeding, writing, and school or work tasks. They may suggest adaptive cutlery, special seats, or wheelchair controls. The mechanism is not biochemical but functional: by changing the environment and tools, the person uses less energy for each task, reducing fatigue and improving independence.
5. Speech and swallowing therapy
Speech therapists help with speech clarity, swallowing safety, and sometimes communication devices. In COXPD26, hypotonia, spasticity, and developmental delay can affect speech and swallowing. Therapy strengthens or coordinates the muscles of the mouth and throat and teaches safe swallowing positions, which reduces the risk of aspiration, chest infections, and poor nutrition.
6. Nutritional counselling and high-energy meal planning
A dietitian plans frequent, energy-dense meals to prevent fasting and under-nutrition. For mitochondrial disease, stable glucose supply helps reduce metabolic stress on cells. The mechanism is simple: enough carbohydrates, proteins, and fats give mitochondria constant fuel, while avoiding long gaps between meals prevents drops in blood sugar and over-use of anaerobic pathways that increase lactate.
7. Feeding therapy and assistive feeding techniques
When chewing or swallowing is difficult, therapists may recommend modified textures, slow feeding, and specific head positions. This reduces the work of eating and keeps nutrition safe. In advanced cases, special cups, spoons, or chairs support posture and coordination. Mechanistically, reducing effort and risk during meals lowers energy use and avoids aspiration-related lung damage.
8. Gastrostomy (feeding tube) support and training
If a feeding tube is placed (see surgeries below), non-drug care includes caregiver training on tube care, feeding schedules, and positioning. Continuous or night feeds can provide slow, steady energy, reducing daytime fatigue. Mechanistically, this bypasses weak swallowing muscles and ensures reliable delivery of calories and medications.
9. Respiratory physiotherapy and airway clearance
When muscles for breathing are weak, chest physiotherapy, coughing techniques, or mechanical cough-assist devices can help clear mucus and prevent infections. These techniques work by increasing airflow and pressure to move secretions from small airways to larger ones where they can be coughed out, protecting the lungs and improving oxygen levels.
10. Non-invasive ventilation support (e.g., BiPAP) training
Some patients benefit from night-time non-invasive ventilation to reduce CO₂ build-up and improve sleep quality. Although the machine is a device, success depends on training and behavioural support. Ventilation supports weak respiratory muscles by providing extra pressure to move air in and out, improving oxygen delivery and reducing morning headaches and fatigue.
11. Orthotics and mobility aids
Ankle–foot orthoses, walkers, or wheelchairs reduce falls and save energy. By stabilizing joints and compensating for muscle weakness or spasticity, orthoses improve gait efficiency and safety. Wheelchairs can be used strategically for longer distances to prevent over-exertion while still encouraging safe standing and walking at home or in therapy.
12. Spasticity management with positioning and splints
Night splints, serial casting, and careful positioning in bed or chairs help prevent fixed contractures. These methods keep muscles at near-normal length, which reduces pain and preserves function. The mechanism is mechanical stretching over time, encouraging muscle and tendon remodeling in a more functional lengthened position.
13. Educational and developmental support services
Children with COXPD26 often need individualized education plans, special education services, and early intervention for developmental delay. Structured teaching, extra time, and assistive technology can maximize learning. Mechanistically, breaking tasks into small steps and using multi-sensory teaching reduces cognitive and physical load, improving participation and quality of life.
14. Psychological counselling and family support
Living with a progressive mitochondrial disease is emotionally hard. Counselling gives patients and families space to process grief, fear, and stress and to learn coping strategies. This does not change mitochondria directly, but it reduces depression and anxiety, which can otherwise worsen fatigue, pain, and adherence to treatment.
15. Genetic counselling for family planning
Because COXPD26 is autosomal recessive, parents are carriers and future children may be affected. Genetic counsellors explain inheritance risks, testing options for relatives, and reproductive choices. Mechanistically, this does not change current disease, but it helps families make informed decisions and may prevent unexpected recurrence in future pregnancies.
16. Sleep hygiene and fatigue management
Simple steps such as a regular sleep schedule, quiet and dark bedrooms, and limiting screens before bed can improve sleep quality. Good sleep is critical because poor rest increases mitochondrial stress, worsens pain and seizures, and decreases daytime function. Conserving energy with planned rest periods reduces the risk of sudden decompensation.
17. Temperature and illness management plans
Fevers and infections increase energy demands and can trigger metabolic crises in mitochondrial disease. Families are taught to seek early medical care for infections, keep fevers under control, and avoid overheating. Lowering temperature and treating infections quickly reduces metabolic stress on already fragile mitochondria.
18. Emergency “sick day” plan
Many mitochondrial centres give patients written “sick day” letters telling emergency doctors how to manage IV glucose, fluids, and medications during acute illness. These plans aim to prevent catabolism, lactic acidosis, and organ failure by ensuring fast, appropriate treatment even in unfamiliar hospitals.
19. Regular multi-system monitoring
Scheduled checks of heart, liver, kidneys, eyes, hearing, and growth help find complications early. Monitoring does not cure the disease, but early detection allows earlier treatment, which can slow decline and improve comfort. Typical tools include echocardiograms, ECGs, blood tests, and developmental assessments.
20. Palliative and supportive care integration
For severe COXPD26, palliative care teams focus on comfort, symptom control, and supporting family decisions. This does not mean “giving up”; it means treating pain, breathlessness, anxiety, and feeding difficulties in the most humane way. The mechanism is holistic: improving quality of life even when the disease cannot be cured.
Drug treatments
Important: No drug is currently approved specifically for COXPD26. Most medicines below are used off-label to treat symptoms or general mitochondrial dysfunction. Doses must always be set by a specialist; this information is not a self-treatment guide, especially for you as a teenager.
1. Levetiracetam (antiepileptic)
Levetiracetam is commonly used to control seizures in mitochondrial diseases because it has relatively fewer mitochondrial toxic effects than some older drugs. It works by modulating synaptic vesicle protein SV2A and reducing abnormal electrical activity in the brain. It is usually given orally or intravenously in divided daily doses. Possible side effects include sleepiness, irritability, mood changes, and rarely behavioural problems.
2. Lamotrigine (antiepileptic)
Lamotrigine may be used for focal seizures and mood stabilization. It blocks voltage-gated sodium channels and reduces glutamate release, calming over-active neurons. It must be started slowly to avoid severe skin rash (Stevens–Johnson syndrome). Side effects include dizziness, nausea, and rash. In mitochondrial disease, doctors weigh benefits against risks carefully for each patient.
3. Benzodiazepines (e.g., diazepam, midazolam) for acute seizures
Benzodiazepines enhance the GABA-A receptor, the main inhibitory system in the brain, and quickly stop prolonged seizures or status epilepticus. They are used as rescue medicines in emergencies, usually as buccal, nasal, or IV preparations. Main side effects are sleepiness, low breathing drive, and, with long-term use, dependence, so they are mostly for short-term control.
4. Baclofen for spasticity
Baclofen is a muscle relaxant that acts as a GABA-B receptor agonist in the spinal cord, decreasing excitatory signals that cause spasticity. In COXPD26 with stiff legs or painful spasms, it can improve comfort and movement. Side effects include sleepiness, weakness, and dizziness. Dosing is slowly adjusted to balance tone reduction with preserved muscle strength.
5. Levocarnitine (CARNITOR®)
Levocarnitine is a naturally occurring molecule that transports long-chain fatty acids into mitochondria for energy production. In some mitochondrial disorders and secondary carnitine deficiency, it can improve energy use and remove toxic acyl groups. FDA labels describe its use for inborn errors causing carnitine deficiency and for dialysis-related deficiency. Side effects include diarrhoea and fishy body odour.
6. Coenzyme Q10 (ubiquinone / ubiquinol)
CoQ10 shuttles electrons within the mitochondrial respiratory chain and acts as an antioxidant. Although not FDA-approved specifically for mitochondrial disease, it is widely used off-label as part of the “mitochondrial cocktail.” Orphan drug designation exists for CoQ10 in other conditions. Typical side effects are mild and include gastrointestinal upset. Evidence suggests possible benefit in some primary mitochondrial disorders.
7. Riboflavin (vitamin B2) / riboflavin-containing preparations
Riboflavin is a cofactor for many mitochondrial enzymes. It can support complex I and II function and is standard in many mitochondrial supplement protocols. Injectable and IV vitamin mixtures, such as INFUVITE, include riboflavin and other vitamins for patients needing parenteral nutrition. Side effects are usually mild (bright yellow urine, rare allergy).
8. Thiamine (vitamin B1)
Thiamine is required for pyruvate dehydrogenase and other key mitochondrial enzymes. High-dose thiamine is used in some mitochondrial and metabolic disorders to improve energy metabolism. It is often part of IV multivitamin products. Side effects are rare but can include allergic reactions with IV forms. Adequate thiamine intake helps reduce lactic acidosis and energy failure in vulnerable patients.
9. Alpha-lipoic acid
Alpha-lipoic acid is a mitochondrial antioxidant and cofactor for oxidative decarboxylation reactions. In theory, it reduces oxidative damage and supports energy production, and it has been studied mainly as part of combination supplements. Side effects may include nausea, skin rash, or low blood sugar. Evidence is limited, so it is usually used under specialist guidance as part of a broader cocktail.
10. L-arginine or L-citrulline
These amino acids are used in some mitochondrial disorders (especially MELAS) to support nitric oxide production and blood flow in the brain and muscles. They may help reduce stroke-like episodes in specific subtypes; evidence in COXPD26 is lacking, but some clinicians consider them for severe vasodilation-related symptoms. Side effects can include stomach upset and low blood pressure at high doses.
11. Folinic acid (leucovorin)
Folinic acid can raise cerebrospinal fluid folate levels and has helped some patients with mitochondrial DNA depletion and seizures. It works by bypassing folate pathway blocks and supporting one-carbon metabolism important for brain function. Side effects are usually mild (nausea, rash). Use in COXPD26 is extrapolated from other mitochondrial syndromes.
12. Elamipretide injection (FORZINITY™)
Elamipretide is a mitochondria-targeted peptide approved to improve muscle strength in Barth syndrome. It binds to cardiolipin in the inner mitochondrial membrane and may stabilize respiratory chain super-complexes, improving ATP production. Clinical trials in other mitochondrial diseases are ongoing. Side effects include injection-site reactions and headache. In COXPD26, its use would currently be experimental and off-label.
13. Nucleoside / deoxynucleoside therapies (e.g., TK2-targeted, KYGEVVI™)
Oral deoxynucleoside mixtures and the combination drug Kygevvi (doxecitine and doxribtimine) are designed to correct nucleotide imbalances in mitochondrial DNA depletion syndromes like TK2 deficiency. They supply missing building blocks for mtDNA replication. These therapies are not approved for TRMT5-related COXPD26 but illustrate a new class of targeted mitochondrial treatments. Side effects and dosing depend on the specific product.
14. Standard heart-failure drugs (ACE inhibitors, beta-blockers, diuretics)
If COXPD26 causes cardiomyopathy, standard cardiac medications used in heart failure can protect the heart. ACE inhibitors and beta-blockers reduce workload and harmful neurohormonal activation, while diuretics remove excess fluid. These drugs act on circulation rather than mitochondria, but preserving heart function is crucial for overall outcomes.
15. Proton pump inhibitors and pro-motility agents for GI symptoms
Gastro-oesophageal reflux, delayed gastric emptying, and constipation are common in mitochondrial disease. Medications such as proton pump inhibitors (for acid) and prokinetics (for motility) improve comfort and nutrition. They work by reducing stomach acid and increasing gut movement. Side effects vary but can include diarrhoea or nutrient malabsorption if used long term.
16. Anti-emetics for nausea and vomiting
Drugs like ondansetron may be used to control severe nausea or vomiting during illness or after surgery. They block serotonin receptors in the gut and brain. By controlling vomiting, they protect hydration, calorie intake, and medication absorption, which is vital in COXPD26.
17. Vitamin D and calcium supplementation
These are often prescribed to prevent osteoporosis in children and adults with limited mobility and chronic illness. Vitamin D improves calcium absorption and bone health, reducing fracture risk. This is especially important when patients have long-term steroids or limited weight-bearing activity.
18. Multivitamin preparations (e.g., INFUVITE)
When oral intake is poor or IV nutrition is needed, multi-vitamin preparations give a balanced mix of B-vitamins, vitamin C, E, and others important for mitochondrial enzyme function and antioxidant defence. They aim to keep vitamin levels in the high-normal physiological range. Side effects are rare but can include allergic reactions.
19. Pain medicines used carefully (e.g., acetaminophen / paracetamol)
Simple analgesics like paracetamol are often preferred to strong opioids because of fewer respiratory and metabolic effects. They act centrally to reduce pain perception. Dose must respect liver function and weight. In mitochondrial diseases, clinicians avoid chronic high doses and combine drugs with non-drug pain strategies.
20. Tailored peri-operative medicines and anaesthetic choices
When surgery is needed, anaesthetists select drugs with lower mitochondrial toxicity and avoid prolonged fasting, certain volatile agents, and high doses of propofol where possible. Peri-operative dextrose-containing fluids and careful temperature control are also “drug-related” decisions that protect mitochondria during stress.
Dietary molecular supplements
1. Coenzyme Q10 – supports electron transport and acts as a fat-soluble antioxidant, possibly improving muscle strength and reducing fatigue in some mitochondrial patients.
2. L-carnitine – helps move fatty acids into mitochondria, improves removal of toxic acyl groups, and may reduce muscle pain and fatigue when deficiency is present.
3. Riboflavin (B2) – cofactor for complex I and II; can improve electron transport and is standard in many mitochondrial cocktails.
4. Thiamine (B1) – supports pyruvate dehydrogenase and other dehydrogenase complexes, helping convert glucose into energy with less lactate.
5. Niacin / NADH-related supplements – help maintain cellular NAD⁺/NADH balance, which is critical for oxidative phosphorylation and redox reactions.
6. Alpha-lipoic acid – a mitochondrial antioxidant that may reduce oxidative stress and support enzyme complexes, used mainly as part of combination regimens.
7. Vitamins C and E – water- and fat-soluble antioxidants that may protect mitochondrial membranes and DNA from reactive oxygen species.
8. Creatine – buffers high-energy phosphate in muscle, helping short bursts of activity and possibly reducing perceived fatigue.
9. Arginine / citrulline – support nitric oxide production and smooth muscle relaxation; may improve blood flow to tissues in certain mitochondrial syndromes.
10. Vitamin D and K2 – support bone and muscle health, which is important when mobility is limited and steroids or anti-seizure medicines are used.
Immune-booster, regenerative and stem-cell-related treatments
1. Elamipretide (mitochondria-targeting peptide)
Elamipretide is designed to bind cardiolipin in the inner mitochondrial membrane, stabilize respiratory chain complexes, and reduce oxidative damage. It has regulatory approval in Barth syndrome and is being studied in other mitochondrial diseases. For COXPD26, it is a theoretical, experimental option under trials or compassionate use only.
2. Nucleoside replacement therapy
Deoxynucleoside supplementation (for example in TK2 deficiency) aims to correct unbalanced nucleotide pools in mitochondria, supporting mtDNA replication and repair. This strategy, now reflected in Kygevvi and related therapies, could inspire future treatments for TRMT5-related disease, although no direct data exist yet for COXPD26.
3. Antioxidant-focused “regenerative” cocktails (CoQ10 + B-vitamins + carnitine)
Combined antioxidant and cofactor regimens try to regenerate mitochondrial function by reducing oxidative stress and supporting enzyme systems. Studies suggest perceived benefit in many mitochondrial patients, although controlled evidence is modest. These regimens may indirectly support immunity by reducing chronic fatigue and inflammation.
4. Experimental gene therapy for mitochondrial disorders
Gene therapy approaches are being developed for some nuclear-encoded mitochondrial diseases, using viral vectors to deliver a functional gene copy. For TRMT5-related COXPD26 this is still theoretical, but in future it may help restore proper tRNA modification and improve oxidative phosphorylation. So far, these therapies remain in early research phases.
5. Induced pluripotent stem cell (iPSC)-based research
Scientists create iPSCs from patient cells to study disease mechanisms and test drugs in vitro. Although this is not a clinical drug, it is a regenerative research tool that may one day support personalised cell-replacement or gene-corrected therapies for mitochondrial disorders, including COXPD26.
6. Hematopoietic or mesenchymal stem-cell therapies (experimental)
Some centres are studying mesenchymal stem-cell infusions or bone-marrow-derived cell therapies in metabolic and neurodegenerative diseases. The idea is that donor cells may deliver healthier mitochondria or supportive growth factors. At present, there is no proven benefit for COXPD26, and such treatments should only occur within strict clinical trials.
Surgeries
1. Gastrostomy tube placement
A gastrostomy tube (G-tube) is placed through the abdominal wall into the stomach when oral feeding is unsafe or insufficient. It allows safe delivery of calories, fluids, and medicines, preventing malnutrition and aspiration. This surgery helps reduce feeding stress and hospital admissions in children with severe swallowing problems.
2. Nissen fundoplication or anti-reflux surgery
When severe reflux causes aspiration, pain, or growth failure and medicines do not help, surgeons may wrap the top of the stomach around the lower oesophagus (fundoplication). This tightens the valve and reduces reflux, protecting lungs and improving comfort.
3. Orthopaedic surgery for contractures and scoliosis
Children with long-standing spasticity or weakness may develop fixed joint contractures or spinal curvature. Surgical tendon releases or spinal fusion can improve sitting balance, pain, and care-giving. These procedures do not change the mitochondrial defect but can greatly improve daily function and comfort.
4. Cardiac device implantation (pacemaker / ICD)
If COXPD26 causes serious heart rhythm problems or cardiomyopathy, pacemakers or implantable cardioverter-defibrillators (ICDs) may be needed. These devices keep the heart rhythm safe and can prevent sudden death. Decisions are based on standard heart-failure and rhythm guidelines.
5. Eye or eyelid surgery (ptosis correction)
Some patients develop drooping eyelids or optic nerve problems. Eye muscle or eyelid surgery can improve vision, eye opening, and appearance. While it does not treat the underlying mitochondrial disease, it can greatly help daily activities such as reading and social interaction.
Prevention strategies
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Avoid prolonged fasting by giving frequent meals and snacks, especially during illness.
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Prevent and treat infections early with vaccinations, good hand hygiene, and quick medical review for fever or cough.
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Avoid known mitochondrial-toxic drugs (for example some aminoglycosides, valproic acid, high-dose propofol), following specialist lists.
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Plan ahead for surgery or anaesthesia using a written protocol, IV glucose, and temperature control.
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Maintain regular gentle exercise to prevent deconditioning and support mitochondrial health.
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Keep vaccinations up to date, including influenza and pneumonia vaccines, to reduce severe infections.
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Monitor growth and nutrition so that calorie or protein deficits are corrected early.
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Provide safe home environment (grab bars, non-slip floors, appropriate aids) to prevent falls and fractures.
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Offer psychological and social support to reduce burnout, depression, and care breakdown, which indirectly protects health.
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Use genetic counselling to prevent unexpected recurrence in future pregnancies when parents wish to plan.
When to see a doctor (or emergency department)
You should see a doctor urgently, or go to an emergency department, if a person with COXPD26 has any of the following:
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New or rapidly worsening shortness of breath, fast breathing, or blue lips.
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Prolonged seizures, repeated seizures, or any seizure that does not stop as usual.
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Sudden severe weakness, inability to stand or sit, or loss of previously gained skills.
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Persistent vomiting, refusal to eat or drink, or signs of dehydration (no urine, dry mouth).
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High fever, especially with lethargy, confusion, or unusual sleepiness.
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Chest pain, irregular heartbeat, or fainting episodes.
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Noticeable swelling of legs, abdomen, or sudden weight gain (possible heart failure).
For any worrying change, caregivers should contact the metabolic or mitochondrial specialist early, because quick treatment can prevent serious organ damage.
Diet: what to eat and what to avoid
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Eat small, frequent meals with complex carbohydrates (rice, pasta, whole grains) to give steady energy and avoid long fasting times.
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Include adequate protein (eggs, beans, fish, lean meat) to support muscle repair and immune function.
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Use healthy fats (olive oil, nuts, seeds, fatty fish) to provide dense calories that are easier to eat in small volumes.
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Ensure enough fluids (water, oral rehydration) to prevent dehydration, which worsens fatigue and kidney stress.
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Add vitamin-rich fruits and vegetables in tolerated forms (purees, soft textures) to supply antioxidants and micronutrients.
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Avoid long periods without food, especially overnight or during illness; nocturnal feeds or bedtime snacks may help.
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Limit very high-sugar drinks and sweets, which cause blood sugar spikes and crashes and give “empty” calories.
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Avoid crash diets and extreme high-protein or high-fat fad diets unless specifically prescribed, because they can stress metabolic pathways.
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Avoid alcohol and smoking exposure (for adults and household members) because these increase oxidative stress and cardiovascular strain.
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Be cautious with unproven “miracle” supplements bought online, as they may interact with medicines or be unsafe; always review with the mitochondrial team first.
Frequently asked questions (FAQs)
1. Is COXPD26 curable?
At present, there is no cure for combined oxidative phosphorylation defect type 26. Treatment focuses on managing symptoms, preventing complications, and supporting the best possible quality of life. Research into mitochondrial-targeted drugs, nucleoside therapies, and gene-based treatments is active and offers hope for the future, but nothing is yet proven specifically for TRMT5-related disease.
2. How is COXPD26 inherited?
COXPD26 is usually autosomal recessive. This means a child inherits one faulty TRMT5 gene from each parent, who are typically healthy carriers. Each pregnancy of two carriers has a 25% chance of an affected child, 50% chance of a carrier child, and 25% chance of an unaffected non-carrier child. Genetic counselling can help families understand their exact risks.
3. Are there specific guidelines doctors follow?
Yes. Doctors use international primary mitochondrial disease care standards that describe how to monitor organs, manage crises, and use supplements and rehabilitation. Because COXPD26 is rare, these guidelines are based on broader mitochondrial disease experience, expert consensus, and limited studies.
4. Can exercise actually help if mitochondria are weak?
Carefully planned, low-to-moderate exercise can be helpful. Studies in mitochondrial myopathies show that supervised aerobic and resistance training can improve fitness, muscle strength, and sometimes mitochondrial enzyme activity. Over-exertion is harmful, so programs must be tailored and increased slowly under professional guidance.
5. Do mitochondrial cocktails really work?
Many patients report feeling better on combinations of CoQ10, carnitine, riboflavin, and other vitamins, and surveys show they are widely used. However, strong controlled trial evidence is limited and benefits vary from person to person. Because side effects are usually mild, specialists may recommend a trial while monitoring response and safety.
6. Are new drugs being developed for mitochondrial diseases?
Yes. Recent years have brought the first approvals of targeted mitochondrial therapies such as elamipretide for Barth syndrome and Kygevvi for TK2 deficiency, and ongoing trials of nucleoside therapy, antioxidant molecules, and metabolic modulators in other mitochondrial conditions. These advances show that disease-specific drugs are possible, but they are not yet available for COXPD26.
7. What is the outlook (prognosis)?
Prognosis is highly variable. Some children with COXPD26 have severe early-onset disease with developmental delay and multi-organ involvement, while others present later mainly with exercise intolerance and neuropathy. Early diagnosis, good supportive care, and prevention of crises can improve quality of life and sometimes survival, but the condition remains serious.
8. Can COXPD26 affect the heart and lungs?
Yes. Some reported patients have hypertrophic cardiomyopathy and breathing problems from weak respiratory muscles or recurrent infections. Regular heart and lung assessments are essential, and early treatment of cardiomyopathy or sleep-disordered breathing can make a big difference.
9. Is normal schooling possible?
Many children with milder forms can attend mainstream school with support such as extra rest breaks, physical aids, and individualized education plans. Others need special education settings. The key is flexible planning so that fatigue, mobility issues, and medical appointments are respected while encouraging learning and social contact.
10. Can infections be especially dangerous?
Yes. Infections raise energy demand and can push already stressed mitochondria into crisis, leading to lactic acidosis, seizures, or organ failure. Vaccinations, early medical review, and emergency “sick day” plans are crucial. Families should not delay seeking help when a child with COXPD26 becomes unwell.
11. Are anaesthetics safe in COXPD26?
Anaesthesia is possible but needs extra planning. Specialists avoid certain drugs and long fasting, use glucose-containing fluids, control temperature, and monitor acid–base balance closely. Written peri-operative protocols from the mitochondrial team help anaesthetists choose safer strategies.
12. Can siblings be tested?
Yes. Once a TRMT5 mutation is known in the family, genetic testing can identify affected siblings, presymptomatic children, or carriers. This helps with surveillance and family planning, but decisions about testing minors should be made carefully with a genetic counsellor.
13. Should we avoid all sports?
Total inactivity is usually harmful. Instead, low-to-moderate intensity activities like walking, swimming, or cycling, adapted to the child’s capacity, are often encouraged. Contact or extreme-intensity sports may be unsuitable for fragile patients, but decisions should be individualized with the medical and physiotherapy team.
14. Do special diets (like ketogenic diets) help?
Ketogenic or very low-carb diets are sometimes used in epilepsy and specific metabolic defects, but they can be risky in many mitochondrial diseases and are not standard for COXPD26. Any special diet must be supervised by experienced metabolic teams; for most patients, a balanced high-energy diet with frequent meals is safer.
15. What can families do right now?
Families can focus on regular follow-up with a mitochondrial centre, vaccinations, good nutrition, tailored exercise, and emotional support. Keeping clear records, emergency letters, and contact details for specialists helps in crises. Joining rare disease or mitochondrial patient organizations can reduce isolation and provide practical advice.
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.
