Combined oxidative phosphorylation deficiency caused by mutation in TRMT5 is a very rare genetic disease of the mitochondria. Mitochondria are tiny parts inside each cell that make energy using a process called oxidative phosphorylation. In this disease, several steps of this energy-making chain do not work properly, so cells cannot make enough energy.
This condition is also called combined oxidative phosphorylation deficiency 26 (COXPD26). Doctors use this name to show that more than one mitochondrial respiratory chain complex is affected, and that this is the 26th type described in medical databases. It mainly affects the brain, nerves, muscles, and sometimes the heart and other organs that need a lot of energy all the time.
The TRMT5 gene gives instructions to make an enzyme that modifies mitochondrial tRNA molecules. These tRNAs help mitochondria build proteins needed for the electron transport chain. If TRMT5 is faulty, the tRNA is not modified in the correct way, the mitochondria cannot make normal proteins, and oxidative phosphorylation does not work properly. This leads to low ATP (energy) inside the cells.
Combined oxidative phosphorylation deficiency caused by mutation in the TRMT5 gene is a very rare inherited mitochondrial disease, usually called combined oxidative phosphorylation deficiency 26 (COXPD26). It is autosomal-recessive, which means a child is affected when they receive a faulty TRMT5 copy from both parents. The TRMT5 gene normally helps modify mitochondrial transfer RNA (tRNA). When it does not work, many mitochondrial proteins are not made correctly, and several respiratory-chain complexes (I–IV) cannot produce enough cellular energy (ATP). Children often present with developmental delay, low muscle tone, neuropathy, exercise intolerance, shortness of breath, and spasticity.
TRMT5 is a mitochondrial tRNA methyltransferase. Mutations in TRMT5 cause faulty post-transcriptional modification of mitochondrial tRNA. This disrupts the mitochondrial ribosome’s ability to translate mitochondrial DNA–encoded proteins needed for oxidative phosphorylation. As a result, multiple respiratory-chain complexes are deficient at the same time, leading to a “combined” oxidative phosphorylation defect. This energy failure particularly harms tissues with high energy demand, such as brain, nerves, heart, and skeletal muscles.
Clinical reports show that COXPD26 can have variable severity. Some children show early-onset developmental delay, gastrointestinal problems, hypotonia, muscle weakness, neuropathy, and spastic diplegia. Others may develop liver disease, portal hypertension, or demyelinating neuropathy as the phenotype of TRMT5-related disease continues to expand. There is no specific curative drug for TRMT5 deficiency yet. Treatment focuses on seizure control, symptom relief, mitochondrial “cocktail” supplements, rehabilitation, and careful monitoring in specialized centers.
Other names
This condition has several other names in medical databases and research papers. It is often called combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation deficiency 26, COXPD26, or TRMT5-combined oxidative phosphorylation deficiency. Some reports also use a longer name: peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay. All of these names refer to the same basic disorder linked to TRMT5 mutations.
Doctors may also group this disease into simple “types” based on how it shows in the body: for example, (1) a neurological-dominant type where brain, movement, and nerves are most affected, (2) a muscle-dominant type where weakness and exercise intolerance are strongest, and (3) a multisystem type where many organs such as brain, heart, liver, and gut are involved. These are clinical groupings meant to help with care and are not strict official categories.
Causes and contributing factors
1. Pathogenic TRMT5 gene mutations (main cause)
The direct cause of this disease is a harmful (pathogenic) mutation in the TRMT5 gene. This mutation stops or reduces the enzyme activity needed to modify mitochondrial tRNA. Without correct tRNA modification, mitochondrial protein building and energy production fail, leading to combined oxidative phosphorylation deficiency.
2. Homozygous TRMT5 mutations
In some families, the affected child inherits the same TRMT5 mutation from both parents (homozygous mutation. This gives the child no working copy of TRMT5 in their cells, which makes the mitochondrial problem more severe and usually causes symptoms early in life.
3. Compound heterozygous TRMT5 mutations
Other patients have two different disease-causing mutations in TRMT5, one from each parent (compound heterozygous). Even though the changes are different, both copies are non-working. Together, they can cause the same energy problem and similar clinical picture known as COXPD26.
4. Missense mutations in TRMT5
Some disease-causing variants change one amino acid in the TRMT5 protein (missense mutation). Even this small change can distort the enzyme’s shape, reduce its ability to modify tRNA, and therefore disturb oxidative phosphorylation in mitochondria.
5. Nonsense or frameshift mutations
Other mutations introduce an early “stop” signal or add/remove bases so that the protein is cut short (nonsense or frameshift). These truncated proteins are usually unstable or non-functional, leading to a complete loss of TRMT5 enzyme activity and more serious mitochondrial energy failure.
6. Splice-site mutations in TRMT5
Some pathogenic variants affect the parts of the gene that control how RNA is spliced. Wrong splicing can remove important sections or insert extra pieces into the RNA. This leads to abnormal TRMT5 protein and reduced tRNA modification in mitochondria.
7. Consanguinity (parents related by blood)
In populations where parents are related (for example, cousins), there is a higher chance that both parents carry the same rare TRMT5 mutation. This increases the risk that a child will inherit two faulty copies and develop combined oxidative phosphorylation deficiency.
8. Family history of mitochondrial disease
A family history of developmental delay, muscle weakness, unexplained lactic acidosis, or diagnosed mitochondrial disease suggests that harmful variants, including in TRMT5, may run in the family. This does not create the mutation, but it is an important background factor for the disease.
9. Other mitochondrial gene variants as modifiers
Some people with TRMT5 mutations may also carry variants in other mitochondrial genes. These additional changes can make the oxidative phosphorylation problem worse or change which organs are most affected, even though TRMT5 is still the main disease gene.
10. High energy demand in brain and muscle
Organs like brain and skeletal muscle have very high energy needs. When TRMT5-related oxidative phosphorylation is weak, these organs suffer the most. This high demand does not cause the mutation, but it explains why symptoms show strongly in these tissues and makes the underlying defect more obvious.
11. Severe infections as triggers
In people who already have TRMT5 mutations, severe infections (such as pneumonia or sepsis) can suddenly increase the body’s energy needs and oxygen use. This stress may trigger or worsen lactic acidosis, weakness, or breathing problems, making the mitochondrial defect more noticeable.
12. Fever and long-lasting illness
High fever speeds up metabolism and increases energy use. For a child with TRMT5-related disease, a long period of fever can push already weak mitochondria beyond their limit, leading to episodes of fatigue, confusion, or even organ failure.
13. Surgery and anesthesia stress
Operations and anesthesia put extra stress on the body. They can change blood pressure, oxygen level, and metabolism. In a person with combined oxidative phosphorylation deficiency, this stress can unmask hidden problems or worsen existing weakness, especially in heart and breathing muscles.
14. Prolonged fasting or low calorie intake
When the body has little food for many hours, it depends more on fat and stored energy. Mitochondria must work harder to make ATP. In TRMT5 disease, this extra demand can lead to low blood sugar, lactic acidosis, or sudden tiredness, so long fasting is risky.
15. Poor vitamin and nutrient intake
Some vitamins (for example B-vitamins, coenzyme Q10 precursors) help mitochondria work properly. If a person with TRMT5 mutations also has poor nutrition, the energy problem can become worse, although nutrition alone does not cause the gene mutation.
16. Medicines that stress mitochondria
Certain medicines can damage mitochondria or increase oxidative stress, such as some older antiepileptic drugs, certain antibiotics, or chemotherapy agents. In people who already have TRMT5-related mitochondrial disease, these drugs may worsen muscle weakness or lactic acidosis, so doctors are often cautious with them.
17. Environmental toxins
Exposure to heavy metals, industrial solvents, or other toxins that damage mitochondria may further reduce oxidative phosphorylation. On their own these toxins usually do not cause TRMT5 mutations, but in someone with this genetic disease they can add extra harm to already fragile energy systems.
18. Endocrine problems (for example thyroid disease)
Hormones such as thyroid hormone control how fast cells use energy. If a person with mitochondrial disease also has thyroid problems or diabetes, their cells may either demand too much energy or not use it efficiently, making oxidative phosphorylation defects more obvious.
19. Repeated strong physical exertion
Very hard or long exercise requires a big increase in ATP production. In TRMT5 disease, the mitochondria cannot answer this demand, so the person may get severe fatigue, muscle pain, or lactic acidosis. This high effort does not cause the mutation but can drive symptoms.
20. Unknown or not yet identified factors
Medicine is still learning about TRMT5-related disease. There may be other genetic or environmental factors that change who gets symptoms, which organs are affected, or how severe the disease becomes. These factors are not fully known yet and are still being studied.
Symptoms and signs
1. Developmental delay
Many children with TRMT5-related combined oxidative phosphorylation deficiency sit, stand, walk, or talk later than expected. They may need extra help to learn basic skills because their brain and muscles do not get enough energy for normal growth and function.
2. Low muscle tone (hypotonia)
Babies may feel “floppy” when they are picked up, with poor head control. This low muscle tone is a common early sign that the muscles and nerves are not working well due to mitochondrial energy shortage.
3. Muscle weakness
As children grow, they may have trouble climbing stairs, standing from the floor, or carrying objects. The weakness often affects both legs and sometimes arms, because skeletal muscles depend heavily on oxidative phosphorylation for strength and endurance.
4. Spasticity and stiffness (especially in legs)
Some people develop stiff, tight leg muscles and increased reflexes, called spastic diplegia. This makes walking difficult and may look similar to cerebral palsy. In TRMT5 disease, this stiffness comes from damage to motor pathways in the brain and spinal cord due to low energy supply.
5. Peripheral neuropathy (nerve damage in limbs)
Numbness, tingling, burning pain, or loss of vibration sense in feet and hands can occur. This happens because the long peripheral nerves are very sensitive to energy problems and oxidative stress, so they can be damaged when mitochondrial function is poor.
6. Exercise intolerance and easy fatigue
Many patients become tired very quickly during walking, running, or playing. They may complain of heavy legs, muscle pain, or breathlessness after only a short activity. This occurs because their muscles cannot increase ATP production enough during exercise.
7. Shortness of breath or breathing problems
Some children have rapid breathing, shortness of breath, or low oxygen levels, especially when they are ill or active. Weak respiratory muscles and heart problems together with lactic acidosis can all make breathing harder in this disease.
8. Gastrointestinal problems
Feeding problems, vomiting, diarrhea, or constipation are reported in some cases. The gut muscles and nerves also need good mitochondrial function. When energy is low, they may move food too slowly or too quickly, causing discomfort and poor nutrition.
9. Poor growth and failure to thrive
Because of feeding difficulties, frequent illness, and high energy needs, children may gain weight slowly and remain smaller than expected. Poor growth can also reflect chronic lactic acidosis and multi-organ involvement from the underlying mitochondrial disorder.
10. Lactic acidosis
Many mitochondrial diseases, including TRMT5-related COXPD26, can cause high levels of lactic acid in blood or urine. When oxidative phosphorylation is weak, cells rely more on anaerobic glycolysis, which produces lactate. High lactate can lead to vomiting, fast breathing, and serious illness if not treated.
11. Seizures or abnormal movements
Some patients develop seizures, jerking movements, or episodes of unresponsiveness. These events show that the brain is under stress and not getting enough reliable energy, which makes nerve cells more likely to misfire.
12. Problems with balance and coordination (ataxia)
Unsteady walking, frequent falls, or difficulty with tasks that need fine control, like picking up small objects, can occur. Ataxia often reflects damage to the cerebellum or its connections, which are very energy-dependent brain regions.
13. Learning difficulties or cognitive problems
Children may have trouble with schoolwork, memory, or concentration. These issues can result from structural brain changes, repeated metabolic crises, or ongoing energy shortage in brain cells.
14. Heart problems (cardiomyopathy or rhythm issues)
Mitochondrial diseases can affect the heart muscle, causing thickened or weak heart walls (cardiomyopathy) and sometimes abnormal heart rhythms. The heart beats all the time and needs a constant supply of ATP, so it is very vulnerable to oxidative phosphorylation defects.
15. Hearing or vision problems
Some individuals may develop hearing loss or visual impairment. The tiny sensory cells in the inner ear and the retina use a lot of energy, so long-term mitochondrial dysfunction can damage them and reduce hearing or vision.
Diagnostic tests
Because this is a rare and complex mitochondrial disease, no single test is enough. Doctors usually combine history, examination, lab tests, imaging, and genetic testing to reach a diagnosis. The goal is to show that mitochondria are not working well and to find the exact TRMT5 mutation.
Physical examination tests
1. General physical exam and growth check
The doctor carefully checks height, weight, head size, body shape, and vital signs. They look for poor growth, small head (microcephaly), or signs of heart and lung strain. These findings help show that the problem is long-lasting and may involve the whole body, as seen in many mitochondrial diseases.
2. Detailed neurological examination
A full nerve and brain exam checks reflexes, muscle strength, coordination, eye movements, and speech. In TRMT5-related disease, doctors may find low tone, weakness, spasticity, or abnormal reflexes, which guide them toward a neurometabolic or mitochondrial cause.
3. Assessment of muscle tone and posture
By gently moving the arms and legs, the doctor checks if the muscles are floppy or stiff. They also watch how the child sits, stands, and holds their head. The pattern of hypotonia or spasticity helps distinguish this disease from purely muscle disorders or from classic cerebral palsy.
4. Observation of gait and balance
For children who can walk, the doctor studies how they step, turn, and stand on one leg. Unsteady gait, toe-walking, scissoring of the legs, or frequent falls may suggest a mitochondrial disorder affecting brain, spinal cord, and peripheral nerves together.
Manual and functional tests
5. Manual muscle testing (MMT)
The clinician asks the patient to push or pull against their hands to test strength in different muscle groups. This simple bedside test shows whether weakness is mild or severe and whether it mainly affects certain areas, as often seen in mitochondrial myopathies.
6. Developmental milestone assessment
For babies and young children, therapists check when they achieve key skills like rolling, sitting, crawling, standing, and speaking. A pattern of delayed motor and language milestones fits with early-onset mitochondrial disease such as TRMT5-related COXPD26.
7. Simple exercise or walk tests
Tests such as a timed stair climb or a short walk test (for example, six-minute walk) can show how quickly the child becomes tired or breathless. A strong drop in performance with modest exercise suggests a problem in energy production rather than pure lack of effort.
8. Bedside sensory testing
Using light touch, vibration tuning forks, or temperature objects, doctors check feeling in the hands and feet. Loss or change in sensation points to peripheral neuropathy, which is one of the key features in some patients with TRMT5-related combined oxidative phosphorylation deficiency.
Laboratory and pathological tests
9. Blood lactate and lactate/pyruvate ratio
High lactate in blood at rest or after stress is a classic clue to mitochondrial disease. Measuring both lactate and pyruvate and calculating their ratio helps doctors see if the problem likely comes from oxidative phosphorylation. However, normal lactate does not fully rule out mitochondrial disease.
10. Serum creatine kinase (CK)
Creatine kinase is a muscle enzyme that leaks into blood when muscle cells are damaged. In mitochondrial myopathies, CK can be normal or mildly raised. An abnormal result supports muscle involvement but is not specific, so it must be interpreted with other tests.
11. Comprehensive metabolic panel
Blood tests for liver enzymes, kidney function, blood sugar, and electrolytes can show organ damage or metabolic stress. For example, liver dysfunction or low blood sugar may appear in severe mitochondrial disease and can support the suspicion of a systemic energy problem.
12. Urine organic acids and plasma amino acids
These tests look for unusual patterns of small molecules that build up when energy pathways are blocked. Certain organic acid or amino acid patterns can point toward mitochondrial dysfunction and help guide further genetic and enzyme studies.
13. Genetic testing for TRMT5 and other mitochondrial genes
Modern genetic tests use next-generation sequencing to read many genes at once. A targeted panel or exome/genome test can detect biallelic TRMT5 mutations and confirm the diagnosis of COXPD26. Genetic testing has become the main way to get a final answer in suspected mitochondrial disease.
14. Muscle biopsy with respiratory chain enzyme analysis
In some cases, doctors take a small piece of muscle and study it under the microscope and with special enzyme tests. They may see abnormal mitochondria and reduced activity of several respiratory chain complexes, proving a combined oxidative phosphorylation defect in tissue.
Electrodiagnostic tests
15. Electromyography (EMG)
EMG uses a thin needle to record electrical activity inside muscles. In mitochondrial disease, EMG can show myopathic changes or signs of nerve involvement. This helps separate mitochondrial myopathy with neuropathy from other nerve or muscle disorders.
16. Nerve conduction studies (NCS)
NCS deliver small electrical pulses to nerves and record how fast and strong the signals travel. Reduced speed or low responses indicate peripheral neuropathy, which fits with the “peripheral neuropathy with variable spasticity” description used for some TRMT5-related cases.
17. Electroencephalogram (EEG)
If seizures or episodes of altered awareness occur, an EEG records the brain’s electrical activity. It can show abnormal spikes or slowing that support a diagnosis of epilepsy or encephalopathy due to mitochondrial dysfunction of the brain.
Imaging tests
18. Brain MRI
Magnetic resonance imaging of the brain can show structural changes such as white matter abnormalities, brainstem or cerebellar changes, or atrophy. These patterns can support a diagnosis of mitochondrial disease and sometimes help separate it from other neurological conditions.
19. Echocardiogram (heart ultrasound)
An ultrasound scan of the heart looks at heart size, wall thickness, pumping strength, and valve function. It can detect hypertrophic or dilated cardiomyopathy and rhythm-related problems that are sometimes seen in mitochondrial disorders.
20. Muscle MRI or MR spectroscopy
MRI of muscles can show patterns of muscle wasting or fatty change that suggest a metabolic myopathy. Magnetic resonance spectroscopy can even measure certain chemicals, such as phosphocreatine or lactate, giving more evidence of a mitochondrial energy problem in muscle tissue.
Non-pharmacological treatments
Below are commonly used supportive and rehabilitative therapies for TRMT5-related combined oxidative phosphorylation deficiency. Evidence is usually extrapolated from broader mitochondrial disease experience, case series, and expert consensus, not from large trials in COXPD26 specifically.
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Individualized physiotherapy
A long-term physiotherapy plan focuses on stretching, strengthening, balance, and posture to reduce contractures, maintain joint range, and support mobility. For children with hypotonia and spasticity, daily exercises, assisted standing, and gait training can slow loss of motor function and improve comfort. Therapy is adapted to energy limits so that over-exertion is avoided and rest breaks are built in. -
Occupational therapy (OT)
OT helps the child manage everyday tasks like feeding, dressing, school activities, and communication. Therapists may recommend adaptive tools (special cutlery, writing aids, switch devices) and teach energy-saving strategies such as sitting instead of standing for tasks. The goal is to maximize independence and reduce caregiver burden while respecting fatigue and muscle weakness. -
Speech and language therapy
Many affected children have dysarthria, swallowing difficulty, or language delay. Speech therapy can work on safe swallowing techniques, better articulation, and alternative communication methods (picture boards, tablets). Early intervention may improve social interaction and reduce aspiration risk. The therapist also guides families and schools on how to support communication. -
Respiratory physiotherapy
Weak breathing muscles and abnormal control can lead to poor cough and recurrent infections. Respiratory therapy teaches airway-clearance techniques, assisted coughing, and safe positioning. In more severe cases, non-invasive ventilation at night may be needed, coordinated by a pulmonologist and the mitochondrial team. -
Nutritional counseling
A dietitian experienced in mitochondrial disease designs a high-energy, high-protein diet adjusted for swallowing ability and GI symptoms. The plan aims to avoid long fasting, stabilize blood sugar, and maintain growth. Texture-modified diets and calorie-dense foods are often needed. Feeding plans are frequently combined with supplements like CoQ10 or vitamins prescribed by the team. -
Feeding support and gastrostomy
If oral intake is unsafe or insufficient because of swallowing problems, vomiting, or severe fatigue, tube feeding via nasogastric tube or gastrostomy (PEG) may be recommended. This provides reliable calories and allows timed feeds, reducing the risk of malnutrition and aspiration while easing the feeding burden on families. -
Structured exercise with pacing
Carefully supervised low-to-moderate intensity exercise (for example cycling or swimming) may improve endurance and mitochondrial function in some patients, while strict pacing prevents over-exertion. Exercise prescriptions are individualized, with attention to heart rate, perceived exertion, and recovery time. -
Orthotic devices and mobility aids
Ankle–foot orthoses, walkers, wheelchairs, and standing frames help keep joints aligned, prevent contractures, and support safe mobility. Devices are chosen to reduce falls and energy cost of movement. Regular reassessment ensures that aids match the child’s changing needs over time. -
Spasticity management with physical methods
Stretching programs, splinting, serial casting, and positioning strategies help reduce spasticity-related deformities. These methods often accompany medications and can delay or lessen the need for orthopedic surgery. Therapists teach caregivers how to carry out daily home stretches safely. -
Educational and cognitive support
Neurodevelopmental and neuropsychological assessments identify learning difficulties, attention problems, or intellectual disability. Early special-education services, individualized education plans, and classroom accommodations help the child participate at school and reduce stress from unrealistic expectations. -
Psychological support and counseling
Living with a chronic, progressive rare disease is emotionally hard for the child and family. Regular psychological counseling, support groups, and social work support can help manage anxiety, grief, and caregiver burnout. Clear communication with the medical team improves coping and shared decision-making. -
Palliative care integration
Specialist palliative care teams can join early, focusing on symptom relief (pain, breathlessness, anxiety), communication about prognosis, and planning for emergencies. Palliative care is not only for end-of-life; it is about maximizing comfort and quality of life at every stage. -
Respiratory infection prevention strategies
Good hand hygiene, vaccination (influenza, pneumococcal, COVID-19 as locally recommended), and early treatment of infections are critical. Families are taught early warning signs and given action plans for when to seek help quickly. -
Thermoregulation and fatigue management
Patients are advised to avoid extreme heat, cold, and prolonged exertion, which can worsen mitochondrial energy failure. Rest periods, cool environments, and activity planning around times of best energy are simple but important strategies. -
Sleep hygiene and respiratory monitoring
Sleep problems and nocturnal hypoventilation can worsen daytime fatigue and cognition. Sleep hygiene routines, attention to bedtime screens and caffeine, and overnight pulse oximetry or sleep studies when indicated help manage these issues. -
Multidisciplinary care coordination
Care ideally involves neurologists, geneticists, cardiologists, pulmonologists, gastroenterologists, dietitians, therapists, and social workers. Regular multidisciplinary clinics reduce conflicting advice, streamline tests, and help families avoid repeated explanations of the same story. -
Genetic counseling for families
Genetic counseling explains autosomal-recessive inheritance, carrier testing, reproductive options, and recurrence risks. Families can discuss prenatal or preimplantation genetic diagnosis if desired. Counseling also helps relatives understand the condition and supports informed decisions. -
Clinical trial and registry participation
When available, joining mitochondrial disease registries or clinical trials can give access to new treatments and improve knowledge about TRMT5 disease. Families must carefully discuss risks and benefits with specialists before enrolling. -
Assistive communication technology
For children with severe speech impairment, tablets with communication apps, eye-gaze systems, or switch-based devices can give a “voice” and greatly improve participation in family and school life. -
Social and financial support services
Social workers can help families access disability benefits, equipment funding, home nursing, and respite care. This reduces financial and emotional strain and allows caregivers to sustain long-term care.
Drug treatments
There is no FDA-approved drug that specifically corrects TRMT5 or COXPD26. Drug treatment focuses on seizures, spasticity, GI symptoms, heart or respiratory problems, and sometimes on mitochondrial “cocktail” components. All doses must follow official prescribing information and be tailored by specialists; here we describe roles and mechanisms in general terms.
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Levetiracetam (Keppra, Keppra XR, Spritam)
Levetiracetam is a broad-spectrum antiseizure medicine commonly used in mitochondrial epilepsy because it has relatively low mitochondrial toxicity. It modulates synaptic vesicle protein SV2A to reduce abnormal neuronal firing. It is FDA-approved for partial-onset and myoclonic seizures in adults and children; dosing and timing follow weight-based guidance in the official label, and side effects can include mood changes, drowsiness, and dizziness. -
Lamotrigine
Lamotrigine is an antiseizure drug that blocks voltage-sensitive sodium channels and stabilizes neuronal membranes, reducing glutamate release. It is used for focal and generalized seizures and sometimes for mood stabilization. In mitochondrial disease, clinicians may choose it when other drugs fail or cause side effects. Doses are slowly titrated to reduce rash risk, and serious skin reactions (including Stevens–Johnson syndrome) are important potential adverse effects. -
Topiramate
Topiramate is a broad-spectrum antiseizure drug that enhances GABA activity, blocks sodium channels, and inhibits carbonic anhydrase. It may help control seizures and migraines in some mitochondrial patients. It can cause weight loss, kidney stones, and cognitive slowing, so specialists consider risks carefully, especially if there is metabolic acidosis risk. -
Valproic acid (often avoided)
Valproate is a common antiseizure medication, but it can be dangerous in some mitochondrial disorders because it may worsen liver failure or cause hyperammonemia. In suspected POLG-related disease it is usually avoided. In TRMT5 disease, many experts prefer other drugs first; if it is ever considered, use is cautious and closely monitored. -
Clonazepam or diazepam (benzodiazepines)
Benzodiazepines enhance GABA-A receptor activity and are used for acute seizure control and sometimes chronic myoclonus. They act quickly but can cause sedation, tolerance, and dependence. In mitochondrial disease, they are mainly used as rescue or adjunctive therapy rather than as sole long-term treatment. -
Baclofen (oral or intrathecal)
Baclofen is a GABA-B agonist used to treat spasticity, especially in the legs. It reduces reflex over-activity and muscle stiffness, making movement and care easier. Side effects include drowsiness and weakness. In severe cases, intrathecal baclofen pumps may be considered by specialized teams. -
Tizanidine
Tizanidine is another antispasticity medicine acting as an alpha-2 adrenergic agonist in the central nervous system to reduce muscle tone. It may help with painful spasms but can cause low blood pressure and liver enzyme elevation, so monitoring is needed. -
Proton-pump inhibitors (PPIs)
Children with severe reflux, vomiting, or GI dysfunction may receive PPIs such as omeprazole to reduce stomach acid and protect the esophagus. They work by blocking acid secretion in gastric parietal cells. Long-term use needs monitoring for nutrient absorption and infection risk. -
Prokinetic agents (for GI dysmotility)
Drugs like metoclopramide may be used cautiously to improve gastric emptying and reduce vomiting in selected patients. They act on dopamine and serotonin receptors to enhance gut motility. Because of potential side effects such as extrapyramidal symptoms, they are used at the lowest effective dose and for limited durations. -
Laxatives for constipation
Osmotic or stimulant laxatives (such as polyethylene glycol or senna) help manage chronic constipation caused by hypotonia and reduced mobility. They work by drawing water into the bowel or stimulating peristalsis. Regular stooling can reduce abdominal pain and feeding intolerance. -
Anti-emetics
Drugs like ondansetron may be used to reduce nausea and vomiting from GI dysmotility or intercurrent illness. They block serotonin (5-HT3) receptors in the gut and brain. Care is taken with heart rhythm monitoring and dosing, especially when combined with other QT-prolonging drugs. -
Cardiac medications (if cardiomyopathy present)
In patients with cardiomyopathy or heart failure, standard drugs such as ACE inhibitors, beta-blockers, and diuretics may be used according to heart-failure guidelines. They reduce cardiac workload, control blood pressure, and manage fluid overload, but must be tailored to the child’s blood pressure and kidney function. -
Respiratory medications
Bronchodilators, inhaled steroids, or mucolytics may be used if there is co-existing asthma or chronic lung disease. These medicines open airways and reduce inflammation, helping breathing and reducing infection risk. Pulmonologists decide indications and dosing. -
Analgesics for pain
Paracetamol (acetaminophen) and carefully chosen non-opioid analgesics treat pain from spasticity, contractures, or procedures. Opioids may be used cautiously for severe pain, weighing respiratory and constipation risks. Pain control improves sleep, movement, and participation in therapy. -
Antidepressants / anxiolytics (when needed)
In older patients, selective serotonin reuptake inhibitors (SSRIs) or other agents may treat depression or anxiety related to chronic illness. They adjust brain neurotransmitters to improve mood, but must be chosen to avoid unsafe drug interactions and to match liver and kidney function. -
Antibiotics for infections
Bacterial infections (pneumonia, sepsis, urinary infections) are treated promptly with appropriate antibiotics, because infections can trigger metabolic decompensation in mitochondrial disease. Drug choice depends on local patterns and culture results, and kidney function is monitored closely. -
Anticoagulants or antiplatelet agents (selected cases)
If the patient develops portal-hypertension–related thrombosis or is at high risk of clots, low-dose anticoagulants or antiplatelets may be prescribed under specialist supervision. These drugs reduce clot formation but increase bleeding risk, so the decision is highly individualized. -
Vitamin and mineral prescriptions
When lab tests show deficiencies (for example vitamin D, iron, or folate), doctors prescribe specific vitamin or mineral preparations at therapeutic doses. Correcting deficiencies supports bone health, blood production, and general wellbeing, and may indirectly improve energy levels. -
Anti-reflux thickening agents and medications
In infants, milk thickeners and specific anti-reflux formulas, sometimes combined with medications, may reduce regurgitation and aspiration risk. These are chosen by pediatric gastroenterologists and dietitians. -
Emergency seizure rescue medicines (e.g., intranasal midazolam)
Families may receive a rescue plan with fast-acting benzodiazepines for prolonged seizures. These medicines are used according to emergency protocols and dosing written by the neurologist and can prevent status epilepticus and hospital admission when used correctly.
Dietary molecular supplements
Supplements are widely used in mitochondrial disease, though high-quality evidence is limited. They should only be started and dosed by specialists, as they can interact with medicines and are sometimes expensive.
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Coenzyme Q10 (ubiquinone / ubiquinol)
CoQ10 is part of the electron transport chain and acts as an antioxidant. Supplementation aims to improve electron transfer and reduce oxidative stress. Doses are weight-based and divided through the day. Some patients report better stamina or fewer headaches, but responses vary and benefits are not guaranteed. -
Riboflavin (vitamin B2)
Riboflavin is a precursor of flavin cofactors FAD and FMN, which are essential for complexes I and II. Supplementation may improve residual complex activity in some mitochondrial disorders. It is usually given in divided oral doses with meals; urine may turn bright yellow. -
Thiamine (vitamin B1)
Thiamine supports pyruvate dehydrogenase and other mitochondrial enzymes. In some energy-metabolism defects, high-dose thiamine improves symptoms. It is often included in a mitochondrial “cocktail.” Side effects are usually mild, but high doses should still be supervised. -
L-carnitine
Carnitine transports long-chain fatty acids into mitochondria for β-oxidation and helps remove toxic acyl compounds. Supplementation may improve fatigue or exercise tolerance in some mitochondrial patients. Doses are weight-based; side effects can include fishy body odor or GI upset. -
Alpha-lipoic acid
Alpha-lipoic acid is a cofactor in mitochondrial dehydrogenase complexes and acts as an antioxidant. It is sometimes used to reduce oxidative stress and neuropathic symptoms. Typical regimens are oral divided doses; it can cause nausea or skin rash in some people. -
Arginine or citrulline
These amino acids are precursors for nitric oxide. In some mitochondrial syndromes with stroke-like episodes, arginine is used to support blood-vessel dilation and tissue perfusion. In TRMT5 disease, use is individualized. Monitoring includes blood pressure and lab tests. -
Vitamin D
Vitamin D supports bone health, muscle function, and immune regulation. Many chronically ill children are deficient. Supplementation to correct deficiency is based on blood levels and local guidelines and can reduce fracture risk and may improve muscle strength. -
Folate and vitamin B12
These vitamins support DNA synthesis and methylation and are important for red-blood-cell production. If deficiency is present, supplementation helps treat anemia and may improve fatigue and cognitive function. Folate and B12 also interact with homocysteine metabolism. -
Multivitamin with trace elements
A carefully selected multivitamin may be used to cover small daily requirements when appetite is limited. This helps prevent multiple mild deficiencies that together worsen fatigue and immune function. Formulations are chosen to avoid excessive iron or fat-soluble vitamins. -
Omega-3 fatty acids
Omega-3 supplements (fish oil or plant-based) are sometimes used for cardiometabolic and neuroprotective properties. They may modestly help inflammation and lipid profiles. Doses are individualized; side effects can include fishy after-taste and, rarely, bleeding tendency at high doses.
Immunity-booster / regenerative / stem-cell–related drugs
There are no approved gene or stem-cell therapies specifically for TRMT5-related COXPD26 yet. Below are general concepts sometimes considered in mitochondrial or related conditions; all are highly specialized and experimental in this context.
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Standard childhood vaccinations
Although not a “drug” in the classic sense, scheduled vaccines are key immune “boosters” that train the immune system to fight infections such as influenza, pneumonia, and COVID-19. Protecting against infections reduces metabolic stress and hospitalizations. Vaccination plans may be slightly adapted but are usually encouraged. -
Immunoglobulin replacement (IVIG / SCIG)
If a patient also has significant antibody deficiency or autoimmune features, clinicians may consider periodic immunoglobulin infusions. IVIG provides pooled antibodies that support infection defense and modulate immune responses. Doses and intervals are individualized; side effects may include headaches, fever, and infusion reactions. -
Erythropoiesis-stimulating agents (in severe anemia)
In patients with chronic anemia not correctable by simple supplements, erythropoiesis-stimulating agents may be used to stimulate red-blood-cell production. Better oxygen-carrying capacity can support tissues stressed by mitochondrial dysfunction. These drugs require careful monitoring for hypertension and thrombosis risk. -
Growth hormone (if documented deficiency)
Some children with complex chronic diseases may have growth hormone deficiency. When confirmed by testing, replacement can improve growth and body composition. Effects on mitochondrial function are uncertain, and treatment requires close monitoring by endocrinologists. -
Experimental gene-targeted or small-molecule therapies
Research into mitochondrial disease is exploring gene therapy, RNA-based therapy, and small molecules that enhance mitochondrial biogenesis or decrease oxidative stress. As of now, no such therapy is approved specifically for TRMT5 mutations, but future clinical trials may emerge. Families can monitor trial registries with their specialists. -
Hematopoietic or mesenchymal stem-cell approaches (very experimental)
In some unrelated metabolic and immune conditions, stem-cell transplantation has been used to replace defective blood or immune cells. For TRMT5-related COXPD26, there is no established role yet. Any such approach would currently be considered experimental and only in the setting of rigorous research protocols.
Surgical and procedural treatments
Surgery does not cure the genetic problem but may address complications and improve quality of life. Decisions are individualized and balance anesthesia risks with expected benefits.
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Gastrostomy tube (PEG) placement
PEG placement creates a small opening into the stomach for long-term feeding. It is done endoscopically under anesthesia. This procedure is performed when oral feeding is unsafe or insufficient and can stabilize nutrition, reduce aspiration risk, and simplify medication delivery. -
Orthopedic surgery for contractures or scoliosis
Tendon-lengthening, release of contractures, or spinal fusion for scoliosis may be considered when deformities cause pain, pressure sores, or major functional limitation. Surgery aims to improve sitting balance, positioning, and hygiene even if walking is not possible. -
Intrathecal baclofen pump implantation
For severe generalized spasticity that does not respond to oral treatment, an intrathecal baclofen pump may be implanted. The device continuously delivers baclofen into the spinal fluid, often giving better spasticity control with fewer systemic side effects. -
Tracheostomy (selected advanced respiratory failure)
In rare, advanced cases of respiratory muscle weakness where long-term ventilation is needed, a tracheostomy may provide a more stable airway. This is a major decision involving discussions about goals of care, quality of life, and long-term support at home. -
Port or central line placement
Some patients require frequent IV medications, nutrition, or blood draws. A central venous catheter or implanted port may reduce repeated needle sticks. However, these devices increase infection and thrombus risk, so their use is limited to clear indications.
Prevention and risk reduction
Complete prevention of TRMT5-related COXPD26 is not yet possible without genetic testing, but several strategies may reduce disease burden and complications.
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Carrier and prenatal testing in high-risk families – When TRMT5 variants are known, carrier testing and prenatal or preimplantation genetic diagnosis can reduce recurrence risk.
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Avoidance of known mitochondrial toxins – Certain drugs (like valproate in some mitochondrial disorders) or environmental toxins may worsen mitochondrial function; specialists help families avoid or replace risky agents.
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Aggressive infection prevention – Vaccines, hygiene, and early treatment of illnesses reduce metabolic decompensation.
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Nutrition and hydration optimization – Avoiding fasting and dehydration lowers risk of acute metabolic crises.
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Careful anesthesia planning – Anesthesia in mitochondrial disease requires special protocols to minimize metabolic stress; families should always inform anesthetists.
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Medication review at every visit – Regular review avoids harmful interactions and unnecessary drugs that may stress mitochondria.
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Early rehabilitation – Starting PT/OT early can delay contractures and preserve function.
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Monitoring of heart, liver, and lungs – Regular screening can catch complications early when they may be easier to manage.
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Emergency plan document – Written emergency plans help local hospitals manage metabolic crises quickly and appropriately.
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Family education – Teaching families how to recognize red-flag symptoms, give rescue meds, and seek timely care is one of the strongest “preventive medicines.”
When to see a doctor or emergency department
Families should maintain regular follow-up with a mitochondrial / neuromuscular specialist, usually every few months, even when the child seems stable. Routine visits allow adjustment of therapies, monitoring of growth and labs, and early detection of complications such as cardiomyopathy, liver disease, or worsening neuropathy.
Urgent or emergency evaluation is needed for signs such as: fast worsening of weakness; new difficulty breathing; blue lips or unusual sleepiness; prolonged seizures or repeated short seizures; persistent vomiting and inability to keep fluids; sudden behavior changes; high fever not responding to usual medicines; or any sudden regression in skills. These signs may indicate infection, metabolic decompensation, or serious organ complications and require immediate care.
What to eat and what to avoid
Diet in TRMT5-related combined oxidative phosphorylation deficiency must be individualized by a dietitian and doctor. The points below are general ideas, not a fixed diet plan.
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Eat small, frequent meals – Regular meals and snacks help prevent low blood sugar and energy crashes.
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Include complex carbohydrates – Foods like rice, oats, and whole grains provide sustained energy.
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Ensure enough protein – Eggs, dairy, fish, meat, or plant proteins help maintain muscles and immune function.
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Use healthy fats – Vegetable oils, nuts, and seeds provide dense calories for children with high energy needs.
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Encourage fruits and vegetables – They supply vitamins, minerals, antioxidants, and fiber, supporting overall health.
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Avoid long fasting – Overnight fasts may need to be shortened with bedtime snacks or special feeds, depending on the care plan.
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Limit very high-sugar foods and drinks – Sudden sugar spikes can be followed by energy drops and may worsen GI symptoms.
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Be cautious with very high-protein fad diets – Extreme diets can stress kidneys and may not suit mitochondrial patients.
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Avoid alcohol and smoking exposure in older patients – These are toxic to mitochondria and many organs.
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Follow texture and swallowing recommendations – If speech therapists or dietitians recommend thickened fluids or soft foods, this helps prevent choking and aspiration.
Frequently asked questions
1. Is there a cure for TRMT5 combined oxidative phosphorylation deficiency?
Right now there is no cure that fixes the TRMT5 gene or fully restores mitochondrial function. Treatment focuses on controlling seizures, supporting breathing and feeding, preventing complications, and using mitochondrial supplements that might improve energy in some patients. Research into gene and mitochondrial therapies is ongoing but not yet specific for this disease.
2. How is this disease diagnosed?
Diagnosis usually involves clinical evaluation, brain and nerve imaging, muscle or liver biopsy in some cases, measurement of respiratory-chain enzyme activities, and genetic testing such as exome sequencing. Finding pathogenic mutations in both copies of the TRMT5 gene confirms COXPD26.
3. Why does TRMT5 cause such wide-ranging symptoms?
TRMT5 is needed to modify mitochondrial tRNA for many proteins involved in oxidative phosphorylation. When this step fails, multiple complexes cannot work well in many tissues. Brain, nerves, muscles, heart, gut, and sometimes liver and lungs all rely heavily on mitochondrial ATP, so symptoms can involve many organs.
4. Do all children with TRMT5 mutations have the same severity?
No. Reports show large variation: some children have early-onset severe disease, while others have milder, later-onset neuropathy or mainly liver-related problems. Differences in the exact variants, other genes, and environment likely influence severity.
5. Are mitochondrial supplements like CoQ10 proven to work?
Many patients with mitochondrial disease take CoQ10, riboflavin, L-carnitine, and other vitamins, and some report improved stamina or fewer hospitalizations. However, strong randomized-trial evidence is limited, and responses are individual. Doctors usually try these supplements as part of a personalized “cocktail” and monitor effect and cost.
6. Can regular exercise help or harm?
Well-planned, gentle exercise can help maintain strength and endurance and may even stimulate mitochondrial biogenesis. Over-exertion, however, can trigger severe fatigue or metabolic decompensation. Exercise plans should be made by physiotherapists and adjusted day-by-day based on how the patient feels.
7. Are seizures always part of TRMT5 disease?
Seizures are common in many mitochondrial disorders but are not universal. Some TRMT5 patients in the literature had epilepsy, while others mainly had neuropathy, spasticity, or liver disease. Electroencephalography (EEG) is used when seizures are suspected.
8. Which antiseizure medicines are safest?
There is no single “best” drug, but many specialists prefer medicines like levetiracetam or lamotrigine and try to avoid agents with known mitochondrial toxicity (for example, valproate in certain genetic backgrounds). Drug choice always depends on seizure type, age, co-morbidities, and prior response.
9. Can this disease be detected before birth?
If the exact TRMT5 mutations in the family are known, prenatal diagnosis during pregnancy or preimplantation genetic testing during IVF is technically possible. These options require careful ethical discussion and genetic counseling.
10. What is the long-term outlook (prognosis)?
Prognosis is highly variable. Some children have life-limiting disease in childhood, while others live longer with chronic disability. Early diagnosis, proactive infection control, nutritional support, and rehabilitation may improve quality of life, but exact life expectancy is hard to predict for an individual child.
11. Does diet alone make a big difference?
Diet cannot cure TRMT5 deficiency, but good nutrition supports growth, immune function, and energy balance. Avoiding fasting and providing adequate calories and protein can reduce hospitalizations and improve daily function, especially when combined with other therapies.
12. Is liver or other organ transplant an option?
For TRMT5 disease, mitochondrial dysfunction is systemic, not limited to a single organ, so isolated organ transplant (for example liver) is unlikely to correct all features. In very specific situations with severe portal hypertension or end-stage organ failure, transplant might be discussed, but there is little published experience so far.
13. Are there registries or support groups for mitochondrial disease?
Yes. Many countries have mitochondrial disease foundations, patient registries, and online support groups. While not TRMT5-specific, they connect families facing similar challenges, help with advocacy, and sometimes support travel for specialist care or trials.
14. How often should my child have follow-up tests?
Typically, mitochondrial specialists recommend regular monitoring of growth, nutrition, blood counts, liver and kidney function, heart (ECG, echocardiogram), and sometimes brain imaging or nerve studies. Frequency depends on severity and previous findings and is adjusted over time.
15. Is this information a substitute for medical care?
No. This article provides general, evidence-based education about TRMT5-related combined oxidative phosphorylation deficiency. It cannot replace personal medical advice. Every child is unique, and all treatment decisions must be made with qualified doctors who know the full medical history, exam, and test results.
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.
