Combined Oxidative Phosphorylation Deficiency Caused by Mutation in MTFMT

Combined oxidative phosphorylation deficiency caused by mutation in MTFMT (also called combined oxidative phosphorylation defect type 15 or COXPD15) is a very rare genetic disease that damages the “power stations” of the cell, called mitochondria. [1] Mitochondria make most of the body’s energy using a process called oxidative phosphorylation. In this disease, changes (mutations) in the MTFMT gene reduce the activity of an enzyme that is needed to start making mitochondrial proteins. When this enzyme does not work well, many mitochondrial respiratory chain complexes do not work properly at the same time. This is called a combined oxidative phosphorylation deficiency. [2]

Combined oxidative phosphorylation deficiency caused by mutation in MTFMT is a very rare inherited mitochondrial disease. Doctors often call it Combined oxidative phosphorylation deficiency 15 (COXPD15). In this condition, changes (mutations) in the nuclear gene MTFMT (mitochondrial methionyl-tRNA formyltransferase) disturb how mitochondria start making proteins that are needed for the respiratory chain complexes (complex I–V). As a result, many tissues, especially the brain and muscles, cannot make enough energy (ATP), which leads to neurologic problems and developmental delay.

Gene and basic mechanism

The MTFMT gene sits on chromosome 15q22.31 and makes an enzyme that adds a small “formyl” group to mitochondrial methionyl-tRNA. This step is needed to start protein synthesis inside mitochondria. When both copies of MTFMT are mutated (autosomal recessive inheritance), the enzyme works poorly or not at all. This causes combined oxidative phosphorylation deficiency, meaning that several respiratory chain complexes do not work properly, leading to lactic acidosis, white-matter brain changes, movement problems, and symptoms that can overlap with Leigh syndrome.

Because the body’s cells cannot make enough energy, organs that need a lot of energy – especially the brain, muscles, and sometimes the heart and eyes – are affected. Many children show signs that look like Leigh syndrome, a mitochondrial brain disease with problems in movement, development, and breathing, often starting in infancy or early childhood. [3]

Other names

Doctors and scientists use several other names for this condition. These names all refer to the same basic disease: problems with oxidative phosphorylation caused by mutations in MTFMT. [4]

• MTFMT combined oxidative phosphorylation deficiency [5]

• Combined oxidative phosphorylation deficiency type 15 [6]

• Combined oxidative phosphorylation deficiency caused by mutation in MTFMT [7]

• Combined oxidative phosphorylation defect type 15 [8]

• COXPD15 (short code used in many databases) [9]

Types

There is only one official disease entry for COXPD15, but doctors sometimes divide patients into “types” based on how and when the disease shows up in the body. These “types” are clinical patterns, not different genes. [10]

• Infant-onset Leigh-like type – Symptoms begin in the first years of life, with low muscle tone, developmental delay, movement problems, and brain scan changes typical of Leigh syndrome (symmetric lesions in basal ganglia or brainstem). [11]

• Childhood-onset milder type – Some children walk and speak but later develop gait ataxia (unsteady walking), mild pyramidal signs (increased reflexes, stiffness), and learning or coordination problems. They may have better survival than classic Leigh syndrome. [12]

• Neuro-eye type – Movement and learning problems plus eye movement problems such as nystagmus (jerky eye movements), strabismus (squint), and reduced vision because of brain or eye involvement. [13]

• Multi-system type – Neurologic problems plus short stature, obesity in some cases, small head size (microcephaly), and lactic acidosis (too much lactic acid in blood) showing more widespread mitochondrial failure. [14]

Causes (mechanisms and contributing factors)

In this disease, the main cause is always genetic: disease-causing variants in both copies of the MTFMT gene. Below are 20 related “causes or contributing mechanisms” described in very simple language. [15]

1. Pathogenic MTFMT mutations (general)
   The direct cause is harmful changes in the MTFMT gene. A child usually inherits one faulty copy from each parent, so both gene copies in the child are affected (autosomal recessive inheritance). [16]

2. Nonsense (stop) variants in MTFMT
   Some mutations create an early “stop” signal in the gene, so the enzyme is cut short and cannot work. This greatly reduces mitochondrial protein production and respiratory chain activity. [17]

3. Missense variants in MTFMT
   Other mutations change a single amino acid in the enzyme. Even one wrong building block can disturb enzyme shape and lower its function, leading to less efficient mitochondrial translation. [18]

4. Splice-site variants
   Some changes occur at the borders of gene regions (introns and exons). These can disturb RNA splicing so that the final MTFMT RNA is missing parts or has extra pieces, producing a faulty enzyme. [19]

5. Frameshift deletions or insertions
   Small insertions or deletions can shift the reading frame of the gene. This often makes a very abnormal or short protein that cannot support normal oxidative phosphorylation. [20]

6. Compound heterozygosity
   Many patients carry two different disease-causing variants, one on each copy of MTFMT (compound heterozygous). The combination still leads to low enzyme activity and disease. [21]

7. Homozygosity due to related parents
   In some families, parents may be related (consanguineous). This increases the chance that a child inherits the same pathogenic variant from both parents (homozygous), causing MTFMT deficiency. [22]

8. Defective mitochondrial methionyl-tRNA formyltransferase activity
   The MTFMT enzyme normally helps start protein synthesis inside mitochondria by modifying methionyl-tRNA. When this step fails, many mitochondrial proteins cannot be made properly. [23]

9. Multiple respiratory chain complex deficiencies
   Because mitochondrial proteins are needed for complexes I–IV and V, MTFMT mutations lead to reduced activity of several complexes at once. This is why it is called a “combined oxidative phosphorylation deficiency.” [24]

10. Energy failure in brain regions (Leigh-like lesions)
    The brainstem and basal ganglia need a lot of energy. When their mitochondria fail, cells die and typical Leigh-like lesions appear on MRI. This energy failure causes many neurologic symptoms. [25]

11. Accumulation of lactic acid
    When oxidative phosphorylation is weak, cells switch to glycolysis and make more lactic acid. This leads to high blood lactate and episodes of lactic acidosis, especially during illness or stress. [26]

12. Metabolic stress from infections
    Fever and infections increase the body’s energy needs. In a child with MTFMT deficiency, this extra stress can reveal or worsen symptoms, because mitochondria cannot meet the higher demand. [27]

13. Fasting or poor feeding
    Long fasting or poor feeding reduces energy intake and can trigger metabolic decompensation (lactic acidosis, lethargy) in mitochondrial diseases, including COXPD15. [28]

14. Surgical or anesthetic stress
    Operations and anesthesia can stress the body’s metabolism. In people with mitochondrial disease, this may cause worsening of lactic acidosis or neurologic problems after surgery. [29]

15. Co-existing mitochondrial DNA background
    The mitochondrial DNA background (haplogroup) can modify how severe a nuclear mitochondrial disease becomes. Different backgrounds may partly explain why some MTFMT patients are milder than others. [30]

16. Other nuclear gene modifiers
    Variants in other nuclear genes that affect mitochondria may act as modifiers. They do not cause COXPD15 alone but can change the severity of symptoms when MTFMT is already mutated. [31]

17. Oxidative stress in cells
    Poor oxidative phosphorylation can increase the production of reactive oxygen species. Extra oxidative stress can further damage mitochondria and brain cells, worsening disease over time. [32]

18. Nutritional deficiencies
    Deficiency of important vitamins or cofactors (for example, thiamine or other B vitamins) may not cause COXPD15, but can make mitochondrial function even worse in affected children if not corrected. [33]

19. Delay in diagnosis and supportive care
    Late recognition of the disease may lead to repeated metabolic crises, poor nutrition, and infections. These secondary factors increase brain injury in children whose mitochondria are already weak. [34]

20. Unknown or not yet identified factors
    COXPD15 is very rare, and only a limited number of patients have been reported. It is likely that other genetic and environmental factors still not fully known also influence who becomes severely affected. [35]

Symptoms (signs and complaints)

Not every person has all of these symptoms, but the list below gathers the most commonly reported features of combined oxidative phosphorylation deficiency caused by mutation in MTFMT. [36]

1. Global developmental delay
   Many children sit, crawl, walk, or speak later than expected. Speech and coordination are often more affected than other skills, because the brain regions that control movement and language need a lot of energy. [37]

2. Intellectual disability or learning problems
   School-age children may have difficulties with understanding, memory, or complex tasks. This comes from long-term damage to brain networks that depend on healthy mitochondria. [38]

3. Generalized hypotonia (low muscle tone)
   Babies may feel “floppy” when held. Low tone makes it hard to lift the head, sit, or walk, and often is one of the earliest signs noted by parents and doctors. [39]

4. Gait ataxia (unsteady walking)
   Children who can walk may have wide-based, wobbly steps and poor balance. This is because brain areas like the cerebellum and brainstem, which coordinate movement, are affected by energy failure. [40]

5. Spasticity or pyramidal signs
   Some patients develop increased muscle tone, stiff legs, and brisk reflexes. These “pyramidal signs” show that parts of the motor pathways in the brain and spinal cord are damaged. [41]

6. Seizures
   Abnormal bursts of electrical activity in the brain may cause seizures. They can present as staring spells, shaking episodes, or loss of consciousness, and often need anti-seizure medicines. [42]

7. Short stature
   Growth can be slower than expected, so height is below the usual range for age. Chronic energy shortage, poor nutrition during illness, and brain involvement can all contribute to short stature. [43]

8. Obesity in some patients
   Interestingly, some reported cases have obesity along with short stature. The exact reason is not fully clear but may involve changes in brain control of appetite and energy use. [44]

9. Microcephaly (small head size)
   Some children have a head size below normal charts. This can reflect reduced brain growth due to ongoing mitochondrial dysfunction during early life. [45]

10. Eye movement problems (nystagmus and strabismus)
    Eyes may move quickly and uncontrollably (nystagmus) or may not line up together (strabismus). Vision can be blurred or reduced because both the eye muscles and brain vision pathways are affected. [46]

11. Reduced visual acuity
    Some patients have difficulty seeing clearly. This may be due to damage in the optic pathways or higher visual centers in the brain affected by Leigh-like lesions. [47]

12. Lactic acidosis episodes
    At times of sickness or stress, lactic acid levels may rise, causing vomiting, rapid breathing, tiredness, and sometimes confusion. These episodes show that the mitochondria cannot keep up with the body’s needs. [48]

13. Fatigue and exercise intolerance
    Older children may tire quickly when walking or playing. Simple activities can feel very exhausting because their muscles cannot produce enough energy through oxidative phosphorylation. [49]

14. Breathing or swallowing difficulties in severe cases
    When brainstem areas are affected, children can have trouble coordinating breathing and swallowing, which increases the risk of aspiration and respiratory problems. [50]

15. Behavioral or emotional changes
    Some patients show irritability, low mood, or changes in behavior. These issues may come from a mix of brain injury, chronic illness stress, and the challenges of living with a rare disease. [51]

Diagnostic tests

Physical examination

1. General pediatric and growth examination
   The doctor checks weight, height, and head size over time, and compares them to normal charts. Short stature, obesity, or microcephaly together with developmental delay can raise suspicion of COXPD15 or another mitochondrial disease. [52]

2. Full neurologic examination
   This exam looks at muscle tone, strength, reflexes, coordination, and gait. Findings such as hypotonia, ataxia, spasticity, and pyramidal signs suggest that both the central and sometimes peripheral nervous systems are involved. [53]

3. Eye and cranial nerve examination
   The doctor checks eye movements, eye alignment, pupil reactions, and visual acuity. Nystagmus, strabismus, and decreased vision, together with neurologic findings, support a mitochondrial or Leigh-like disorder. [54]

Manual and functional tests

4. Manual muscle strength testing
   Using simple bedside tests (for example, asking the child to push or pull against resistance), the doctor grades muscle strength. Weakness, especially with low tone or fatigue, is common in mitochondrial disease and helps guide further testing. [55]

5. Coordination and gait testing (ataxia tests)
   Simple tasks such as finger-to-nose, heel-to-shin, standing with feet together, or walking in a straight line are used to test balance and coordination. Difficulty doing these tasks is a key sign of gait ataxia in COXPD15. [56]

6. Developmental and functional assessment
   Tools like structured developmental checklists or standardized scales help measure motor, speech, and cognitive milestones. Persistent delays across several domains support the suspicion of an underlying genetic or mitochondrial disorder. [57]

Laboratory and pathological tests

7. Serum lactate and pyruvate levels
   Blood tests often show high lactate, sometimes with an altered lactate-to-pyruvate ratio. Persistent or stress-induced lactic acidosis strongly suggests a mitochondrial energy production problem. [58]

8. Blood gas analysis
   Arterial or capillary blood gases can reveal metabolic acidosis (low pH, low bicarbonate) during acute episodes. This helps distinguish lactic acidosis from other causes of illness in a child with suspected mitochondrial disease. [59]

9. Metabolic screening (amino acids, organic acids, acylcarnitines)
   Urine organic acids, plasma amino acids, and acylcarnitine profiles help look for other inborn errors of metabolism and may show patterns seen in some Leigh syndrome or mitochondrial patients. [60]

10. Creatine kinase (CK) level
    CK can be normal or mildly raised. A high CK suggests some muscle breakdown but is usually not as high as in primary muscle diseases. It helps the doctor consider mitochondrial myopathy in the differential diagnosis. [61]

11. Liver function tests
    Liver enzymes and other markers may be checked, because some combined oxidative phosphorylation deficiencies can involve the liver. Abnormal results may suggest a broader systemic mitochondrial disorder. [62]

12. Targeted MTFMT gene sequencing
    The most direct test is sequencing of the MTFMT gene using next-generation sequencing (NGS). Finding disease-causing variants in both copies confirms the diagnosis of MTFMT-related combined oxidative phosphorylation deficiency. [63]

13. Mitochondrial or neuro-metabolic gene panel / exome sequencing
    If targeted testing does not give a clear answer, broader panels or whole exome sequencing can look at many mitochondrial and neurologic genes at once, increasing the chance of identifying rare causes like COXPD15. [64]

14. Muscle biopsy with respiratory chain enzyme analysis
    In some cases, a small piece of muscle is studied under the microscope and with special tests to measure mitochondrial respiratory chain complex activities. Combined reduction in several complexes supports oxidative phosphorylation deficiency. [65]

Electrodiagnostic tests

15. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity. It can show abnormal patterns or epileptic discharges in patients with seizures, helping guide treatment and supporting the presence of an underlying encephalopathy. [66]

16. Electromyography (EMG)
    EMG uses small needles or surface electrodes to study muscle activity. It may show a myopathic pattern or be near normal, but helps rule out other neuromuscular conditions and supports the overall assessment of muscle involvement. [67]

17. Nerve conduction studies
    These tests measure how fast electrical signals travel along nerves. They can detect peripheral neuropathy if present, adding more information about how widely the disease affects the nervous system. [68]

Imaging tests

18. Brain MRI (magnetic resonance imaging)
    MRI often shows bilateral symmetrical lesions in the basal ganglia, brainstem, or other deep brain structures, typical of Leigh syndrome. These characteristic patterns strongly support a mitochondrial disease like COXPD15. [69]

19. MR spectroscopy
    Magnetic resonance spectroscopy can show a lactate peak in affected brain areas, indicating abnormal energy metabolism. This non-invasive test adds support to the diagnosis of mitochondrial encephalopathy. [70]

20. Echocardiography (heart ultrasound)
    Although not always abnormal in COXPD15, an ultrasound of the heart checks for cardiomyopathy or heart dysfunction, which can occur in some combined oxidative phosphorylation deficiencies. Detecting heart involvement is important for safe clinical care. [71]

Non-pharmacological treatments

These approaches do not replace medicines when needed, but they support overall health and mitochondrial function. They must always be planned and supervised by a specialist team.

1. Individualized aerobic exercise program
   Light to moderate regular exercise (like walking, cycling, or swimming) can improve muscle strength, endurance, and quality of life in mitochondrial disease. The plan is slowly increased and carefully monitored to avoid over-fatigue and rhabdomyolysis. The purpose is to train the “healthy” mitochondria in muscle to work more efficiently, improving oxygen use and energy production. The mechanism is improved mitochondrial biogenesis, better blood flow, and better muscle conditioning.

2. Physiotherapy for motor function
   Regular physiotherapy focuses on balance, posture, stretching, and muscle strengthening. The goal is to reduce contractures, improve walking and coordination, and prevent deformities in joints and spine. Mechanistically, repeated guided movements keep muscles flexible, reduce stiffness from spasticity or hypotonia, and support neuromuscular re-training to use available motor pathways more efficiently.

3. Occupational therapy (OT)
   OT teaches practical strategies for daily activities like dressing, writing, feeding, and school tasks. The purpose is to maintain independence and adapt the environment (special grips, adapted desks, wheelchairs, bathroom aids). The mechanism is not biochemical but functional: OT breaks complex tasks into simpler steps and uses assistive tools so the child can use remaining strength and coordination effectively.

4. Speech and language therapy
   Many children with COXPD15 have speech delay, dysarthria, or swallowing difficulty. Speech therapy aims to improve articulation, breathing control for speech, and safe swallowing, and may introduce communication boards or devices if needed. Mechanistically, repeated practice strengthens speech muscles and builds new brain-speech connections, while swallowing strategies reduce aspiration risk.

5. Nutritional counselling and high-energy diet
   A dietitian experienced in mitochondrial disease designs a high-energy, well-balanced diet with adequate protein, complex carbohydrates, and healthy fats. The purpose is to prevent fasting, weight loss, and catabolism, which can worsen mitochondrial stress. Mechanistically, regular intake of calories and nutrients reduces the need for the body to break down its own tissues, lowering lactate production and helping mitochondria keep up with energy demand.

6. Avoidance of prolonged fasting and dehydration
   Families are usually advised to give frequent meals and snacks, especially during illness, and to maintain good fluid intake. The purpose is to prevent hypoglycemia and dehydration, which can trigger metabolic crises or lactic acidosis. Mechanistically, stable blood glucose and good circulation help mitochondria receive enough substrate and oxygen, reducing stress on already weak oxidative phosphorylation.

7. Emergency “sick-day” plan
   A written plan explains what to do when the child is ill (e.g., when to go to emergency, IV fluids with dextrose, avoid certain drugs). The purpose is to treat infections, vomiting, or poor intake quickly and prevent metabolic decompensation or encephalopathy. Mechanistically, early IV glucose and fluids support energy production, while avoiding mitochondrial-toxic medicines reduces extra injury to the respiratory chain.

8. Educational support and special schooling
   Cognitive issues, learning difficulties, and fatigue often need an individualized education plan (IEP) with extra time, reduced workload, or support teacher. The aim is to achieve the best possible learning outcome while respecting fatigue and hospital visits. Mechanistically, this is psychosocial: by adapting the learning environment, the child can use their cognitive abilities without excessive physical or mental stress.

9. Psychological counselling and family support
   Living with a rare chronic disease is emotionally hard. Psychologists or counsellors can help with anxiety, low mood, and coping strategies for the child and family. Mechanistically, reducing chronic stress hormones, improving sleep, and building coping skills can indirectly help energy levels and overall functioning.

10. Assistive mobility devices
    Wheelchairs, walkers, orthotic braces, and customized shoes can reduce falls, joint stress, and fatigue. The purpose is to preserve independence and protect joints and spine. Mechanistically, by mechanically supporting weak muscles and unstable joints, the devices reduce the energy cost of walking and prevent secondary musculoskeletal damage.

11. Respiratory physiotherapy and support
    If respiratory muscles are weak or if there is central breathing dysfunction, breathing exercises, cough-assist devices, and sometimes non-invasive ventilation (e.g., BiPAP at night) may be used. The purpose is to maintain good oxygen and carbon dioxide levels and prevent infections. Mechanistically, better ventilation improves oxygen delivery to tissues and reduces chronic hypercapnia, which can worsen fatigue and brain function.

12. Seizure safety education and lifestyle adjustments
    For patients with epilepsy, education about seizure first aid, avoiding sleep deprivation, and managing fever is crucial. The purpose is to reduce injury risk and seizure triggers. Mechanistically, adequate sleep and illness control reduce neuronal excitability and metabolic stress, helping keep seizures under better control.

13. Vision and hearing rehabilitation
    Some patients have eye movement problems, visual field defects, or hearing loss. Early use of glasses, low-vision aids, and hearing aids can improve communication and learning. Mechanistically, although these aids do not fix mitochondrial dysfunction, they optimize remaining sensory input, allowing the brain to function as well as possible.

14. Occupational ergonomics and energy-saving strategies
    Teaching the child to sit instead of stand, use wheeled school bags, and plan rest periods can conserve energy. The purpose is to match activity to limited energy reserves and delay fatigue. Mechanistically, lowering overall energy demand partially compensates for the reduced ATP production from impaired oxidative phosphorylation.

15. Vaccination according to specialist advice
    Routine vaccines and sometimes extra vaccines (like influenza or pneumonia vaccines) are recommended to reduce serious infections. The purpose is to prevent fever and systemic illness that can trigger metabolic crises. Mechanistically, preventing infections reduces inflammatory and metabolic stress on already fragile mitochondria.

16. Sleep hygiene and, if needed, sleep studies
    Good sleep routines and, when indicated, polysomnography (sleep study) to detect sleep apnea can be important. Treating sleep apnea with CPAP/BiPAP improves oxygenation at night. Mechanistically, good sleep and oxygen levels reduce night-time hypoxia and help mitochondria and brain recover.

17. Cardiac monitoring and lifestyle advice
    Regular echocardiograms and ECGs can detect cardiomyopathy or conduction problems early. Activity advice is adjusted if heart involvement is present. Mechanistically, early detection allows timely treatment (e.g., pacemaker, heart drugs) before decompensation, indirectly protecting brain and muscle.

18. Avoidance of known mitochondrial-toxic drugs
    Families receive lists of medicines that should be avoided or used with caution (e.g., valproic acid, some aminoglycosides, high-dose statins) unless absolutely necessary. The purpose is to avoid extra injury to mitochondrial DNA or respiratory chain complexes. Mechanistically, avoiding these agents reduces risk of liver failure, lactic acidosis, and worsening weakness.

19. Genetic counselling for the family
    Because COXPD15 is autosomal recessive, parents and siblings may want information about carrier status and future pregnancies. The purpose is informed reproductive planning and early diagnosis in future children. Mechanistically, this does not change disease biology but helps prevent repeated unexpected cases and supports early supportive care if another child is affected.

20. Participation in clinical trials or registries
    When available, joining studies for mitochondrial disease (e.g., trials of new mitochondrial-targeted therapies) can give access to experimental treatments and help research. Mechanistically, some investigational agents aim to stabilize mitochondrial membranes, improve electron transport, or reduce oxidative stress, but evidence is still emerging.

---

Drug treatments

There is no FDA-approved medicine specifically for “MTFMT-related combined oxidative phosphorylation deficiency”. Medicines are used to treat complications such as seizures, spasticity, heart problems, or metabolic crises, following general mitochondrial-disease guidelines. Below are examples; doses must always be set by the treating physician.

1. Levetiracetam (KEPPRA) – anticonvulsant for seizures
   Levetiracetam is widely used for focal and generalized seizures and is often preferred in mitochondrial epilepsy because it has no known direct mitochondrial toxicity. According to the FDA label, usual oral doses in adults range up to 3,000 mg/day in divided doses, with lower weight-based dosing in children; dose is adjusted by kidney function. Common side effects include sleepiness, dizziness, mood changes, and irritability. The mechanism is believed to involve binding to synaptic vesicle protein 2A, modulating neurotransmitter release and neuronal excitability.

2. Lamotrigine (LAMICTAL) – anticonvulsant and mood stabilizer
   Lamotrigine is another option for epilepsy and mood symptoms. The FDA label stresses very slow dose titration (for example, starting with low doses and increasing over weeks) to reduce the risk of serious skin rashes such as Stevens–Johnson syndrome. Side effects include rash, dizziness, headache, and, rarely, life-threatening skin reactions. Lamotrigine blocks voltage-sensitive sodium channels and stabilizes neuronal membranes, reducing abnormal firing. It is often chosen when valproate is avoided due to mitochondrial risks.

3. Levocarnitine (CARNITOR) – cofactor for fatty acid transport
   Levocarnitine is FDA-approved for primary and some secondary carnitine deficiencies and is often used off-label in mitochondrial disease to support fatty acid transport into mitochondria. The label describes typical oral and IV doses based on weight and serum carnitine levels. Common side effects include nausea, vomiting, and fishy body odor. Mechanistically, levocarnitine shuttles long-chain fatty acids into mitochondria and helps remove toxic acyl groups, which may improve energy production in patients with carnitine depletion.

4. Standard heart-failure drugs (e.g., ACE inhibitors, beta-blockers)
   If cardiomyopathy or heart failure develops, doctors may use standard heart medications such as ACE inhibitors (e.g., enalapril), beta-blockers (e.g., carvedilol), and diuretics, according to heart-failure guidelines and FDA-approved labelling for each drug. These medicines reduce heart workload, improve pumping efficiency, and control fluid overload. Mechanistically, they modulate neurohormonal pathways (renin–angiotensin–aldosterone system, sympathetic nervous system) to improve cardiac output and symptoms.

5. Antispasticity agents (e.g., baclofen)
   For spasticity and muscle stiffness, agents like baclofen (a GABA_B receptor agonist) may be used; baclofen reduces excessive reflex activity in spinal motor neurons. The purpose is easier movement, less pain, and improved comfort. Side effects can include drowsiness and weakness. Dosing and monitoring follow the FDA label and neurology guidelines, but therapy must be carefully balanced so that muscle tone is reduced without causing dangerous weakness.

6. Antiemetics and GI motility drugs (e.g., ondansetron)
   Nausea, vomiting, or gastroparesis may be managed with drugs such as ondansetron, which blocks serotonin 5-HT3 receptors, or pro-motility agents, following their FDA labels. The aim is to maintain oral intake and prevent dehydration. Mechanistically, these medicines act on gut and brainstem receptors to reduce vomiting and improve gastric emptying, indirectly protecting against metabolic decompensation by improving nutrition and hydration.

7. Analgesics and antipyretics (e.g., acetaminophen/paracetamol with caution)
   Fever and pain management is important because high fever increases metabolic demand and seizure risk. Drugs like acetaminophen are used within label-approved doses to control pain and temperature. The mechanism is central inhibition of prostaglandin synthesis. In mitochondrial patients, clinicians monitor liver function carefully and avoid overdosing to reduce risk of hepatotoxicity.

8. Bronchodilators and inhaled therapies (if respiratory involvement)
   In children with reactive airway disease or respiratory muscle weakness, inhaled bronchodilators and sometimes steroids may be used according to standard respiratory guidelines. Their purpose is to improve airflow, reduce wheeze, and support oxygenation. Mechanistically, they relax airway smooth muscle and reduce inflammation, helping maintain adequate gas exchange for tissues with impaired mitochondrial function.

9. Emergency IV dextrose and electrolytes
   During acute decompensation, hospital teams often use IV fluids containing dextrose (glucose) with electrolytes based on metabolic guidelines. These are not disease-specific drugs but life-saving supportive treatments. Mechanistically, IV glucose supplies immediate fuel for glycolysis, helping maintain ATP production even when mitochondrial oxidative phosphorylation is impaired, and helps correct lactic acidosis and dehydration.

10. Careful avoidance or restricted use of valproic acid
    Valproic acid is an effective antiepileptic drug but is relatively contraindicated in many mitochondrial diseases because it can cause severe liver failure and worsening disease, especially in POLG-related disorders. FDA labels highlight mitochondrial-disease warnings, and recent reviews and guidelines recommend avoiding it when possible. The mechanism of harm includes interference with fatty acid metabolism and mitochondrial toxicity. In MTFMT-related disease, specialists usually choose safer alternatives unless no other option controls seizures.

(In practice, many additional drugs may be used for individual symptoms – for example, anti-reflux drugs, laxatives, or antidepressants – but they are not specific treatments for the mitochondrial defect itself.)

---

Dietary molecular supplements

Evidence for supplements in mitochondrial disease is mixed, but many centers use them as part of a “mitochondrial cocktail.” Always discuss doses with a specialist.

1. Coenzyme Q10 (ubiquinone/ubiquinol) – Supports electron transport in the respiratory chain and acts as an antioxidant. Typical doses in mitochondrial disease are weight-based and higher than normal multivitamin doses. Mechanistically, CoQ10 carries electrons between complexes I/II and III, which may improve ATP production in some patients.

2. Riboflavin (vitamin B2) – Precursor of FAD and FMN, which are cofactors for complex I and II enzymes. Supplementation may help some complex I/II-related disorders. Mechanistically, it increases availability of flavin cofactors needed for redox reactions in mitochondrial enzymes.

3. Thiamine (vitamin B1) – Cofactor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. In some mitochondrial disorders with lactic acidosis, thiamine may improve pyruvate handling and reduce lactate. Mechanistically, it supports entry of pyruvate into the Krebs cycle, indirectly supporting oxidative phosphorylation.

4. L-carnitine (oral) – Overlaps with drug use above; given orally as part of the cocktail to support fatty acid transport and clearing of toxic acyl compounds, especially if carnitine levels are low.

5. Alpha-lipoic acid – A mitochondrial antioxidant that participates in energy metabolism. It may help reduce oxidative damage to mitochondrial membranes and enzymes, although evidence is limited.

6. Creatine – Acts as a phosphate buffer in muscle, storing high-energy phosphate groups as phosphocreatine. Supplementation may improve muscle strength and exercise tolerance by enhancing rapid ATP regeneration in muscle cells.

7. Arginine – In certain mitochondrial disorders (especially MELAS), arginine can help treat or prevent stroke-like episodes by improving nitric oxide–mediated blood flow. Its role in COXPD15 is less clear but may be considered in specific situations.

8. Vitamin C and vitamin E – Antioxidant vitamins that may help neutralize reactive oxygen species generated by dysfunctional mitochondria. Mechanistically, they protect lipids and proteins from oxidative damage, which could preserve mitochondrial and cellular membranes.

9. Folate (vitamin B9) and vitamin B12 – Support one-carbon metabolism and red-blood-cell production. Folate and B12 supplementation can be important if deficiency is present and may help reduce homocysteine levels and support neurologic function.

10. Combination mitochondrial “cocktails” – Many centers use combinations of CoQ10, riboflavin, thiamine, L-carnitine, alpha-lipoic acid, and vitamins C/E rather than single agents. The idea is that multiple small benefits may add up. Evidence varies, but these combinations are often tried because side effects are usually mild when monitored.

---

Immunity-booster / regenerative / stem-cell-related drugs

For COXPD15, there are no approved stem-cell or regenerative drugs that correct the genetic defect. Below are concepts sometimes discussed in mitochondrial disease research or care; they are mostly experimental or supportive.

1. Standard vaccines (not a “drug booster” but key for immunity) – Routine and sometimes additional vaccines protect against infections and indirectly “boost” the immune defense by preparing the immune system against specific germs. Preventing infections reduces metabolic stress on mitochondria.

2. Immunoglobulin therapy (IVIG) in selected cases – If a patient has proven antibody deficiency or immune dysregulation, IVIG may be used per immune-deficiency guidelines. It supplies pooled antibodies to fight infections. Evidence is case-based rather than specific to MTFMT mutations.

3. Experimental mitochondria-targeted drugs (e.g., elamipretide) – Agents like elamipretide have been studied for mitochondrial myopathies; they bind to cardiolipin in the inner mitochondrial membrane and may stabilize respiratory chain function. Regulatory reviews show they are still investigational and not approved for general mitochondrial disease or COXPD15.

4. Hematopoietic stem-cell transplantation (HSCT) for specific immune or marrow problems – HSCT is not a standard treatment for COXPD15 itself but may be considered in other genetic diseases with bone-marrow failure or severe immune defects. It replaces the blood-forming system with donor stem cells. In COXPD15, this would not correct mitochondrial dysfunction in brain and muscle.

5. Gene-therapy and mitochondrial-replacement research – Experimental gene-editing and mitochondrial-replacement techniques are under investigation for some mitochondrial disorders, mostly at research level and not as routine therapy for COXPD15. The idea is to correct or bypass the genetic defect, but safety and long-term effects are still being studied.

6. General immune health (sleep, nutrition, infection control) – Good sleep, balanced diet, prompt treatment of infections, and avoidance of smoking or second-hand smoke support normal immune function. These “regenerative” approaches work by reducing chronic stress and inflammation, helping the body recover day by day.

---

Surgeries

Surgery does not treat the gene defect but can manage complications. Decisions are individualized and require careful anesthetic planning in mitochondrial disease.

1. Gastrostomy tube (G-tube) placement
   When oral intake is unsafe or insufficient because of swallowing issues, poor weight gain, or extreme fatigue, a gastrostomy tube can be placed directly into the stomach. This allows safe feeding and medication delivery, reduces aspiration risk, and stabilizes nutrition.

2. Orthopedic surgery for contractures or scoliosis
   If spasticity or muscle weakness causes severe joint contractures or scoliosis that interfere with sitting, standing, or breathing, orthopedic procedures (tendon releases, spinal fusion) may be considered. The aim is better posture, comfort, and lung function.

3. Strabismus surgery
   Some patients have eye misalignment (strabismus) that affects vision and causes double vision. Eye-muscle surgery can straighten the eyes, improving visual function and quality of life, especially when done early.

4. Epilepsy surgery (rare)
   In very resistant focal epilepsy with a clear structural lesion, epilepsy surgery may be discussed. In mitochondrial disease this is rare and must be weighed carefully against anesthesia risks, but it may reduce seizure burden in selected cases.

5. Cardiac device implantation (e.g., pacemaker)
   If conduction problems or arrhythmias are present, a pacemaker or other cardiac device may be implanted. This keeps heart rhythm stable, prevents fainting, and reduces risk of sudden cardiac events.

All these procedures require experienced anesthesiologists who understand mitochondrial disease and can avoid prolonged fasting, hypothermia, and mitochondrial-toxic drugs during surgery.

---

Prevention and lifestyle

You cannot currently prevent being born with MTFMT mutations, but you can reduce complications:

1. Avoid prolonged fasting; give small, frequent meals.

2. Treat infections early; follow a written emergency plan.

3. Keep vaccinations up to date after discussion with specialists.

4. Avoid or be very cautious with mitochondrial-toxic medicines (e.g., valproate, certain aminoglycosides).

5. Maintain good hydration, especially in hot weather or during illness.

6. Encourage gentle, regular physical activity within the child’s limits.

7. Protect sleep and treat any sleep-disordered breathing.

8. Provide psychological and educational support to reduce stress.

9. Use sun and heat protection to avoid extra fatigue and dehydration.

10. Offer genetic counselling for future pregnancy planning.

---

When to see a doctor urgently

Someone with combined oxidative phosphorylation deficiency caused by MTFMT mutation should seek urgent medical care if they have:

• Sudden change in consciousness, confusion, or new seizures.

• Fast breathing, trouble breathing, or blue lips/face.

• Severe vomiting or diarrhea with inability to keep fluids down.

• High or persistent fever or signs of serious infection.

• Sudden loss of skills (walking, talking) or new weakness or ataxia.

• Chest pain, palpitations, or fainting.

Regular follow-up with a mitochondrial disease specialist, neurologist, cardiologist, and other team members is also essential even when the child seems stable.

---

Diet – what to eat and what to avoid

1. Eat frequent, balanced meals with complex carbs (rice, whole grains), lean protein, and healthy fats to maintain steady energy.

2. Include nutrient-dense foods such as fruits, vegetables, and dairy or alternatives to supply vitamins and minerals needed for mitochondrial enzymes.

3. Ensure enough fluids (water, oral rehydration solutions) daily; more during fever or hot weather.

4. Consider medical-grade formulas or high-energy drinks if oral intake is poor, under dietitian supervision.

5. Limit very high-sugar drinks and junk food that give quick spikes then crashes in blood sugar.

6. Avoid long periods without food, especially overnight; sometimes a bedtime snack or slow-release carbohydrate is recommended.

7. Avoid crash diets or weight-loss programs, which can cause dangerous catabolism and worsen muscle weakness.

8. Be cautious with herbal supplements not reviewed by the care team; some may interact with medicines or stress the liver.

9. Follow any fluid or salt restrictions carefully if heart or kidney problems are present.

10. Work closely with a dietitian experienced in metabolic or mitochondrial disease to tailor the plan over time.

---

FAQs

1. Is combined oxidative phosphorylation deficiency caused by MTFMT mutation curable?
   At present, there is no cure that corrects the genetic defect. Treatment focuses on managing symptoms, supporting nutrition and development, and preventing complications using general mitochondrial-disease care standards.

2. How is this condition inherited?
   It is usually autosomal recessive. This means a child is affected when they inherit one non-working MTFMT copy from each parent. Parents are typically healthy carriers.

3. What are common symptoms?
   Symptoms can include developmental delay, low muscle tone, gait ataxia, seizures, learning difficulties, and MRI changes in deep brain structures. Severity varies widely between individuals.

4. Why is lactic acid sometimes high in this disease?
   When mitochondria cannot make enough ATP through oxidative phosphorylation, cells switch more to anaerobic glycolysis, which produces lactate. This can lead to elevated blood or CSF lactate and metabolic acidosis.

5. Does every patient need the same “mitochondrial cocktail”?
   No. Supplement combinations and doses are individualized based on symptoms, lab results, tolerance, and specialist preference. Some patients feel better; others may not notice clear changes.

6. Are CoQ10 and other supplements FDA-approved for this specific disease?
   Most supplements (CoQ10, creatine, alpha-lipoic acid) are not FDA-approved specifically for mitochondrial disease and are used off-label based on limited studies and expert opinion.

7. Why is valproic acid usually avoided?
   Valproic acid can be mitochondrial-toxic, causing liver failure and serious worsening in some mitochondrial diseases, especially with POLG mutations. Because safer seizure medicines exist, guidelines recommend avoiding valproate when possible.

8. Can children with this disease go to regular school?
   Many can, with support such as adapted schedules, special education services, and physical aids. The school plan should be flexible and updated as the child’s needs change.

9. Will the disease always get worse?
   The course is variable. Some children have relatively stable symptoms; others may slowly worsen or have episodes of regression during illness. Close follow-up helps detect and manage changes early.

10. Is pregnancy possible in the future for someone with this condition?
    This depends on the person’s overall health, heart function, and independence. With good pre-pregnancy counselling and monitoring, some women with mitochondrial disease can have pregnancies, but risks must be carefully reviewed with specialists.

11. Should brothers and sisters be tested?
    Genetic counselling can help families decide. Testing siblings for carrier or affected status may be useful, especially if they have mild symptoms, or for future reproductive planning.

12. Can lifestyle really make a difference if the gene is faulty?
    Yes. While lifestyle cannot fix the gene, careful management of nutrition, exercise, sleep, infections, and medications can significantly reduce complications and improve function and quality of life.

13. Are clinical trials available?
    Some trials for mitochondrial disease (e.g., new mitochondrial-targeted drugs) may accept patients with various genetic causes. Eligibility depends on age, symptoms, and location. Families can ask their specialist or look at clinical-trial registries.

14. What type of doctors should be involved in care?
    A multidisciplinary team is ideal, including a mitochondrial specialist or metabolic geneticist, neurologist, cardiologist, dietitian, physiotherapist, occupational and speech therapists, and psychologist.

15. Is it safe to use information from the internet to change treatment?
    No. Online information is only for education. Any change in medicines, supplements, or diet must be discussed with the child’s own medical team, because each patient’s situation is unique.

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

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

Last Updated: February 19, 2025.