Combined Oxidative Phosphorylation Deficiency Caused by Mutation in C12orf65

Combined oxidative phosphorylation deficiency caused by mutation in C12orf65 is a very rare genetic disease of the mitochondria, the “power plants” inside our cells. [1] It belongs to a group of conditions called combined oxidative phosphorylation deficiencies, where several parts of the energy-making chain in mitochondria do not work well at the same time. [1][2] Because of this, cells cannot make enough energy, especially in the brain, eyes, and nerves, which need a lot of energy to work properly. [1][3]

Combined oxidative phosphorylation deficiency caused by mutation in C12orf65 (also called combined oxidative phosphorylation deficiency type 7, COXPD7) is a very rare genetic mitochondrial disease. In this condition, cells cannot make enough energy (ATP) in their mitochondria, especially in brain, eyes, and nerves. This disease happens when a person inherits harmful changes (mutations) in both copies of the C12orf65 gene on chromosome 12. It follows an autosomal recessive pattern, so parents are usually healthy carriers. The faulty gene affects mitochondrial protein translation and blocks normal oxidative phosphorylation, the final step of energy production.

Most people with C12orf65-related combined oxidative phosphorylation deficiency show early problems like optic atrophy (damage to the optic nerve), developmental delay, muscle weakness, spasticity (stiff muscles), and sometimes Leigh-like brain lesions on MRI. Some children also have trouble moving their eyes, swallowing, and keeping balance.

In this disease, both copies of the C12orf65 gene are changed (mutated). [1][4] The gene normally helps the mitochondria finish making their proteins during a step called translation. [4][5] When the gene does not work, some mitochondrial proteins are not made correctly, and important enzyme complexes (especially complex I and IV of the respiratory chain) become weak or low. [1][5] This lack of energy can cause problems like delayed development, loss of skills, muscle weakness, vision loss, and movement problems. [1][2][5]

This condition is inherited in an autosomal recessive way. [2] A child usually becomes sick only when they receive one faulty C12orf65 gene from each parent. [2][4] The parents are usually healthy carriers and often do not know they have the gene change. [2][6]

Other names

Doctors and researchers use several other names for this condition. [1] It is often called “combined oxidative phosphorylation deficiency 7 (COXPD7)”, which is its numbered place in this disease group. [1][2] Some articles also use “combined oxidative phosphorylation defect type 7”, or simply “C12orf65 combined oxidative phosphorylation deficiency”. [2][3] Because the gene C12orf65 is now also called MTRFR (mitochondrial translation release factor in rescue) in some databases, you may also see the disease linked with this name. [4][5] A few sources describe it as “severe C12orf65-related combined oxidative phosphorylation defect” when the symptoms are very strong and start early in life. [2][6] All these names point to the same basic problem: a mitochondrial energy disease caused by C12orf65 mutations. [1][2]

Types

Researchers have seen that C12orf65-related disease can look different from one family to another. [1] The main problem is the same (weak mitochondrial energy), but the exact set of symptoms and their strength can vary. [1][2] Many experts now think of several clinical “forms” or types, based on the main signs: [4][5]

• Early-onset encephalomyopathy type – babies or young children have poor muscle tone, delayed development, brain changes on MRI, and crisis episodes that look like Leigh syndrome. [1][3]

• Optic atrophy with spastic paraparesis type (Behr-like) – main problems are early vision loss from optic nerve damage and stiff, weak legs (spastic paraparesis); walking slowly worsens over time. [2][4]

• Optic atrophy with peripheral neuropathy type – children or young adults have optic atrophy and damage to the long nerves in the legs and arms; this causes foot weakness, thin leg muscles, and problems with balance. [2][5]

• Distal motor neuropathy with pyramidal signs type – some patients mainly have weakness in the feet and hands, plus signs of damage to the brain motor pathways (such as increased reflexes and stiffness). [5][6]

• Leigh-like brainstem lesion type – a group of patients have early optic atrophy, mild delay, and later develop typical symmetrical lesions in the brainstem and deep brain areas, similar to classic Leigh syndrome. [3][4]

These types are not strict boxes but patterns that help doctors describe how the disease looks in each person. [2][4]

Causes (genetic and medical factors )

The root cause of this disease is always a mutation in both copies of the C12orf65 gene, but doctors describe many related genetic and medical factors as “causes” or contributors. [1][2]

1. Homozygous frameshift mutation in C12orf65 – a small deletion or insertion shifts the reading frame and creates a short, non-working protein. [1][3] This has been reported in several families. [1][3][4]

2. Homozygous nonsense mutation – a single base change makes a “stop” signal too early in the gene, so the protein is cut short and cannot do its job. [2][3]

3. Compound heterozygous mutations – some patients inherit two different harmful mutations (for example one frameshift and one nonsense change) in C12orf65, one from each parent. [3][6]

4. Splice-site mutations – changes at the edges of exons can cause skipping of an exon (such as exon 2) and remove important parts of the protein. [4]

5. Truncation of the C-terminal part of the protein – many disease variants cut off the tail end of the C12orf65 protein, which is needed for normal mitochondrial translation rescue. [4][5]

6. Damage to the GGQ-like functional domain – this small motif is important for stopping protein synthesis; when it is missing, mitochondrial proteins may not be released correctly, and they stay incomplete. [4][5]

7. Reduced mitochondrial protein translation – because C12orf65 is a mitochondrial translation factor, its loss leads to reduced production of several proteins that form complexes of the respiratory chain. [1][4]

8. Decreased activity of respiratory chain complexes I and IV – muscle biopsies from patients often show low enzyme activity of these two complexes, which strongly cuts down ATP production. [1][3]

9. Autosomal recessive inheritance (two mutated copies) – disease appears when a child inherits a faulty gene from each healthy carrier parent. This pattern is a key cause at the family level. [2][6]

10. Carrier parents with no symptoms – because carriers are usually healthy, the gene change can silently pass through generations until two carriers have a child together. [2]

11. Consanguinity (parents related by blood) – when parents are related, they have a higher chance of carrying the same rare mutation, so the risk of a homozygous child rises. [3][6]

12. Early start of mitochondrial damage in brain and optic nerve – in many cases, energy failure begins in early childhood, which makes the disease severe and leads to developmental delay. [1][3]

13. Energy failure in long motor and sensory nerves – lack of ATP in long nerves causes axonal neuropathy, muscle wasting, and weakness in legs and arms. [4][5]

14. Damage to upper motor pathways (pyramidal tracts) – low energy in these brain tracts can cause stiffness and spastic paraparesis in the legs. [4][5][6]

15. Energy failure in brainstem and basal ganglia – some patients develop Leigh-like lesions in these areas, leading to breathing problems, eye movement problems, and swallowing issues. [3]

16. Lactic acidosis – because mitochondria cannot use oxygen well, cells make more energy through anaerobic pathways and produce extra lactic acid; this can worsen symptoms and crises. [1][3]

17. Muscle mitochondrial dysfunction – small muscle samples show many abnormal mitochondria and reduced respiratory chain activity, which contributes to poor tone and tiredness. [1][4]

18. Optic nerve vulnerability – the optic nerve has very high energy demands; when mitochondria fail, these fibers degenerate and cause optic atrophy and vision loss. [2][5]

19. Peripheral nerve vulnerability – long motor and sensory nerves also need steady energy, so mitochondrial failure in these cells leads to neuropathy with weakness, numbness, and loss of reflexes. [4][5][6]

20. Natural variation between mutations (genotype–phenotype effect) – different C12orf65 mutations may cause different levels of residual protein activity, which explains why some patients have milder or more severe disease. [4][6]

These “causes” describe how gene changes and energy problems together lead to the visible disease. External lifestyle factors have very little influence compared with the strong genetic effect, although good general health care may support the patient. [1][2]

Symptoms

Not every person has all of these symptoms, but the signs below are commonly reported in C12orf65-related combined oxidative phosphorylation deficiency. [1][2]

1. Optic atrophy – this means the optic nerve, which carries signals from the eye to the brain, becomes thin and pale. [1][2] Children often start to have poor vision early in life, and eye exam shows pale optic discs. [1][2][5]

2. Loss of visual acuity – many patients cannot see fine details; they may hold books very close, bump into things, or have trouble at school because they cannot see the board clearly. [2][5]

3. Nystagmus and other eye movement problems – some children have fast, uncontrolled eye movements (nystagmus) or limited eye movement (ophthalmoplegia), which makes focusing and tracking objects hard. [1][3][4]

4. Developmental delay – sitting, standing, walking, or talking may happen later than in other children, because the brain and muscles do not get enough energy for normal growth and learning. [1][3]

5. Psychomotor regression – some children first develop normally and then lose skills they had already learned, such as walking or speaking, when the disease becomes more active. [1][2][3]

6. Spastic paraparesis – this means the legs become stiff and weak. [2][4] Children may walk with a scissoring gait, have trouble running, or need support to walk long distances. Reflexes in the legs are often very brisk. [2][4][6]

7. Peripheral neuropathy – damage to the long nerves causes weakness, especially in the feet and lower legs, loss of ankle reflexes, numbness, or tingling. [4][5] Over time the muscles in the legs can become thin (atrophy). [4][6]

8. Ataxia and poor balance – some patients have shaky or unsteady movement, stumble easily, or have trouble with tasks that need fine coordination, such as buttoning clothes. [1][4]

9. Muscle weakness and hypotonia – muscles may feel floppy in babies (low tone) or weak in older children. [1][3] Children may struggle to stand up from the floor or climb stairs. [1][3]

10. Bulbar symptoms (swallowing and speech problems) – when the brainstem and bulbar nerves are affected, children may have nasal speech, difficulty chewing or swallowing, choking episodes, or drooling. [1][3]

11. Leigh-like episodes – some patients have episodes with vomiting, fast breathing, abnormal eye movements, or sudden loss of skills, and brain imaging shows symmetric lesions in deep brain and brainstem areas, similar to Leigh syndrome. [3][5]

12. Intellectual disability or learning problems – many, but not all, patients have mild to moderate intellectual disability or struggle with school tasks that need concentration and memory. [2][4]

13. Seizures (in some patients) – not every child has seizures, but some reports describe epileptic attacks, especially when brain lesions are more severe. [3][6]

14. Growth and feeding problems – poor feeding, low weight gain, or short stature can occur because of increased energy needs, trouble swallowing, and chronic illness. [1][3]

15. Fatigue and reduced exercise tolerance – even mild activity can quickly cause tiredness and shortness of breath, because muscles cannot produce enough ATP during effort. [1][2]

The exact mix of these symptoms is different in each family, but vision problems, leg stiffness, and nerve problems are considered the central triad in many patients. [2][4][5]

Diagnostic tests

Because this is a rare and complex disease, diagnosis usually needs several kinds of tests. [1][2] Doctors combine the story from the family, the physical exam, and special lab and imaging tests, and finally confirm with genetic testing. [1][2][3]

Physical exam tests

1. Full neurological examination – the doctor checks muscle strength, muscle tone, reflexes, coordination, and sensation in all limbs. [1] In C12orf65 disease, they may find weak distal muscles, increased reflexes in the legs, spasticity, or reduced sensation. [2][4]

2. Gait and posture assessment – watching how the child stands and walks helps reveal spastic gait (stiff, scissoring steps) or foot drop from neuropathy. [2][4] The doctor may ask the child to walk on heels or toes and to turn quickly. [4][6]

3. Ophthalmologic clinical examination – an eye specialist looks at visual acuity, eye movements, and pupil responses. [1][2] Early optic atrophy and sometimes nystagmus or ophthalmoplegia are common clues. [1][2][5]

4. Developmental and cognitive assessment – simple bedside tests or formal developmental scales help see if there is delay or regression in motor and language skills or learning problems at school. [1][3]

Manual tests (bedside functional tests)

5. Manual muscle strength testing – the doctor tests power in arms and legs by asking the patient to push or pull against resistance. [1] This helps grade weakness, which is often worse in the feet and lower legs in this disease. [4][5]

6. Manual tone and spasticity testing – by moving the joints, the doctor feels if there is stiffness that increases with faster movement, which is a sign of spasticity in the legs. [2][4]

7. Deep tendon reflex testing with a hammer – tapping the knees and ankles shows whether reflexes are absent (often in neuropathy) or exaggerated (as in spastic paraparesis). [2][4] In C12orf65 disease, mixed findings can appear. [4][6]

8. Manual coordination tests – simple tests like finger-to-nose, heel-to-shin, or rapid alternating movements help show ataxia and poor coordination that may result from cerebellar or sensory pathway involvement. [1][4]

Lab and pathological tests

9. Blood lactate and pyruvate levels – high lactate in blood at rest or after exercise suggests a mitochondrial energy problem. [1][3] Many patients with COXPD7 show elevated lactate, and sometimes a high lactate-to-pyruvate ratio. [1][3]

10. Serum creatine kinase (CK) – CK may be normal or mildly raised; checking it helps rule out primary muscle diseases and supports the overall view of neuromuscular involvement. [1][3]

11. Comprehensive metabolic panel and amino acids – basic blood and urine tests help look for other metabolic problems and rule out more common causes of developmental delay and neuropathy. [1][2]

12. Respiratory chain enzyme analysis in muscle biopsy – a small piece of muscle is studied to measure the activity of mitochondrial complexes. [1] In COXPD7, complexes I and IV are often reduced, showing combined oxidative phosphorylation deficiency. [1][4]

13. Muscle histology and electron microscopy – under the microscope, doctors may see abnormal mitochondria, ragged-red fibers, or other signs of mitochondrial myopathy. [1][3] This supports a mitochondrial origin of the disease. [1][3]

14. Molecular genetic testing of C12orf65 – sequencing of the C12orf65 gene (or gene panels/exome) is the key test to confirm the diagnosis. [2][4] It can detect homozygous or compound heterozygous pathogenic variants in the gene. [2][6]

15. Segregation analysis in the family – once a mutation is found, testing parents and siblings helps show that each parent carries one copy and the affected child has two copies. [2] This confirms autosomal recessive inheritance and guides family planning. [2][6]

Electrodiagnostic tests

16. Nerve conduction studies (NCS) – electrodes on the skin measure how fast and how strongly signals travel along the nerves. [4][5] In C12orf65 disease, NCS often show an axonal peripheral neuropathy, especially in the motor nerves of the legs. [4][5]

17. Electromyography (EMG) – a fine needle in the muscle records electrical activity. [4] EMG can show signs of chronic denervation and reinnervation, which is typical of axonal neuropathy, and helps separate nerve from muscle disease. [4][6]

18. Electroencephalogram (EEG) – if seizures or episodes of altered awareness occur, EEG records brain electrical activity and can show epileptic discharges or diffuse slowing caused by brain dysfunction. [3][6]

Imaging tests

19. Brain MRI – MRI is very important. [1][3] Many patients show symmetrical lesions in the basal ganglia and brainstem, sometimes looking like classic Leigh syndrome. [1][3][5] MRI may also show brain atrophy or optic nerve thinning. [3][5]

20. Magnetic resonance spectroscopy (MRS) – this special MRI technique looks at brain chemicals. [3] In COXPD7, MRS can show a lactate peak in the affected brain areas, which is a strong sign of mitochondrial energy failure. [3][6]

In many reported patients, the final diagnosis of “combined oxidative phosphorylation deficiency type 7 caused by C12orf65 mutation” is made only after combining these findings and confirming the genetic change. [1][2][3]

Non-pharmacological treatments (Therapies and others)

1. Physiotherapy and gentle stretching
   Regular physiotherapy helps keep joints flexible, muscles less stiff, and posture better. Simple daily stretching, range-of-motion exercises, and guided play-based movement reduce contractures and help children keep as much mobility as possible. The main purpose is to prevent loss of movement and reduce pain by keeping muscles and tendons from becoming short and rigid.

2. Occupational therapy
   Occupational therapists teach easier ways to do daily tasks like dressing, feeding, and writing. They may suggest special tools, grips, or adapted cutlery. The purpose is to keep the child as independent as possible. The mechanism is practical: changing the task or tools so that weak or stiff muscles do not limit life activities.

3. Speech and swallowing therapy
   Speech-language therapists help with delayed speech, weak voice, and swallowing problems. They use exercises to strengthen mouth and throat muscles and teach safe eating positions. The purpose is to improve communication and reduce choking or food going “down the wrong way,” lowering the risk of pneumonia.

4. Low-intensity aerobic exercise
   Very gentle, carefully supervised exercise such as slow cycling or short walks can improve stamina without over-tiring the child. The purpose is to train muscles to use oxygen more efficiently. The mechanism is gradual conditioning of remaining healthy mitochondria and improved blood flow to muscles.

5. Energy-conservation training
   Therapists teach “pacing”: planning the day, taking breaks, and sitting when possible to save limited energy. The purpose is to avoid sudden exhaustion. The mechanism is behavioral—matching activity level to the child’s reduced mitochondrial energy supply so that they do not “crash” after small tasks.

6. Assistive mobility devices
   Walkers, standing frames, wheelchairs, and ankle-foot orthoses can support weak or spastic legs. The purpose is safer mobility and prevention of falls. These devices work by giving mechanical support and stabilizing joints, so the child can move using less muscle power and better alignment.

7. Vision rehabilitation and low-vision aids
   Because optic atrophy is common, children may need glasses, magnifiers, high-contrast reading materials, or electronic readers. The purpose is to make the most of remaining vision. The mechanism is simple optics: enlarging print, increasing contrast, and improving lighting so visual signals are easier for damaged optic nerves to use.

8. Nutritional counseling
   Dietitians design meals with enough calories, protein, vitamins, and fluids, adjusted to swallowing ability and energy needs. The purpose is to prevent weight loss and malnutrition, which can worsen muscle weakness. The mechanism is providing all needed nutrients so that remaining mitochondria can work as well as possible.

9. Gastrostomy feeding support (non-drug aspect)
   If swallowing is unsafe or exhausting, a feeding tube into the stomach (PEG) can be used. The therapy includes teaching families how to give feeds, keep the tube clean, and prevent aspiration. The purpose is safe, reliable nutrition. It works by bypassing weak mouth and throat muscles.

10. Respiratory physiotherapy
    Chest physiotherapy, breathing exercises, and devices that help clear mucus can support weak breathing muscles. The purpose is to prevent chest infections and improve oxygen levels. The mechanism is mechanical: helping move secretions, expanding lungs, and training breathing muscles.

11. Orthopedic management and splinting
    Splints, braces, and sometimes casting are used to correct or slow deformities of feet, ankles, or knees caused by spasticity and muscle imbalance. The purpose is better alignment and easier walking or standing. The mechanism is continuous gentle positioning of joints in more normal angles.

12. Psychological support and counseling
    Living with a chronic rare disease is stressful for child and family. Counseling, support groups, and school-based emotional support can reduce anxiety and depression. The purpose is mental well-being. The mechanism is talk therapy, coping skills, and social support that help families manage long-term uncertainty.

13. Individualized education plans (IEP)
    Children often need extra help at school for learning or physical access. An IEP can include extra time, note-takers, or breaks. The purpose is fair education despite disability. The mechanism is adjusting the learning environment so the child’s cognitive strengths are used and fatigue is respected.

14. Temperature and infection control
    Parents learn how to avoid extreme heat, cold, and infections, because fever and illness can worsen symptoms. The purpose is to prevent metabolic stress. The mechanism is practical: handwashing, vaccines, avoiding sick contacts, and early treatment of minor infections.

15. Sleep hygiene and positioning
    Good sleep habits, comfortable positioning, and sometimes special mattresses or cushions help reduce pain and night-time breathing problems. The purpose is deeper, more restorative sleep. The mechanism is reducing pressure points, supporting weak muscles, and promoting regular sleep cycles.

16. Spasticity management with stretching and heat
    Warm baths, heat packs, and slow stretching can relax tight muscles. The purpose is to reduce stiffness and pain without drugs when possible. The mechanism is warmth-induced muscle relaxation and gentle lengthening of muscle fibers.

17. Balance and coordination training
    Simple balance games, supported standing, and task-specific practice (for example, stepping over small objects) can strengthen the brain’s control of movement. The purpose is to reduce falls. The mechanism is neuroplasticity: repeating safe movement patterns so the brain finds more efficient control strategies.

18. Communication aids (AAC)
    If speech becomes very difficult, communication boards, tablets, or eye-gaze devices can be used. The purpose is to keep the child able to express needs and feelings. The mechanism is replacing spoken words with visual symbols or text controlled by hands, head, or eyes.

19. Palliative care support (symptom-focused)
    Palliative care is not only for end of life. Teams can help manage pain, breathing distress, feeding problems, and emotional stress at any stage. The purpose is comfort and quality of life. The mechanism is holistic care that looks at symptoms, goals, and family values together.

20. Genetic counseling for family
    Genetic counselors explain inheritance, testing of relatives, and options for future pregnancies. The purpose is informed family planning and emotional support. The mechanism is education about autosomal recessive risk (25% affected in each pregnancy) and available testing.

Drug treatments

Important: There is no specific drug that cures the C12orf65 mutation. Medicines treat symptoms like seizures, spasticity, reflux, or infections. Doses below are typical ranges from labels or guidelines but must only be decided by doctors for each patient.

1. Levetiracetam (Keppra) – anti-seizure drug
   Levetiracetam is a commonly used seizure medicine that does not heavily stress mitochondria. It belongs to the antiepileptic drug (AED) class. Typical doses range around 20–60 mg/kg/day divided twice daily, adjusted by a neurologist. It works by modulating synaptic vesicle proteins and reducing abnormal electrical firing. Side effects can include sleepiness, mood changes, irritability, and rarely serious behavioral symptoms.

2. Clonazepam – benzodiazepine for myoclonus and seizures
   Clonazepam can help myoclonic jerks and some seizure types. It is a benzodiazepine that enhances GABA, the main calming chemical in the brain. Dosing often starts very low (for example 0.01–0.03 mg/kg/day) and is slowly increased to effect. It is given 2–3 times daily. Side effects include drowsiness, drooling, unsteadiness, and dependence with long-term use.

3. Baclofen – oral antispastic agent
   Baclofen reduces spasticity by activating GABA-B receptors in the spinal cord, which lowers muscle tone. Doses start very low (for example 0.3 mg/kg/day divided three times) and increase slowly. The purpose is to ease stiffness, improve comfort, and sometimes help walking or sitting. Side effects may include sleepiness, low muscle tone, and, if stopped suddenly, dangerous withdrawal.

4. Diazepam – short-term spasticity and seizure rescue
   Diazepam is another benzodiazepine used as a rescue drug for seizures or severe spasms. It enhances GABA-A receptors. Rectal or buccal forms can stop prolonged seizures at home, following an emergency plan from the neurologist. Side effects include strong drowsiness, breathing depression at high doses, and risk of dependence.

5. Proton pump inhibitors (for example omeprazole)
   PPIs reduce stomach acid and help reflux, which is common when swallowing is weak. They are acid-suppressing drugs taken once daily before food, with doses set by weight. The mechanism is blocking the proton pump in stomach cells. Side effects may include diarrhea, low magnesium, and increased infection risk with long-term use.

6. H2-blockers (for example ranitidine, where available)
   H2-blockers also reduce stomach acid and can be used if PPIs are not tolerated. They block histamine H2 receptors on stomach cells. Doses are weight-based and usually given twice daily. Side effects include headache and, rarely, liver or blood problems. Availability has changed in some countries because of impurity concerns, so doctors choose carefully.

7. Prokinetic agents (for example metoclopramide, domperidone)
   These medicines help move food through the stomach in children with slow gastric emptying or severe reflux. They increase gut motility and tighten the lower esophageal sphincter. Doses are small and limited in duration because of possible side effects like movement disorders (for metoclopramide) or heart rhythm problems (for domperidone).

8. Broad-spectrum antibiotics (for example amoxicillin-clavulanate)
   Children with weak cough or swallowing may get frequent chest infections. Doctors sometimes prescribe broad-spectrum antibiotics to treat bacterial pneumonia or severe sinusitis. The purpose is to clear infection quickly and prevent worsening weakness. Doses and duration depend on infection site and weight. Side effects include diarrhea, rash, and possible allergy.

9. Inhaled bronchodilators (for example salbutamol)
   If there is reactive airway disease or wheeze, inhaled bronchodilators can open the airways. They are beta-agonist drugs taken by inhaler or nebulizer. The mechanism is relaxing smooth muscle in the airways. Side effects include fast heart rate, tremor, and jitteriness, especially at higher doses.

10. Anti-emetic medicines (for example ondansetron)
    Some children have severe nausea or vomiting, especially during infections or feeding changes. Ondansetron blocks serotonin 5-HT3 receptors in the gut and brain. It is usually given in small, short courses. Side effects may include constipation, headache, and changes in heart rhythm in sensitive patients.

11. Laxatives (for example polyethylene glycol)
    Constipation is common because of low mobility and weak abdominal muscles. Osmotic laxatives soften stool by drawing water into the bowel. Doses are adjusted to keep stool soft but not watery. The purpose is to prevent pain, leakage, and appetite loss from severe constipation. Side effects are usually mild, such as bloating or loose stool if overused.

12. Simple analgesics (paracetamol / acetaminophen)
    Pain from contractures, procedures, or infections can be treated with paracetamol at standard weight-based doses, not exceeding daily limits. It works mainly in the brain to reduce pain and fever. Side effects are few at correct doses but overdose can badly damage the liver, so dosing must be carefully supervised.

13. Non-steroidal anti-inflammatory drugs (NSAIDs)
    Ibuprofen and similar drugs may help pain and inflammation in joints or muscles. They block prostaglandin production. Doses are weight-based and short term. Side effects include stomach irritation, kidney stress, and bleeding risk, so they must be used cautiously in children with feeding or kidney problems.

14. Vitamin D supplements (when deficient)
    Vitamin D may be prescribed when levels are low, to protect bones weakened by immobility. It acts as a hormone to support calcium absorption and bone mineralization. Doses depend on blood levels and local guidelines. Side effects are rare at normal doses but excessive intake can cause high calcium and kidney damage.

15. B-complex vitamin preparations (prescription formulations)
    Some mitochondrial patients are given prescription-strength B-vitamin mixes, especially riboflavin, thiamine, and niacin, under medical supervision. They serve as cofactors for enzymes in energy pathways. Doses are higher than simple multivitamins and adjusted by age and weight. Side effects are usually mild but can include flushing (niacin) or nerve issues if imbalanced.

16. Arginine infusions (selected cases of stroke-like episodes)
    In some mitochondrial diseases with stroke-like episodes, intravenous arginine may be used during acute events. It is a semi-essential amino acid that supports nitric oxide production and blood vessel dilation. Dosing is specialist-level and not routine in C12orf65 disease but may be considered if overlapping phenotypes appear. Side effects include low blood pressure and high potassium.

17. Sodium bicarbonate or citrate (for metabolic acidosis)
    If blood becomes too acidic due to lactic acidosis, doctors may give bicarbonate or citrate solutions to buffer the acid. The purpose is to protect organs from low pH. Doses are calculated from blood tests. Side effects can include fluid overload and electrolyte imbalance if given too fast.

18. Enteral formula feeds (special medical nutrition)
    Some children need special high-calorie formulas through tube feeds. These are medical foods, not normal drinks. They provide balanced macronutrients and micronutrients in an easy-to-digest form. The mechanism is reducing digestive work while maintaining adequate intake. Side effects may include diarrhea or intolerance to certain formulas.

19. Vaccines (routine and extra, as advised)
    Routine childhood vaccines and sometimes extra vaccines (like pneumococcal or influenza) are strongly recommended to prevent infections that can trigger deterioration. Vaccines prime the immune system to recognize germs faster. Side effects are usually mild fever or soreness. Doctors balance benefits and risks in each child.

20. Avoided or cautious drugs (for example valproic acid)
    Some drugs can be harmful in mitochondrial disease, especially valproic acid in certain genetic backgrounds, because it can worsen liver and mitochondrial function. The “treatment” here is actually avoidance or very careful specialist-supervised use. The mechanism is risk reduction: choosing safer alternatives first.

Dietary molecular supplements

Note: Evidence for supplements is limited and mixed, and many are used off-label. They should only be used under a metabolic specialist.

1. Coenzyme Q10 (ubiquinone)
   CoQ10 is part of the electron transport chain in mitochondria. Supplements aim to improve electron transfer and act as antioxidants. Doses in mitochondrial disease studies often range around 5–30 mg/kg/day divided doses, adjusted by age. Possible benefits include better stamina in some patients, but evidence is variable. Side effects are usually mild, like stomach upset.

2. L-carnitine
   L-carnitine helps transport long-chain fatty acids into mitochondria for energy. Supplements may support energy production and reduce toxic acyl-compounds in some patients. Oral doses in mitochondrial practice often range 50–100 mg/kg/day, split 2–3 times. Side effects can include fishy body odor, diarrhea, or rare heart rhythm issues at very high doses.

3. Riboflavin (vitamin B2)
   Riboflavin is a cofactor for many mitochondrial enzymes. In some flavoprotein defects, high-dose riboflavin can lead to clear improvement. Doses in mitochondrial cocktails may be 50–100 mg/day in children, under supervision. It works by supporting enzyme function in complex I and II pathways. Side effects are mild, such as bright yellow urine.

4. Thiamine (vitamin B1)
   Thiamine is essential for pyruvate dehydrogenase and other enzymes connecting sugar breakdown to the Krebs cycle. High-dose thiamine can help in specific enzyme defects and is often included in mitochondrial cocktails. Doses vary but can be several times the daily requirement. Side effects are rare, mainly mild stomach upset or allergic reactions with injections.

5. Alpha-lipoic acid
   Alpha-lipoic acid is an antioxidant and cofactor in mitochondrial dehydrogenase complexes. Supplements aim to reduce oxidative stress and improve energy use. Doses used in adults range from 100–600 mg/day; pediatric dosing is specialist-directed. Side effects include nausea or skin rash, and it may lower blood sugar, so monitoring is needed.

6. Vitamin C (ascorbic acid)
   Vitamin C is a water-soluble antioxidant that can neutralize free radicals formed during impaired oxidative phosphorylation. It is often added to supplement regimens at modest doses within daily limits. The idea is to protect cell membranes and DNA. High doses can cause stomach upset and kidney stones in susceptible people.

7. Vitamin E (tocopherols)
   Vitamin E is a fat-soluble antioxidant that stabilizes cell and mitochondrial membranes. Low-to-moderate doses within recommended upper limits are sometimes used in mitochondrial cocktails. The mechanism is reducing lipid peroxidation. Overdose can increase bleeding risk, so doses must not exceed specialist advice.

8. Biotin
   Biotin is a cofactor for carboxylase enzymes in mitochondria and is essential for fatty-acid and amino-acid metabolism. In specific carboxylase deficiencies, high-dose biotin is crucial; in other mitochondrial disorders it is sometimes added empirically. Side effects are rare, but high doses can interfere with some lab tests.

9. Folate (5-methyltetrahydrofolate forms)
   Folate is needed for one-carbon metabolism and nucleotide synthesis, which support cell repair. In some mitochondrial diseases with brain involvement, folate levels in spinal fluid are low and replacement may be used. The mechanism is improving DNA and RNA synthesis and possibly neurotransmitter balance. Side effects are usually mild; very high doses can mask B12 deficiency.

10. Arginine / citrulline oral supplements
    Oral arginine or citrulline may be used between episodes in diseases with stroke-like attacks, to support nitric oxide production and blood vessel dilation. They are less central in C12orf65 disease but may be considered if similar crises occur. Side effects include stomach discomfort and possible changes in potassium or blood pressure.

Immunity-supporting and regenerative / stem-cell related drugs

Important: No stem-cell drug is approved specifically for C12orf65 combined oxidative phosphorylation deficiency. Treatments below are general concepts sometimes used in complex mitochondrial or neuromuscular disease care and must only be considered in specialist centers or research.

1. Intravenous immunoglobulin (IVIG)
   IVIG is pooled antibodies given by infusion in some patients who have immune problems or recurrent infections. It “borrows” a healthy immune system for a short time. Doses are weight-based (for example 0.4–2 g/kg per course) and given in hospital. It can reduce infection frequency but may cause headache, fever, and rare serious reactions like kidney problems or clots.

2. Granulocyte colony-stimulating factor (G-CSF)
   If a patient has low white blood cells from other causes, G-CSF can stimulate the bone marrow to make more neutrophils. It is injected under the skin at doses chosen by hematologists. The mechanism is binding to receptors on marrow precursors to boost production. Side effects can include bone pain, spleen enlargement, and rare lung issues.

3. Experimental redox-modulating drugs (for example EPI-743/vatiquinone)
   EPI-743 (vatiquinone) is an experimental drug studied in some mitochondrial diseases. It targets cellular redox systems to support antioxidant defenses. Doses are set only in clinical trials. Early studies suggest possible benefits in selected disorders but evidence is still limited. Side effects may include gastrointestinal upset and abnormal liver tests. It is not standard of care yet.

4. Idebenone (investigational in some optic neuropathies)
   Idebenone is a synthetic analog of CoQ10 studied for inherited optic neuropathies and some mitochondrial conditions. It may help electron transfer in the respiratory chain and act as an antioxidant. Doses in studies vary widely, and benefits are not proven in C12orf65 disease. Side effects include diarrhea and liver test changes. Use is usually restricted to trials or very specialized centers.

5. Hematopoietic stem-cell transplantation (HSCT – concept, not routine)
   In a few metabolic diseases, HSCT can replace bone marrow cells and sometimes improve enzyme defects. For C12orf65-related COXPD7, there is no clear evidence that HSCT helps, so it is not standard. It is mentioned as a regenerative idea only. HSCT carries major risks like infection, graft-versus-host disease, and death, so would only be considered in research settings.

6. Cell-based or gene therapies under investigation
   Researchers are exploring gene therapy, mitochondrial replacement, or cell-based therapies for mitochondrial diseases in general. For C12orf65, work is still at genetic and cellular study level. These approaches aim to deliver correct genes or healthy mitochondria to cells. At present, they are not available as treatment and may only appear in future clinical trials.

Surgeries and procedures

1. Gastrostomy tube placement (PEG)
   A small operation creates a channel through the abdominal wall directly into the stomach, and a feeding tube is placed. It is done when eating by mouth is unsafe or too tiring. The purpose is secure long-term nutrition, medicine delivery, and less risk of aspiration, helping growth and energy.

2. Orthopedic tendon-lengthening or deformity correction
   In severe spasticity with fixed contractures, surgeons may lengthen tendons or correct bone deformities in feet or legs. The purpose is better positioning, easier hygiene, and sometimes improved standing or walking. Surgery changes the mechanics of muscles and joints but needs long physiotherapy afterward.

3. Spinal surgery for severe scoliosis
   Some children develop severe spinal curvature that affects breathing and sitting. Spinal fusion or instrumentation may be considered in selected cases. The purpose is to stabilize the spine, protect lung function, and improve sitting balance. These operations are major and require careful risk–benefit discussion.

4. Tracheostomy (airway opening) in advanced respiratory weakness
   If breathing muscles fail and long-term ventilation is needed, a tracheostomy may be performed, creating a direct airway in the neck. The purpose is safer, more comfortable ventilation and easier secretion removal. It changes airflow mechanics and requires intensive home-care training.

5. Deep brain or intrathecal procedures (rare, highly specialized)
   In some severe spasticity or dystonia cases, intrathecal baclofen pumps or other neuromodulation procedures may be considered. They deliver medicine directly to the spinal fluid or modulate brain circuits. The purpose is strong tone reduction with lower systemic doses. These procedures are complex and reserved for selected patients in expert centers.

Prevention and lifestyle tips

1. Avoid long fasting – frequent small meals and night-time snacks can prevent low blood sugar and metabolic stress.

2. Prompt treatment of infections – seeing a doctor early for fever, cough, or vomiting can prevent rapid deterioration and hospital stays.

3. Routine and extra vaccines – keeping vaccines up to date reduces serious infections that can trigger regression.

4. Avoid over-exertion and overheating – gentle activity is good, but pushing to exhaustion, especially in hot weather, can worsen weakness and lactic acidosis.

5. Regular monitoring by a metabolic / neuromuscular clinic – planned check-ups allow early detection of new problems in vision, growth, or lungs.

6. Dental and oral care – good mouth hygiene lowers risk of aspiration pneumonia from infected teeth or gums.

7. Safe medication lists – families should carry a list of drugs to use with caution (for example valproate) and safer options, agreed with their specialist team.

8. Emergency plan – written instructions for hospitals on fluids, glucose, antibiotics, and seizure rescue help avoid delays and inappropriate treatments.

9. Fall-prevention at home – clear floors, grab rails, and proper lighting reduce injuries in children with weak or stiff legs.

10. Family genetic testing and counseling – knowing carrier status can prevent unexpected recurrence and allow early diagnosis in future children.

When to see a doctor

Families should see a doctor urgently if the child suddenly loses skills, has new seizures, shows breathing difficulty, very poor feeding, long fever, confusion, or severe pain. Rapid change can signal infections, metabolic crises, or brain involvement that need hospital care.

Regular appointments with neurology, metabolic, ophthalmology, rehabilitation, and nutrition teams are also important even when things seem stable. These visits allow careful tracking of vision, movement, growth, and learning so that therapies and equipment can be updated before major problems appear.

Diet – what to eat and what to avoid

1. Eat balanced meals with complex carbohydrates (rice, potatoes, whole grains) to give steady energy.

2. Eat enough protein (eggs, fish, beans, lean meat) to support muscle repair and growth.

3. Eat healthy fats (olive oil, nuts, seeds, oily fish) for extra calories when needed.

4. Eat plenty of fruits and vegetables for vitamins, minerals, and natural antioxidants.

5. Eat small, frequent meals if large meals cause fatigue or reflux.

6. Avoid long periods without food, especially overnight, unless a doctor has made a plan.

7. Avoid very high-sugar “energy” drinks and sweets that give a short spike then crash in energy.

8. Avoid fad diets like strict ketogenic or fasting diets unless they are prescribed and closely supervised by specialists.

9. Avoid alcohol and tobacco exposure in older patients and at home, because they add oxidative stress and harm lungs and nerves.

10. Avoid unsupervised high-dose supplements bought online; always discuss with the metabolic team first.

Frequently asked questions

1. Is there a cure for C12orf65 combined oxidative phosphorylation deficiency?
   Right now there is no cure that can fix the underlying C12orf65 gene problem. Treatment focuses on managing symptoms, preventing complications, and supporting the child’s development and comfort with many therapies and careful follow-up. Research on mitochondrial gene and cell therapies is ongoing.

2. Can children with this condition live into adulthood?
   Outcomes vary a lot. Some children with severe early disease have shortened life spans, especially if there are major breathing or feeding problems. Others with milder, mainly nerve or vision involvement may live longer and reach adulthood with disability. Prognosis depends on how many systems are affected and the quality of supportive care.

3. Is it my fault that my child has this disease?
   No. This condition is inherited in an autosomal recessive way. Parents usually carry one silent copy of the mutation without knowing. When both parents are carriers, each pregnancy has a 25% chance of being affected, and this happens by chance, not by anything they did or did not do.

4. Can brothers and sisters also have the disease?
   Yes, siblings may be affected, carriers, or completely unaffected. Genetic testing and counseling can help understand the risk for each child and guide early evaluation if developmental or visual problems appear.

5. Will vitamins or supplements cure the problem?
   Supplements like CoQ10, L-carnitine, and B-vitamins may help some symptoms or energy levels in selected patients, but they do not repair the gene defect. Evidence is mixed, and they should be taken only under specialist guidance as part of a broader treatment plan.

6. Are seizures common in this disease?
   Many, but not all, patients with mitochondrial encephalopathy have seizures. If seizures occur, they are treated with carefully chosen anti-seizure drugs that are safer for mitochondria, like levetiracetam, while avoiding more toxic options when possible.

7. Why is my child’s vision getting worse?
   C12orf65 disease often causes optic atrophy, where the nerve that carries visual signals slowly degenerates due to lack of energy in its long fibers. This damage can lead to gradually worse vision and nystagmus. Low-vision aids and school support are very important, even though we cannot reverse the damage yet.

8. Can my child attend regular school?
   Many children can go to regular school with adaptations: extra time, assistive devices, wheelchair access, and support teachers. Some with significant cognitive or visual impairment may do better in special education. The key is an individualized education plan that matches abilities and fatigue levels.

9. Will exercise make the disease worse?
   Over-exertion can temporarily worsen symptoms, but gentle, supervised exercise often helps maintain strength and function. The goal is a careful balance: enough activity to keep muscles and heart healthy, without long periods of exhaustion afterward. Therapists can design safe programs.

10. Can we travel with a child who has this condition?
    Travel is possible with planning. Families should carry medical summaries, enough medicines, emergency seizure plans, and know where hospitals are at their destination. Avoid very high altitudes and extreme temperatures. Discuss plans with the medical team before long trips.

11. Is special mitochondrial “energy” food or drink helpful?
    Many marketed products claim to boost mitochondria, but most lack strong evidence and may be costly. A balanced diet, prescribed supplements, and good hydration usually matter more than special drinks. Always ask the metabolic team before trying new products.

12. Should we take part in research studies?
    Research studies and registries help scientists understand rare diseases and test new treatments. Participation is voluntary and should be considered after careful discussion of risks and benefits. For some families, research brings hope and access to advanced monitoring.

13. How often should my child have scans and tests?
    The frequency of MRI scans, blood tests, eye checks, and heart or lung tests depends on symptoms and age. Typically, regular eye exams, growth checks, and labs are done yearly or more often, with MRI when there is new neurological change. The specialist team will make an individualized schedule.

14. Can future pregnancies be tested?
    Yes. Once the family’s C12orf65 mutations are known, options like prenatal testing or preimplantation genetic testing (PGT) can be discussed with genetics and fertility specialists. These methods can help parents reduce the chance of having another affected child, if they wish.

15. What is the most important message for families?
    The most important message is that you did not cause this disease, and you are not alone. There is no cure yet, but a combination of therapies, careful monitoring, and good support can make a meaningful difference in comfort and abilities. Connecting with experts and other families can give both knowledge and emotional strength.

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 24, 2025.