C12orf65 Combined Oxidative Phosphorylation Deficiency

C12orf65 combined oxidative phosphorylation deficiency is a very rare genetic disease that affects how the “power stations” of the cell (mitochondria) make energy. In this condition, a gene called C12orf65 (also called MTRFR) does not work properly. Because of this, the mitochondria cannot finish making some important proteins that are needed for the energy-making chain, called the oxidative phosphorylation (OXPHOS) system. [1]

c12orf65 combined oxidative phosphorylation deficiency (also called Combined Oxidative Phosphorylation Deficiency 7, COXPD7, or MTRFR/C12orf65-related mitochondrial disease) is a very rare genetic disease. It happens when both copies of the C12orf65 (MTRFR) gene have harmful changes (mutations). This gene helps mitochondria (the “power plants” of the cell) finish making proteins needed for energy production. When it does not work well, the oxidative phosphorylation system in mitochondria cannot make enough ATP, so many organs—especially brain, nerves, muscles, and eyes—do not get the energy they need.

The condition is usually inherited in an autosomal recessive pattern. Children may show early problems such as delayed motor milestones, learning difficulties, ataxia (poor balance), spasticity (stiff muscles), optic atrophy (damage of the optic nerve with vision loss), eye movement problems, and general muscle weakness or wasting. Some people may develop a Leigh-like syndrome (a severe brain energy disorder) or a Charcot-Marie-Tooth type 6-like neuropathy affecting the peripheral nerves.

This gene problem is autosomal recessive. This means a child becomes sick when they receive one faulty copy of the gene from each parent. The parents usually feel healthy but are “carriers”. The disease often starts in infancy or early childhood and can cause problems with the brain, eyes, muscles, and nerves. Common features include delayed development, trouble walking, weak or stiff muscles, and loss of vision from damage to the optic nerve. [2]

Doctors sometimes describe this disease as a type of mitochondrial encephalomyopathy. “Encephalo” means brain, “myo” means muscle, and “pathy” means disease. In many children, brain scans show changes that look similar to Leigh syndrome, a severe mitochondrial brain disease, so doctors may say “Leigh-like” changes. [3]

The problem in this disease happens because the C12orf65 protein is normally part of a group called mitochondrial translation release factors. These proteins help finish and release newly made mitochondrial proteins from ribosomes. When C12orf65 is missing or broken, some mitochondrial proteins are not made correctly, so several complexes of the respiratory chain (like complex I and complex IV) do not work well. This is why it is called a combined oxidative phosphorylation deficiency. [4]

Because cells do not make enough energy, tissues that need a lot of energy, such as the brain, eyes, and muscles, are affected most. This leads to slow growth, movement problems, and often progressive (worsening) symptoms over time. [5]

Other names

Doctors and scientists use many names for the same disease. Knowing these names can help when you read reports or search the medical literature. [1]

• Combined oxidative phosphorylation deficiency 7 (COXPD7) – the standard number used in many genetic databases. [2]

• Combined oxidative phosphorylation defect type 7 – another way to write the same name. [3]

• Severe C12orf65-related combined oxidative phosphorylation defect – used when the disease course is very serious. [4]

• C12orf65 combined oxidative phosphorylation deficiency – a simple descriptive name that links the gene and the problem. [5]

• MTRFR-related mitochondrial disease – a name using the newer gene name MTRFR. [6]

What happens in the body

In healthy cells, mitochondrial DNA and many nuclear genes work together to build the protein parts of the respiratory chain complexes. C12orf65 sits inside the mitochondria and helps “release” newly made proteins from the mitochondrial ribosome once protein building is finished. [1]

When both copies of the C12orf65 gene are faulty, the protein is short, missing, or unable to do its job. Mitochondria then make some proteins incorrectly or not at all. Several complexes in the OXPHOS chain are weak, so ATP (energy) production drops. Cells then switch more to “emergency” pathways like glycolysis, which produce less energy and more lactic acid. [2]

The brain, eyes, and muscles need a lot of energy all the time. When they do not get enough, nerve cells may be damaged or die. This can cause developmental delay, difficulty moving, problems with coordination, and vision loss. Over time, MRI scans can show typical lesions, especially in deep brain regions like the basal ganglia and brainstem. [3]

Types

Doctors do not have one official “type list”, but studies show that C12orf65 disease can look different in different people. Here is a simple way to group the patterns. [1]

• Type 1 – Infantile-onset severe (Leigh-like) type
  In this type, babies or very young children develop symptoms early. They may have poor head control, trouble feeding, and significant developmental delay. Brain MRI often shows Leigh-like lesions in the basal ganglia and brainstem.

• Type 2 – Childhood-onset optic atrophy with developmental delay
  In this group, children may first be noticed because of poor vision, pale optic nerves, and school or motor delay. They may later develop balance problems and weakness.

• Type 3 – Spastic paraplegia with optic atrophy
  Some patients, often older children or young adults, mainly have stiff, weak legs (spastic paraplegia) and optic atrophy. These people can sometimes walk for many years but with increasing difficulty.

• Type 4 – Mixed neurological type with seizures and neuropathy
  A few patients show a combination of developmental delay, seizures, peripheral neuropathy (nerve damage in arms and legs), and muscle wasting.

These types overlap. Even within one family, one child may have more severe disease than another, even though they share the same gene change. [2]

Causes

Here, “causes” means reasons why the disease happens or gets worse. The basic cause is always a change in the C12orf65 gene, but there are different kinds of changes and factors that influence how bad the disease becomes. [1]

1. Homozygous loss-of-function mutation in C12orf65
   When a child inherits the same faulty C12orf65 change from both parents, the protein can be severely reduced or absent. This is the most typical cause of COXPD7. [2]

2. Compound heterozygous C12orf65 mutations
   Sometimes the child gets two different mutations (one from each parent). Together they still make the protein non-functional and cause disease. [3]

3. Nonsense mutations
   Nonsense mutations create a “stop” signal too early in the gene code. The protein is cut short and cannot work as a release factor in mitochondria. [4]

4. Frameshift mutations
   Small insertions or deletions shift the reading frame of the gene. This usually produces a very abnormal and unstable protein, leading to severe disease. [5]

5. Splice-site mutations
   Some mutations change how the gene is cut and joined (spliced). This can skip important parts of the gene or insert extra pieces, damaging protein structure.

6. Missense mutations affecting key domains
   Missense mutations swap one amino acid for another. If this happens in the GGQ motif or other key parts, the protein may lose its release-factor role. [6]

7. Large deletions of the C12orf65 gene region
   Rarely, bigger pieces of DNA can be missing, removing all or part of the gene. Without the gene, the protein cannot be made at all.

8. Autosomal recessive inheritance with carrier parents
   When both parents carry one faulty copy but are healthy, each pregnancy has a 25% chance of producing an affected child. This inheritance pattern is the basic cause in many families. [7]

9. Consanguinity (parents related by blood)
   In families where parents are cousins or otherwise closely related, the chance that both carry the same rare C12orf65 mutation is higher. This can increase the risk of an affected child.

10. De novo mutation in one parent’s egg or sperm
    Sometimes a mutation appears for the first time in a child. It may still cause disease if combined with another faulty allele. This is rare but possible.

11. Impaired mitochondrial translation
    All pathogenic C12orf65 mutations share a common effect: mitochondrial translation (protein building) is disturbed. This leads to poor synthesis of oxidative phosphorylation proteins. [8]

12. Combined respiratory chain complex deficiency
    Because C12orf65 acts in general mitochondrial translation, several complexes (often I and IV, sometimes III) can be partially deficient in muscle or fibroblast tests. This combined defect is a direct consequence of the gene problem. [9]

13. High energy demand in the developing brain
    The immature brain needs a lot of energy. When mitochondria cannot supply this, neurons are more likely to be damaged, which explains early-onset disease.

14. High energy demand in the optic nerve
    The optic nerve has long, energy-hungry fibers. With weak mitochondria, these fibers can degenerate, causing optic atrophy and vision loss. [10]

15. Intercurrent infections and fever
    Infections increase energy needs and metabolic stress. In children with C12orf65 disease, such stress can trigger regression or worsening of symptoms.

16. Poor nutrition or fasting
    Long fasting or poor nutrition can reduce available energy sources and may aggravate mitochondrial dysfunction and lactic acidosis.

17. Exposure to some mitochondrial-toxic drugs
    Drugs like valproic acid and some certain antibiotics can be harmful in mitochondrial disease. They may worsen weakness, liver function, or encephalopathy. [11] (general mitochondrial guidance)

18. Secondary mitochondrial DNA changes
    In some patients, there may also be changes or stress in mitochondrial DNA, which can further impair oxidative phosphorylation on top of the C12orf65 problem.

19. Genetic modifiers in other nuclear genes
    Variants in other mitochondrial genes can make the phenotype milder or more severe. This may explain why severity can differ between patients with similar C12orf65 mutations. [12]

20. Unknown environmental or genetic factors
    For many families, doctors cannot fully explain why one child is more severely affected than another. There are likely still unknown genetic and environmental contributors.

Symptoms

Symptoms can vary from person to person, but these are common problems seen in C12orf65 combined oxidative phosphorylation deficiency. [1]

1. Global developmental delay
   Many children sit, crawl, walk, or talk later than usual. They may need extra help at school and in daily activities because their brain and muscles cannot use energy normally.

2. Regression of skills
   Some children lose abilities they already had, such as walking or speaking. This often happens after an illness or as the disease progresses.

3. Muscle weakness (hypotonia or later atrophy)
   Babies may feel “floppy” because their muscles are weak. Over time, muscles can become thin and wasted, especially in the legs and arms. [2]

4. Spasticity and stiff legs (spastic paraplegia)
   In some patients, the main problem is stiffness and tightness of the leg muscles. This makes walking awkward or impossible without aids. [3]

5. Poor coordination (ataxia)
   Children may have shaky movements, wide-based walking, or trouble with fine hand tasks. This is because the brain areas that control balance and coordination are affected.

6. Optic atrophy and vision loss
   The optic nerves become pale and thin, which can cause blurred vision, reduced visual fields, or even severe vision loss over time. [4]

7. Nystagmus (involuntary eye movements)
   The eyes may move quickly and uncontrollably from side to side. This can make it harder for the child to focus and see clearly. [5]

8. External ophthalmoplegia (eye movement weakness)
   Some patients cannot move their eyes fully in all directions. This can cause double vision or the need to turn the head instead of moving the eyes.

9. Ptosis (droopy eyelids)
   The upper eyelids may droop because the small muscles that lift them are weak. This can partially cover the eyes and affect vision.

10. Peripheral neuropathy
    Damage to nerves in the arms and legs can cause numbness, tingling, sharp pains, or further weakness. It is often found on nerve conduction tests. [6]

11. Feeding difficulties and failure to thrive
    Babies may have trouble sucking, swallowing, or keeping up with feeding. Weight gain may be poor because of high energy needs and low energy production.

12. Breathing problems or bulbar weakness
    Weakness of the muscles involved in swallowing and breathing (bulbar muscles) can cause choking, nasal speech, or breathing difficulties, especially in severe cases.

13. Seizures in some patients
    A few children may develop seizures. These can range from brief staring spells to more obvious convulsions and need careful medical management.

14. Fatigue and exercise intolerance
    Even mild activity can cause extreme tiredness because the muscles cannot increase energy production enough. Children may need frequent rest.

15. Behavioral or learning difficulties
    Because of brain involvement, some children have problems with attention, memory, or behavior, and may need special education support.

Diagnostic tests –

Physical examination

General physical and growth examination

The doctor first does a full physical check-up. They look at height, weight, and head size to see if the child is growing as expected. They check muscles, skin, breathing, and heart. In C12orf65 disease, the doctor may notice poor weight gain, thin muscles, or delayed growth. This basic exam guides which specialized tests are needed next. [1]

Detailed neurological examination

A neurological exam checks how the brain, spinal cord, and nerves are working. The doctor tests muscle strength, tone (stiff or floppy), reflexes, sensation, coordination, and walking pattern. In this disease, they may find weak or stiff muscles, abnormal reflexes, poor balance, and gait problems. These signs suggest a central and peripheral nervous system problem typical for mitochondrial encephalomyopathy. [2]

Eye and vision examination

An eye doctor (ophthalmologist) looks at visual acuity, eye movements, and the back of the eye with an ophthalmoscope. In C12orf65 deficiency, they often see optic nerve pallor (optic atrophy) and sometimes nystagmus or limited eye movements. This eye exam supports the diagnosis because optic atrophy is a key feature in many patients. [3]

Musculoskeletal and posture assessment

The doctor watches how the child sits, stands, and walks, and checks the spine and joints. They may notice scoliosis, contractures (tight joints), or a scissoring gait from spastic paraplegia. This helps measure how much the disease affects daily movement and guides physical therapy planning. [4]

Manual tests

Manual muscle testing (MMT)

In manual muscle testing, the clinician asks the patient to move arms and legs against resistance. They grade strength on a simple scale (for example, 0–5). In C12orf65 disease, MMT often shows weakness in the legs and sometimes in the arms. This simple bedside test helps monitor progression and response to therapies such as physiotherapy

 Gowers’ sign assessment

Gowers’ sign is checked by asking the child to rise from sitting on the floor. Children with proximal muscle weakness push on their thighs with their hands to stand up. A positive Gowers’ sign suggests weakness of hip and thigh muscles, which is common in mitochondrial and neuromuscular diseases, including C12orf65 deficiency.

Gait and balance testing

The doctor asks the child to walk normally, on heels, on toes, and in a straight line (tandem gait). They may also stand with feet together, eyes closed (similar to a Romberg test). Abnormal or shaky walking, frequent falls, or inability to stand still without swaying show balance and coordination problems that fit with cerebellar and pyramidal involvement in this disease.

Developmental milestone screening

For babies and toddlers, the clinician uses simple developmental checklists or tools (for example, “Can the child sit without support? Can the child use simple words?”). Scoring behind expected milestones confirms developmental delay. This kind of manual screening helps document the impact of the mitochondrial disease on brain development.

Laboratory and pathological tests

Blood lactate and pyruvate levels

A common blood test measures lactate and pyruvate. High lactate, especially with a high lactate-to-pyruvate ratio, suggests mitochondrial oxidative phosphorylation problems. Many children with COXPD7 show raised lactate levels in blood and sometimes in cerebrospinal fluid (CSF). [1]

Blood gas and acid–base status

Arterial or venous blood gases check pH, bicarbonate, and carbon dioxide. Mitochondrial failure can cause lactic acidosis, leading to low pH and low bicarbonate. This test helps doctors understand how serious the metabolic disturbance is, especially during acute illness.

Serum creatine kinase (CK)

CK is an enzyme released when muscles are damaged. In some mitochondrial diseases, CK can be mildly raised, showing muscle stress. In C12orf65 deficiency, CK may be normal or moderately increased; this helps doctors distinguish it from primary muscular dystrophies, where CK is often very high.

Metabolic screening (acylcarnitine, amino acids, organic acids)

Special laboratories can analyze acylcarnitine profiles, plasma amino acids, and urine organic acids. These tests look for other metabolic disorders and sometimes show patterns suggesting mitochondrial dysfunction, though they may be non-specific. They are important to exclude other treatable metabolic diseases

Cerebrospinal fluid (CSF) lactate

A lumbar puncture can measure lactate in the cerebrospinal fluid. High CSF lactate supports a diagnosis of mitochondrial encephalopathy, especially when combined with MRI changes and blood findings. [2]

Muscle biopsy with histology

A small sample of muscle can be taken and studied under a microscope. In mitochondrial disease, doctors may see ragged-red fibers, abnormal mitochondria, or other specific changes. In C12orf65 deficiency, findings can include reduced staining of specific respiratory chain complexes, helping to prove that oxidative phosphorylation is impaired. [3]

Respiratory chain enzyme analysis

Specialist laboratories can measure the activity of respiratory chain complexes (I, II, III, IV, V) in muscle or fibroblasts. In combined oxidative phosphorylation deficiency, activities of several complexes are reduced. This widely supports the diagnosis and shows that the defect is not limited to a single complex.

Genetic testing (C12orf65 / MTRFR sequencing)

The final and most specific test is genetic testing. Doctors may order a targeted C12orf65 gene test, a mitochondrial nuclear gene panel, or whole-exome/genome sequencing. Finding biallelic pathogenic variants in C12orf65 confirms the diagnosis of COXPD7. This test also allows carrier testing for parents and family planning discussions. [4]

Electrodiagnostic tests

Nerve conduction studies (NCS)

NCS measure how fast and how strongly electrical signals travel along peripheral nerves. In some patients with C12orf65 disease, NCS show an axonal polyneuropathy, meaning the nerve fibers themselves are damaged. This explains symptoms like numbness, weakness, and reduced reflexes in the limbs. [1]

Electromyography (EMG)

EMG uses a needle electrode in the muscle to record electrical activity. It can show whether weakness is mainly due to muscle disease (myopathic pattern) or nerve disease (neurogenic pattern). In C12orf65 deficiency, EMG can reveal neurogenic changes from neuropathy and sometimes myopathic features from mitochondrial myopathy. This helps describe how widespread the neuromuscular involvement is.

Imaging tests

Brain MRI

Magnetic resonance imaging (MRI) provides detailed pictures of the brain. In C12orf65 disease, MRI often shows symmetric lesions in the basal ganglia and brainstem, which look similar to those in Leigh syndrome. Over time, there may also be atrophy (shrinkage) of brain structures. These characteristic findings strongly support a mitochondrial diagnosis when combined with clinical and lab data. [1]

MR spectroscopy (MRS) of the brain

MRS is a special MRI technique that measures certain chemicals in brain tissue. In many mitochondrial diseases, including COXPD7, MRS can show an elevated lactate peak, especially in affected areas like the brainstem. This finding shows that local energy metabolism is disturbed and supports the diagnosis of mitochondrial encephalopathy. [2]

Non-Pharmacological Treatments (Therapies and Other Supports)

1. Multidisciplinary care team
   A coordinated team (neurology, genetics, physiotherapy, occupational therapy, speech therapy, dietitian, ophthalmology, pulmonology) is the backbone of care. The goal is to look at the whole child or adult, keep a long-term plan, and adjust early if any new problem appears.

2. Regular physiotherapy (physical therapy)
   Physical therapy helps keep muscles as strong and flexible as possible. Simple daily exercises, stretching, and supported standing or walking reduce contractures, improve balance, and may delay scoliosis and joint deformities caused by chronic weakness and spasticity.

3. Occupational therapy
   Occupational therapists teach safer ways to do daily tasks (feeding, dressing, writing, using a computer). They can recommend special grips, chairs, splints, and adapted utensils to save energy and protect joints, so the person can stay more independent at home and school.

4. Speech and language therapy
   Some people have trouble speaking clearly or swallowing. Speech therapists help with communication strategies, teach safe swallowing techniques, and may suggest thickened fluids or different food textures to prevent choking and aspiration.

5. Nutritional counselling and energy-supportive diet
   A dietitian with mitochondrial experience plans meals that give steady energy with enough calories, protein, and complex carbohydrates. The aim is to avoid low blood sugar, malnutrition, or excess weight, all of which can increase mitochondrial stress.

6. Avoiding prolonged fasting
   People with mitochondrial disease should usually not go many hours without food, especially during illness. Small, frequent meals and bedtime snacks help to keep blood sugar stable and lower the risk of metabolic crises and extreme fatigue.

7. Vision rehabilitation
   Optic atrophy and other eye problems are common, so early low-vision assessment is important. Magnifiers, special lighting, large-print materials, and electronic reading aids help children and adults use the vision they still have and stay engaged at school and work.

8. Assistive mobility devices
   Walkers, canes, ankle–foot orthoses, standing frames, and wheelchairs can be introduced step-by-step. These devices save energy, lower the risk of falls, and can sometimes delay joint damage by improving posture and alignment.

9. Respiratory physiotherapy
   Weak respiratory muscles can lead to poor cough, mucus retention, and chest infections. Techniques such as chest physiotherapy, assisted coughing devices, and breathing exercises lower the risk of pneumonia and help keep oxygen levels more stable.

10. Non-invasive ventilation support
    If night-time breathing is shallow, a specialist may recommend BiPAP or CPAP during sleep. This gentle air pressure reduces sleep-related hypoventilation, improves sleep quality, and can lessen daytime headaches and fatigue.

11. Orthopaedic management and splinting
    Braces, night splints, and early management of contractures or scoliosis can slow musculoskeletal complications. In some cases, bracing delays or reduces the need for orthopaedic surgery later.

12. Special education and learning support
    Because learning difficulties can occur, children often benefit from individualized education plans, extra time during exams, and the use of computers or tablets for writing. Early support can greatly improve school participation and long-term independence.

13. Psychological and family counselling
    Living with a chronic, rare disease is emotionally hard. Psychological support helps patients cope with anxiety, low mood, and uncertainty. Family counselling supports parents and siblings, improving communication and resilience at home.

14. Pain management strategies (non-drug)
    Physiotherapy, heat or cold packs, massage, positioning, and relaxation or mindfulness can reduce chronic pain from neuropathy, stiffness, or muscle overuse. These methods may reduce the dose needed for pain medicines.

15. Energy-conservation and pacing training
    Occupational therapists teach how to plan the day with rest breaks, use wheelchairs or scooters for long distances, and sit for tasks instead of standing. Pacing prevents “boom and bust” cycles of over-activity followed by exhaustion.

16. Infection-control practices
    Because infections can trigger serious regressions, families are taught careful hand hygiene, rapid medical review for fevers, up-to-date vaccinations, and early treatment of chest or urinary infections.

17. Emergency care plan
    A written plan for hospitals explains the diagnosis, baseline status, medicines to avoid, and what to do during acute illness (for example, give IV glucose, avoid prolonged fasting). This helps emergency staff act quickly and safely.

18. Environmental temperature control
    Extreme heat or cold can stress mitochondria and worsen fatigue. Simple measures like avoiding hot environments, staying hydrated, and using cooling vests or fans can reduce symptom flares.

19. Genetic counselling for the family
    Parents and adult patients can learn their carrier status, recurrence risks in future pregnancies, and options such as prenatal or preimplantation genetic testing. This helps families make informed reproductive choices.

20. Participation in registries and natural-history studies
    Joining research studies, such as C12orf65/MTRFR natural-history projects, helps doctors understand how the disease changes over time and may speed up future clinical trials, including gene therapy approaches.

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Drug Treatments

There are no drugs yet approved specifically for c12orf65 deficiency, but many FDA-approved medicines are used to manage seizures, spasticity, pain, reflux, and other complications. Labels for these medicines are available on accessdata.fda.gov, and they should only be used under specialist supervision, often at lower or carefully adjusted doses in mitochondrial disease.

For all drugs below, the exact dose, timing, and combination must be decided by a physician, usually a neurologist or metabolic specialist. Information about dosage and side effects here is general and simplified.

1. Levetiracetam (e.g., KEPPRA®, SPRITAM® – anti-seizure)
   Levetiracetam is often a first-line anti-seizure medicine in mitochondrial disorders because it does not strongly stress mitochondria. It is usually given twice daily by mouth or IV; the doctor slowly increases the dose based on weight and seizure control. Common side effects include sleepiness, dizziness, and mood changes.

2. Lamotrigine (LAMICTAL® – anti-seizure, mood stabilizer)
   Lamotrigine can help control focal and generalized seizures and may also improve mood. It is started at a very low dose and increased slowly to reduce the risk of severe skin rashes such as Stevens–Johnson syndrome. Other side effects include dizziness, headache, and nausea.

3. Clobazam (ONFI® – benzodiazepine anti-seizure)
   Clobazam is used as an add-on therapy for difficult seizures, including epileptic spasms and Lennox–Gastaut syndrome, and may be used similarly in severe mitochondrial epilepsy. It acts on GABA receptors to calm over-active brain circuits but can cause drowsiness, drooling, and dependence with long-term use.

4. Diazepam rectal gel (DIASTAT® – rescue for prolonged seizures)
   Rectal diazepam is used as an emergency medicine at home for long seizures or seizure clusters. Caregivers are trained to recognise seizure patterns and give a single weight-based dose. It can cause sleepiness and, rarely, breathing depression, so careful instruction is essential.

5. Gabapentin (NEURONTIN® – neuropathic pain, sometimes seizures)
   Gabapentin can help with neuropathic pain or discomfort from nerve damage and is sometimes used for focal seizures. It is typically given three times daily, with gradual titration. Side effects may include dizziness, weight gain, swelling, and tiredness.

6. Topiramate (TOPAMAX® – anti-seizure, migraine prevention)
   Topiramate may be used for refractory seizures or migraine-like headaches. It works on several brain receptors and ion channels. Doctors usually start with a low once-daily dose and slowly increase. Side effects can include weight loss, tingling, kidney stones, and difficulty finding words.

7. Baclofen (oral) (e.g., OZOBAX®, FLEQSUVY® – antispastic)
   Baclofen relaxes spastic muscles by acting on GABA-B receptors in the spinal cord. It is started at a low dose one to three times daily and increased slowly. Sudden stopping can cause serious withdrawal with high fever and muscle rigidity, so tapering is important. Side effects include drowsiness and weakness.

8. Intrathecal baclofen (LIORESAL® INTRATHECAL – pump-delivered baclofen)
   For severe spasticity not controlled by pills, baclofen can be delivered directly around the spinal cord via an implanted pump. This allows lower total doses but needs careful monitoring and pump refills. Risks include infection, catheter problems, overdose, or withdrawal if the pump fails.

9. Proton pump inhibitors (e.g., omeprazole, lansoprazole)
   These medicines reduce stomach acid and help treat reflux, which is common with swallowing problems and feeding tubes. They are usually taken once daily before meals. Long-term use must be monitored because of possible effects on mineral absorption and infection risk.

10. H2 receptor blockers (e.g., famotidine)
    H2 blockers also lower stomach acid and can be used if proton pump inhibitors are not tolerated. They are usually given once or twice daily. Side effects are often mild, such as headache or diarrhoea, but dosing must be adjusted in kidney disease.

11. Antiemetic: ondansetron
    Ondansetron helps control nausea and vomiting during acute illness, after surgery, or with feeding intolerance, reducing the risk of dehydration and metabolic stress. It can be given by mouth, IV, or dissolving tablets. Common side effects are constipation and headache; rare heart rhythm effects require caution.

12. Bronchodilators (e.g., salbutamol/albuterol inhalers)
    If there is reactive airway disease or recurrent chest infections, inhaled bronchodilators can open the airways and make breathing easier. They work quickly but may cause shakiness or a fast heartbeat, so the dose is adjusted by the respiratory specialist.

13. Inhaled corticosteroids
    In some patients with chronic airway inflammation or asthma-like symptoms, inhaled steroids reduce swelling of the airways and lower the risk of wheezing. They must be used regularly, and the mouth should be rinsed afterwards to avoid fungal infections.

14. Laxatives (e.g., polyethylene glycol)
    Constipation is common due to low mobility and weak abdominal muscles. Osmotic laxatives keep water in the stools, making them softer and easier to pass. Regular use with proper fluid intake can prevent painful impaction, but dosing should be guided by a clinician.

15. Analgesics (paracetamol/acetaminophen, carefully used NSAIDs)
    Simple painkillers can treat headaches, musculoskeletal pain, or post-surgical discomfort. Acetaminophen is usually first-line; NSAIDs must be used with caution because of possible effects on kidneys and stomach, especially in fragile patients.

16. Antispastic alternative: tizanidine
    Tizanidine is another muscle-relaxing medicine that acts on alpha-2 adrenergic receptors. It can reduce tone and spasms but may cause low blood pressure, drowsiness, and liver-enzyme changes, so blood tests and slow dose titration are needed.

17. Botulinum toxin injections
    For focal spasticity (for example, in the calves or hip adductors), botulinum toxin can be injected into specific muscles to reduce stiffness for several months. This can make braces or physiotherapy more effective but must be repeated and used cautiously.

18. Antidepressants or anxiolytics (carefully selected)
    Some older antidepressants and antipsychotics can harm mitochondria, so specialists choose agents with safer profiles and start at low doses for mood or anxiety symptoms. Psychological therapies are always combined to reduce medicine doses.

19. Antibiotics for intercurrent infections
    Prompt, appropriate antibiotics for bacterial chest, ear, or urinary infections are vital to prevent decompensation. Doctors choose agents that are effective but try to avoid drugs that are especially toxic to mitochondria whenever possible.

20. Vaccines and immunisations
    Although not “drugs for the disease,” routine and additional vaccines (influenza, pneumococcal, COVID-19, etc.) are essential medicines that lower the risk of severe infections, hospitalisation, and regression in mitochondrial disorders.

Dietary Molecular Supplements

Evidence for supplements in mitochondrial disease is mixed and often limited, but some are commonly used as “mitochondrial cocktails” under specialist guidance. They are usually considered adjunctive and not a cure.

1. Coenzyme Q10 (CoQ10)
   CoQ10 is part of the electron transport chain and helps cells make ATP and handle oxidative stress. Oral CoQ10 is often used in oxidative phosphorylation disorders, though large trials show mixed benefit. Doses vary widely (often divided twice daily). Side effects are usually mild (stomach upset, headache).

2. L-carnitine
   L-carnitine transports fatty acids into mitochondria for energy production. Supplementation may help prevent carnitine deficiency and support energy metabolism, especially during illness. It is given two to three times per day; higher doses can cause diarrhoea or fishy body odour.

3. Riboflavin (vitamin B2)
   Riboflavin is a cofactor for multiple mitochondrial enzymes. In some mitochondrial disorders, high-dose riboflavin has shown clinical benefit, and it is sometimes used in general mitochondrial cocktails. It is usually taken one to three times daily with food; urine may turn bright yellow.

4. Thiamine (vitamin B1)
   Thiamine is essential for pyruvate dehydrogenase and other energy-producing enzymes. Supplementation is low risk and may help in patients with overlapping energy-metabolism defects or borderline intake. High doses can rarely cause allergic reactions, especially if given IV.

5. Alpha-lipoic acid
   Alpha-lipoic acid is an antioxidant and enzyme cofactor that can help reduce oxidative stress. In some studies, combinations with CoQ10 and creatine improved biochemical markers in mitochondrial disease. It is usually given orally with food; side effects include nausea and, rarely, low blood sugar.

6. Creatine monohydrate
   Creatine serves as a quick energy buffer in muscle and brain. Supplementation may modestly improve exercise tolerance or muscle strength in some mitochondrial patients. It is usually taken daily, sometimes split into two doses. Stomach upset and weight gain from water retention can occur.

7. B-complex vitamins / NADH support
   Complete B-vitamin complexes and NADH precursors support many mitochondrial enzymes and redox reactions. They are often included in low-risk mitochondrial cocktails. Excessive doses, especially of vitamin B6, can cause neuropathy, so dosing must be supervised.

8. Vitamin D
   Vitamin D supports bone health, immune function, and muscle performance. Many chronically ill or low-mobility patients are deficient. Replacement is usually once daily or once weekly, based on blood levels. Very high doses without monitoring can cause high calcium and kidney problems.

9. Omega-3 fatty acids
   Omega-3s from fish oil or algae have anti-inflammatory effects and may support neuronal health. They are sometimes used to support brain and nerve function in mitochondrial disease, with typical dosing once or twice daily with meals. Main side effects are fishy aftertaste and mild stomach upset.

10. Mitochondria-targeted antioxidants (e.g., MitoQ)
    MitoQ (mitoquinone) is a coenzyme Q10 analogue designed to concentrate in mitochondria and reduce oxidative damage. It is sold as a supplement and is being studied in various conditions, but robust data in primary mitochondrial disease are still limited.

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Immunity-Boosting, Regenerative, and Stem-Cell-Related Approaches

There are no approved stem-cell or gene-replacement drugs yet for C12orf65 deficiency. All approaches below are experimental or supportive and must only be considered in expert centres or research studies.

1. Optimised vaccination and infection prevention
   The most realistic “immunity booster” is not a pill but up-to-date vaccines, good nutrition, sleep, and infection control. This lowers hospitalisations and severe metabolic stress, giving the body a better chance to cope with the mitochondrial defect.

2. Nutritional immune support (balanced diet + micronutrients)
   Adequate calories, protein, vitamins, and minerals support immune cells that rely on healthy mitochondria. Correcting deficiencies (for example, vitamin D or zinc) can improve immune responses, but mega-doses are not recommended without tests.

3. Mitochondria-targeted antioxidant “cocktails”
   Combinations of CoQ10, L-carnitine, alpha-lipoic acid, and B-vitamins aim to reduce oxidative damage and may indirectly support immune and tissue recovery. Evidence is modest, and these are best seen as supportive tools rather than regenerative cures.

4. Hematopoietic or mesenchymal stem-cell therapies (research only)
   In some mitochondrial and neuromuscular diseases, stem-cell therapies are being explored, but there is no standard stem-cell treatment for C12orf65 deficiency. Participation should only occur in approved clinical trials with clear safety monitoring.

5. Gene-replacement and gene-therapy strategies (pre-clinical)
   Recent work suggests that MTRFR/C12orf65 deficiency may be a promising target for gene-replacement therapy in animal and cell models, but human trials have not yet started. In future, viral vectors or other technologies may restore part of the missing mitochondrial function.

6. Rehabilitation-driven neuroplasticity
   Intensive, personalised physiotherapy, occupational therapy, and communication training help the brain form new connections despite underlying damage. This “functional regeneration” cannot fix the gene, but it can maximise remaining abilities and independence.

Surgeries and Procedures (Why They May Be Done)

1. Gastrostomy tube (PEG or button) placement
   When swallowing is unsafe or oral intake is too low, a feeding tube directly into the stomach can be placed via a short procedure. It allows safe feeding, hydration, and medicine delivery, improving nutrition and lowering aspiration risk.

2. Tracheostomy
   In severe cases with chronic respiratory failure or repeated aspiration, a tracheostomy (surgical opening in the neck into the windpipe) may be needed. It allows secure ventilation support and easier suctioning but requires intensive home-care training.

3. Orthopaedic surgery for contractures or scoliosis
   Tendon-lengthening, hip or foot surgery, or spinal fusion may be recommended when contractures or scoliosis cause pain, sitting problems, or breathing restriction. Surgery aims to improve posture, comfort, and the ability to use wheelchairs or standers.

4. Ophthalmologic procedures
   Some patients may benefit from squint surgery or eyelid surgery to improve eye alignment or lid closure, which can help vision use and protect the cornea, even though surgery cannot reverse optic atrophy.

5. Implantation of intrathecal baclofen pump
   For severe generalised spasticity not controlled with oral medicines, a pump delivering baclofen into the spinal fluid can reduce stiffness and pain. The procedure involves implanting the pump under the skin and connecting a catheter to the spinal canal.

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Key Prevention and Lifestyle Strategies

1. Avoid prolonged fasting; use small, frequent meals and fluids.

2. Treat fevers and infections promptly and follow an emergency plan.

3. Keep vaccinations up-to-date, including influenza and pneumonia vaccines.

4. Avoid clearly mitochondria-toxic drugs when possible (for example, certain aminoglycosides or valproate in many mitochondrial disorders).

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

6. Use energy-saving strategies and avoid extreme over-exertion.

7. Protect from extreme heat or cold and allow rest in cool environments.

8. Keep regular follow-up with neurology, genetics, and other specialists.

9. Monitor growth, weight, and bone health, adjusting diet and supplements as needed.

10. Provide psychological, social, and educational support to reduce stress on the child and family.

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When to See a Doctor Urgently

You should seek urgent medical help (emergency department or immediate contact with your mitochondrial/neurology team) if there is:

• A first-time seizure, seizure lasting longer than usual, or repeated seizures without recovery.

• Sudden change in breathing, blue lips, or repeated pauses in breathing.

• New trouble swallowing, choking, or coughing with feeds.

• High fever, repeated vomiting, or inability to drink and keep fluids down.

• Loss of skills (cannot sit, stand, or speak as before) over days to weeks.

• Sudden vision loss or major change in vision.

For non-urgent questions (for example, mild change in stamina, school difficulties, or behaviour changes), you should still discuss them at the next clinic visit with the mitochondrial team.

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What to Eat and What to Avoid Points

Diet must be personalised by a dietitian, but these simple rules often help in mitochondrial disease:

1. Eat regularly – three meals plus snacks; do not skip breakfast.

2. Include protein and complex carbohydrates (for example, beans + rice, meat + whole grains) in every meal or snack.

3. Use healthy fats (olive oil, nut butters, avocado) for extra calories when needed.

4. Drink fluids steadily during the day, especially in hot weather or during illness.

5. Focus on whole foods – fruits, vegetables, whole grains, lean meats, and dairy or alternatives.

6. Avoid very low-calorie or crash diets, which can worsen fatigue and risk metabolic crises.

7. Avoid long periods without food, especially overnight; consider a bedtime snack if recommended.

8. Limit highly processed, very sugary foods and drinks, which may cause quick energy swings.

9. Avoid excess caffeine and energy drinks, which may worsen sleep, heart rate, or anxiety.

10. Discuss special diets (like ketogenic or high-fat diets) only with specialists, as they can help some patients with seizures but may harm others.

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Frequently Asked Questions (FAQs)

1. Is c12orf65 combined oxidative phosphorylation deficiency always severe?
   Severity varies. Some people have very early-onset disease with major disabilities, while others walk, talk, and live into adulthood with support. The exact mutation and other genes, plus environment and care, all influence how the disease looks.

2. Can children with this condition go to school?
   Yes. Many children can attend school with help such as special education plans, physical access supports, and vision aids. Early involvement of teachers and therapists helps the child take part as fully as possible.

3. Is there a cure now?
   There is no cure yet. All current treatments are supportive and focus on reducing symptoms, preventing complications, and improving quality of life. Research into gene therapy and better mitochondrial treatments is ongoing.

4. Will symptoms get worse over time?
   Many mitochondrial diseases are progressive, but the speed of change differs from person to person. Good nutrition, infection control, therapy, and regular specialist care may slow some problems, but they cannot fully stop the underlying genetic defect.

5. Can exercise help or harm?
   Gentle, regular, supervised exercise usually helps maintain muscle strength and fitness and can improve mood. Over-exertion and extreme sports may trigger severe fatigue, so pacing and rest are very important.

6. Are supplements like CoQ10 mandatory?
   No. Supplements are optional tools. Some people feel better on them, others notice little change. Because evidence is limited, they should be used only under specialist advice, especially at high doses.

7. Can vaccines make the disease worse?
   Vaccines protect against infections that can be very dangerous for people with mitochondrial disease. For most patients, the benefit is much greater than the risk, though timing and choice may be adjusted by the specialist team.

8. Is this condition inherited from the mother’s mitochondria?
   No. C12orf65 is a nuclear gene (on chromosome 12), so the condition is usually autosomal recessive: the child inherits one faulty copy from each parent. It is not a classic “mitochondrial DNA” disease passed only through mothers.

9. Can brothers or sisters also be affected?
   Yes. In autosomal recessive disease, each full sibling has a 25% chance to be affected, a 50% chance to be a healthy carrier, and a 25% chance to inherit two working copies, unless one parent is not a carrier. Genetic counselling is recommended.

10. Does every patient develop seizures?
    No. Some people never have seizures, while others develop severe epilepsy. Regular neurological follow-up allows early detection and treatment if seizures appear.

11. Can vision loss be reversed?
    Optic atrophy usually represents permanent damage to the optic nerve. Glasses may improve any refractive error, and low-vision aids can make the best use of remaining sight, but there is currently no way to rebuild the damaged nerve.

12. Will gene therapy be available soon?
    Pre-clinical studies suggest C12orf65/MTRFR deficiency may respond to gene-replacement approaches, but human trials have not yet started. It is impossible to predict timing, but taking part in registries and studies helps move the field forward.

13. Is anaesthesia safe for surgery?
    Anaesthesia can be used, but it must be carefully planned by an anaesthetist familiar with mitochondrial disease. They choose drugs and fluid plans that minimise metabolic stress and monitor closely before, during, and after surgery.

14. Can adults with this condition work and live independently?
    Some adults, especially those with milder forms, can work and live semi-independently with supports such as mobility aids, modified working hours, and home help. Others need significant daily support. Early rehabilitation and education planning improve the chances of independence.

15. Where can families find more help and information?
    Families can ask their specialists about national mitochondrial disease foundations, patient support groups, and registries focusing on C12orf65/MTRFR. These groups share information, emotional support, and updates on clinical trials and research.

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.