Severe C12orf65-related combined oxidative phosphorylation defect is a very rare inherited disease of the mitochondria. Mitochondria are tiny “power stations” inside almost every cell, and they make most of the cell’s energy using a process called oxidative phosphorylation. In this disease, that energy-making process does not work properly in many tissues at the same time (combined defect), so the brain, eyes, nerves, and muscles do not get enough energy. The problem comes from harmful changes (mutations) in a nuclear gene called C12orf65 (also known today as MTRFR). This gene gives the instructions for a small protein that helps finish protein-making inside mitochondria. When this protein does not work, mitochondrial protein production falls, so several parts (complexes) of the respiratory chain become weak, and the cell cannot make enough energy from food and oxygen.
Severe C12orf65-related combined oxidative phosphorylation defect is an ultra-rare inherited mitochondrial disease. It is also called combined oxidative phosphorylation deficiency 7 (COXPD7) or severe C12ORF65-related COXPD. In this condition, both copies of the C12orf65 (MTRFR) gene are changed (mutated), usually in an autosomal recessive pattern, so a child inherits one faulty copy from each parent.
The C12orf65 gene makes a protein that helps ribosomes inside mitochondria finish making new proteins and release them correctly. When this protein does not work, mitochondrial protein production is disturbed. As a result, several parts of the oxidative phosphorylation (OXPHOS) chain do not work properly at the same time, so cells cannot make enough energy.
Severe forms often start in infancy or early childhood. Common problems can include developmental delay, low muscle tone or weakness, spasticity (stiff tight muscles), optic atrophy leading to visual loss, peripheral neuropathy, movement problems, feeding difficulties, and sometimes a Leigh-like brainstem and basal ganglia pattern on MRI. Over time the disease may progress and can affect breathing and swallowing.
Because the disease affects many energy-hungry tissues, children often show problems such as poor development, loss of skills, vision loss from optic nerve damage, muscle weakness, and sometimes changes in the brain that look like Leigh syndrome on MRI. The disease usually starts in infancy or childhood, often gets worse over time, and is very rare, with a frequency estimated at less than 1 in 1,000,000 people worldwide.
Other names
Doctors and researchers may use several different names for the same condition:
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Combined oxidative phosphorylation deficiency 7 (COXPD7)
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C12orf65 combined oxidative phosphorylation deficiency
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Severe C12ORF65-related combined oxidative phosphorylation defect
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Severe C12ORF65-related COXPD
All of these names describe the same basic disease caused by mutations in the C12orf65 gene on chromosome 12q24.31.
How the C12orf65 gene and mitochondria are involved
The C12orf65/MTRFR protein belongs to a family called mitochondrial translation release factors. These proteins help the mitochondrial ribosome stop protein-making correctly and clear stuck protein-RNA complexes. If C12orf65 does not work, mitochondrial translation is impaired, so many mitochondrial proteins cannot be finished.
Studies on patients with this disease have shown a global and uniform decrease in mitochondrial translation in their cells. This leads to reduced activity of several respiratory chain complexes, especially complexes I and IV, and sometimes others, so the disease is called a “combined oxidative phosphorylation defect.”
Because brain, optic nerve, spinal cord, and long peripheral nerves all need a lot of energy, they are especially sensitive to this problem. This is why many patients show a triad of early optic atrophy (pale, damaged optic nerves), axonal neuropathy (damage to long nerves in the limbs), and spastic paraparesis (stiff, weak legs), sometimes with intellectual disability or encephalomyopathy.
Types (clinical patterns)
Doctors do not have official “types” like type 1, type 2, etc., but cases can be grouped into several patterns based on symptoms and MRI findings:
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Classic severe childhood encephalomyopathy with optic atrophy – early developmental delay or regression, visual loss, brain MRI changes, and peripheral neuropathy.
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Leigh-like syndrome pattern – lesions in basal ganglia and brainstem on MRI, high lactate peak on MR spectroscopy, with optic atrophy and motor delay.
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Spastic paraplegia / Behr-like phenotype – main problems are stiff, weak legs (spastic paraparesis), optic atrophy, and neuropathy, sometimes called SPG55 in the spastic paraplegia classification.
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Distal motor neuropathy with optic atrophy – marked weakness of distal limb muscles and optic atrophy, with fewer central brain signs in some patients.
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Milder late-onset forms – some adults may have milder and slower symptoms, though severe childhood-onset disease is more typical.
These patterns overlap, and the exact picture usually depends on where the mutation is located in the gene and how strongly it damages the C12orf65 protein.
Causes and mechanisms
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Homozygous loss-of-function mutations in C12orf65
The main direct cause is having two copies of a harmful mutation (homozygous mutation) in the C12orf65 gene, one from each parent. These mutations stop the protein from working and cause a combined oxidative phosphorylation defect. -
Compound heterozygous C12orf65 mutations
Some patients inherit two different disease-causing variants in C12orf65 (compound heterozygous). Even though the two mutations are not identical, together they remove normal protein function and lead to the same disease. -
Frameshift mutations truncating the protein
Frameshift changes, such as the c.210del (p.Gly72fs) deletion, shift the reading frame and create a very short, non-working protein. These early truncating mutations are strongly linked with severe disease in childhood. -
Nonsense mutations (stop codons) in C12orf65
Nonsense mutations introduce an early “stop” signal in the gene code. This also leads to a shortened, unstable protein that cannot perform its role in mitochondrial translation. -
Splice-site mutations causing exon skipping
Some disease variants change splice sites, so parts of the gene (exons) are skipped when making the RNA. Skipping an important exon (like exon 2) changes the protein structure and disables its function. -
Mutations disrupting the GGQ motif
The C12orf65 protein contains a small GGQ sequence that is crucial for its action as a translation release factor. Mutations that damage this region are linked to more severe, early-onset disease with cognitive problems. -
C-terminal truncating mutations
Mutations near the tail (C-terminal) of the protein remove part of the end region. These can still cause disease but may be linked with somewhat milder forms, such as optic atrophy with spastic paraparesis and less cognitive impairment. -
Global impairment of mitochondrial translation
All these genetic changes lead to poor mitochondrial protein synthesis. When mitochondria cannot make enough of their own proteins, several respiratory chain complexes fail, and oxidative phosphorylation is globally reduced. -
Combined deficiency of several respiratory chain complexes
Biopsy and cell studies often show decreased activity of complex I and complex IV, and sometimes other complexes. Because more than one complex is affected, the disease is called a “combined” oxidative phosphorylation defect. -
Autosomal recessive inheritance from carrier parents
The disease follows an autosomal recessive pattern. Parents usually carry one mutated copy but are healthy. When both parents are carriers, each pregnancy has a 25% chance of a child with the disease. -
Consanguinity (parents related by blood)
In some families, parents are related (for example, cousins). This makes it more likely that both parents carry the same rare C12orf65 mutation, so the risk of having affected children increases. -
Energy vulnerability of the optic nerve
The optic nerve needs a lot of energy to send signals from the eye to the brain. When oxidative phosphorylation is weak, these nerve fibers can slowly die, leading to optic atrophy and vision loss. -
Energy failure in deep brain structures
Basal ganglia and brainstem also use a lot of energy. Poor mitochondrial function in these regions can cause Leigh-like lesions on MRI and problems with movement, swallowing, and breathing. -
Axonal peripheral neuropathy due to long nerve involvement
Long peripheral nerves in the arms and legs are very sensitive to energy failure. Damage to these nerves leads to distal weakness, loss of reflexes, and reduced sensation, which are common in C12orf65-related disease. -
Spinal cord tract degeneration causing spastic paraparesis
The long tracts in the spinal cord that control leg movement can degenerate when mitochondria do not supply enough energy, causing stiff, weak legs (spastic paraparesis). -
Muscle fiber damage and atrophy
Muscle cells packed with abnormal mitochondria may become weak and thin over time. This chronic mitochondrial myopathy can cause muscle atrophy, poor tone, and fatigue. -
Modifier genes in mitochondria and nucleus
Other genetic factors, both in mitochondrial DNA and other nuclear genes, likely modify how severe the disease is. This helps explain why people with similar C12orf65 mutations can have different symptoms. -
Metabolic stress from infections or fasting
In many mitochondrial diseases, infections, fever, or long fasting can worsen energy shortage in cells and trigger regression or new neurological symptoms. Similar stress may aggravate this C12orf65-related defect. -
High energy demand during growth and development
During early childhood, the brain and nervous system grow fast and need stable energy supply. A fixed mitochondrial defect will show more clearly at this time, leading to childhood-onset symptoms. -
Impaired mitochondrial quality control and ribosome rescue
C12orf65 is thought to help “rescue” stalled mitochondrial ribosomes and clear abnormal protein-RNA complexes. When this quality control pathway fails, damaged translation products may build up and further harm mitochondrial function.
Symptoms
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Developmental delay and regression
Many children are slow to sit, stand, walk, or talk. Some gain skills and then lose them later (regression) when the brain cannot get enough energy, leading to encephalomyopathy. -
Intellectual disability or learning problems
Cognitive function can be affected, from mild learning difficulties to more serious intellectual disability, especially in severe early-onset forms with mutations in crucial regions of C12orf65. -
Optic atrophy and visual loss
The optic nerves become thin and pale, which is called optic atrophy. This causes reduced vision, problems with sharpness and sometimes color vision, and can slowly worsen over time. -
Nystagmus (involuntary eye movements)
Some patients have rapid, jerky eye movements called nystagmus. This can blur vision and is a sign that the visual pathway and brainstem are not working normally. -
External ophthalmoplegia (eye movement weakness)
Weakness of the muscles that move the eyes can lead to limited eye movements and sometimes droopy eyelids (ptosis). This reflects muscle and nerve involvement around the eyes. -
Ataxia (poor balance and coordination)
Many patients have unsteady walking, clumsiness, and difficulty with coordination tasks, such as reaching for objects. This is often due to cerebellar and sensory pathway involvement. -
Spastic paraparesis (stiff, weak legs)
Damage to long motor tracts in the spinal cord leads to stiffness, increased reflexes, and weakness in the legs. This may cause scissoring gait, toe walking, or the need for walking aids. -
Peripheral axonal neuropathy
Patients can have tingling, numbness, and weakness in the feet and hands because long peripheral nerves are damaged. Nerve conduction tests often show an axonal neuropathy pattern. -
Muscle weakness and hypotonia
Muscle tone may be low (floppy baby), and strength is reduced, especially in the limbs and trunk. Over time, muscles can become thin and weak due to chronic mitochondrial myopathy. -
Bulbar dysfunction (feeding and speech problems)
Some children have trouble swallowing, choking on feeds, nasal speech, or weak voice because the muscles in the throat and lower brainstem nuclei are affected. -
Seizures or abnormal movements
Seizures, myoclonus (sudden jerks), or other abnormal movements may occur in some patients. These symptoms reflect energy failure and structural lesions in the brain. -
Leigh-like episodes with regression
MRI can show symmetrical lesions in brainstem and basal ganglia similar to Leigh syndrome. During these episodes, children may lose skills, have breathing problems, or become less alert. -
Fatigue and exercise intolerance
Even simple activities can cause tiredness, breathlessness, or leg pain because muscles cannot produce enough energy during exercise. This is common in mitochondrial diseases. -
Growth failure or short stature
Some children grow more slowly than expected. Chronic illness, poor feeding, and energy shortage all contribute to low weight or height. -
Multi-system involvement (heart, endocrine, others) in some cases
Although the main problems are neurological and visual, mitochondrial diseases may sometimes involve the heart, endocrine glands, or other organs, so doctors must look for these as well.
Diagnostic tests
Doctors use many tests to confirm the diagnosis and to rule out other causes. Below, tests are grouped as requested: physical exam, manual tests, lab/pathological tests, electrodiagnostic tests, and imaging tests.
Physical exam tests
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Comprehensive physical exam and growth assessment
The doctor checks weight, height, head size, vital signs, and general appearance. Poor growth, small head size, or other physical clues can suggest a chronic metabolic or mitochondrial problem that needs deeper testing. -
Detailed neurological examination
The neurologist checks tone, strength, reflexes, sensation, eye movements, coordination, and gait. Findings like spasticity, reduced reflexes in neuropathy, or ataxia help show that the nervous system is widely involved. -
Basic eye examination (visual acuity and fields)
An ophthalmologist measures visual acuity, checks visual fields, and looks at eye alignment. Reduced vision and visual field defects are common in optic atrophy due to C12orf65-related disease. -
Developmental and functional assessment
Standard developmental scales and functional assessments (for example, gross motor and fine motor milestones) are used to document delays and regression. This helps track disease course over time.
Manual (bedside) tests
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Manual muscle strength testing
The examiner asks the child to push or pull against resistance and grades strength using simple scales. This bedside test can show weakness patterns that suggest myopathy or neuropathy. -
Gait and balance tests (walking, heel-toe, Romberg)
The patient is observed walking, walking on heels or toes, and standing with feet together, sometimes with eyes closed (Romberg). Spastic gait, unsteadiness, or falls can point to spinal cord or cerebellar involvement. -
Coordination tests (finger-to-nose, heel-to-shin)
The doctor asks the patient to touch their nose and then the doctor’s finger, or to slide the heel down the opposite shin. Difficulty doing these tasks shows ataxia or proprioceptive problems, common in energy-deficient brain circuits. -
Bedside eye movement (oculomotor) tests
The doctor moves a target in different directions and asks the patient to follow it with their eyes. Limited movement, double vision, or nystagmus can be seen in C12orf65-related disease and suggest brainstem or muscle involvement.
Laboratory and pathological tests
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Blood lactate and pyruvate levels
Elevated blood lactate, and sometimes an abnormal lactate-to-pyruvate ratio, are common signs of mitochondrial dysfunction, including combined oxidative phosphorylation defects. However, normal values do not rule out disease. -
Blood alanine and plasma amino acids
High alanine levels and abnormal plasma amino acids can also point toward mitochondrial disease and help separate it from other metabolic disorders. -
Urine organic acid analysis
The lab looks for unusual organic acids in the urine. Some patterns suggest mitochondrial respiratory chain problems or related metabolic stress, supporting the diagnosis. -
Serum creatine kinase (CK)
CK is an enzyme released from damaged muscles. In mitochondrial disease, CK may be normal or mildly elevated, but a raised CK can still support muscle involvement. -
Muscle biopsy with histology (including ragged-red fibers)
A small piece of muscle is taken and studied under the microscope. The pathologist may see ragged-red fibers or other signs of abnormal mitochondria, which strongly support a mitochondrial myopathy. -
Respiratory chain enzyme analysis in muscle or fibroblasts
Special biochemical tests measure the activity of complexes I–IV in muscle or fibroblast samples. In C12orf65-related COXPD7, combined decreases of several complexes often confirm the oxidative phosphorylation defect. -
Molecular genetic testing of C12orf65 and gene panels
Today, the most definitive test is DNA sequencing to look for C12orf65 mutations, often as part of a mitochondrial or neuro-optic gene panel or exome/genome sequencing. Finding two pathogenic variants confirms the genetic diagnosis.
Electrodiagnostic tests
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Nerve conduction studies and electromyography (NCS/EMG)
These tests measure how fast and how strongly electrical signals travel along nerves and muscles. In C12orf65-related disease, they often show an axonal neuropathy pattern, explaining distal weakness and sensory loss. -
Visual evoked potentials (VEP)
VEP records brain responses to visual stimuli. Delayed or reduced VEP signals show that the optic pathway is damaged, supporting the diagnosis of optic neuropathy due to mitochondrial disease. -
Electroencephalogram (EEG)
EEG records electrical activity in the brain. It helps detect seizures or background slowing that may occur in encephalomyopathy and Leigh-like lesions associated with combined oxidative phosphorylation defects.
Imaging tests
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Brain MRI
Brain MRI can show symmetric lesions in the basal ganglia and brainstem, white-matter changes, or cerebellar atrophy. These patterns can look similar to Leigh syndrome and are highly suggestive of mitochondrial disease in the right clinical setting. -
Brain MR spectroscopy (MRS) for lactate peak
MRS is an MRI-based technique that measures brain chemicals. In mitochondrial disease, it may show a lactate peak in affected areas, which is a strong marker of impaired oxidative phosphorylation and supports the diagnosis. -
Imaging of the optic nerves (MRI or OCT)
MRI of the orbits or optical coherence tomography (OCT) can show thinning of the optic nerves and retinal nerve fiber layer. These findings match the clinical picture of optic atrophy in C12orf65-related disease.
Non-pharmacological treatments (Therapies and other approaches)
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Multidisciplinary care team
Children with severe C12orf65-related combined oxidative phosphorylation defect usually benefit from a team that includes neurologists, metabolic specialists, physiotherapists, occupational therapists, speech therapists, dietitians, and psychologists. Working together helps them build a single, clear care plan, reduce duplicated tests, and respond quickly when new problems appear, which is strongly recommended in modern mitochondrial disease management. -
Energy conservation and pacing
Because cells cannot make energy efficiently, even simple activities can cause exhaustion. Pacing means planning the day so that demanding tasks are spread out, with frequent rest breaks and flexible school schedules. This avoids “boom-and-bust” cycles where a child does too much on good days and then crashes. Energy-saving aids (wheelchairs, adaptive strollers) can be part of this strategy. -
Physiotherapy and stretching
Regular physiotherapy focuses on gentle stretching, maintaining joint range of motion, and preventing contractures from spasticity or weakness. Low-impact strengthening and balance exercises are added slowly as tolerated. In mitochondrial disease, carefully supervised exercise can improve muscle efficiency and fitness, but over-exertion must be avoided and programs must be customized. -
Occupational therapy for daily skills
Occupational therapists help the child manage dressing, feeding, toileting, writing, and play with less effort and more independence. They may suggest adapted cutlery, special seating, splints, and strategies to simplify tasks. This reduces fatigue, improves safety, and supports school participation, which is central to long-term quality of life in mitochondrial disease. -
Speech, swallowing, and feeding therapy
If brainstem and cranial nerves are affected, there may be speech and swallowing problems. Speech therapists can work on articulation, safe swallowing techniques, and communication tools (for example, communication boards or devices). Early management reduces the risk of choking, aspiration pneumonia, and poor nutrition, which can worsen mitochondrial stress. -
Low-vision and optic atrophy support
Optic atrophy is a core feature of many C12orf65-related phenotypes. Low-vision specialists can train the child to use remaining vision, suggest high-contrast print, magnifiers, and electronic devices, and advise schools on modifications. Early visual support can greatly improve learning and orientation even if vision cannot be restored. -
Mobility aids and orthotics
Spasticity, neuropathy, and weakness often make walking difficult. Ankle-foot orthoses, walkers, standing frames, wheelchairs, or adapted buggies can give more stability and reduce falls. The goal is not to “give up walking” but to allow safe movement, conserve energy, and protect joints. This is standard supportive care in complex neuromuscular mitochondrial disorders. -
Respiratory physiotherapy and support
If respiratory muscles are weak or brainstem control is affected, breathing may become shallow or irregular. Chest physiotherapy, assisted coughing devices, and sometimes non-invasive ventilation (like BiPAP at night) can help keep lungs clear and improve sleep quality. Early recognition of breathing problems is crucial in progressive mitochondrial encephalomyopathies. -
Seizure safety planning
Many mitochondrial diseases can involve seizures, even if not every C12orf65 patient has them. Families are taught seizure first-aid, when to call emergency services, and how to use any prescribed rescue medicine. Schools and caregivers should have written plans. Good seizure management helps avoid hypoxia, injury, and additional metabolic stress on the brain. -
Nutritional optimization with a dietitian
A dietitian experienced in mitochondrial disease can help maintain adequate calories, protein, and micronutrients. Avoiding both prolonged fasting and large, heavy meals can stabilize energy supply. Sometimes higher-calorie formulas or tube feeding are needed to prevent weight loss and muscle wasting in severe combined oxidative phosphorylation defects. -
Aggressive infection prevention and early treatment
Any infection increases metabolic demand, fever, and catabolism. Families are taught to seek early medical review for fever, vomiting, or dehydration. Some centers provide “sick day” protocols with increased fluids and sometimes temporary IV glucose. Fast treatment of infections can prevent decompensation and regression in mitochondrial disorders. -
Temperature and stress management
Extreme heat, prolonged cold, or emotional stress can worsen fatigue and symptoms. Simple steps like staying cool in hot weather, avoiding long hot baths, and building predictable routines can reduce stress on the body. This may not change the disease course but can make symptoms easier to live with. -
Psychological support and family counseling
Chronic rare disease affects the whole family. Emotional support, counseling, and sometimes child psychiatry input help manage anxiety, depression, or behavioral difficulties. Parents may also need help coping with uncertainty, complicated decisions, and grief. Psychosocial care is now considered a key part of mitochondrial disease management. -
Special education and cognitive rehabilitation
Some children with C12orf65-related disease have learning difficulties or intellectual disability. Early assessment allows tailored school support, assistive technology, and cognitive training. Structured routines, visual supports, and repetition help the child use remaining abilities. This approach can improve function even if it does not change the genetic cause. -
Sleep hygiene and fatigue management
Good sleep is essential for brain repair and energy balance. Simple rules include regular bedtimes, quiet and dark bedrooms, limiting screens before sleep, and managing pain or reflux that interrupts rest. If breathing problems or seizures disrupt sleep, medical review is needed. Better sleep often reduces daytime fatigue and irritability. -
Regular monitoring and screening
Because C12orf65-related disease can affect many organs, regular check-ups look at vision, growth, nutrition, motor skills, breathing, heart function, and lab markers like lactate. MRI and EEG may be repeated when symptoms change. Early detection of new complications gives more chance to treat or slow problems. -
Genetic counseling for the family
Genetic counseling explains the autosomal recessive inheritance and the risk to future pregnancies and siblings. Carrier testing, prenatal diagnosis, or pre-implantation genetic testing may be discussed. This helps parents make informed reproductive choices and allows wider family members to understand their own risks. -
Palliative and supportive care in advanced disease
When disease is very severe or clearly progressive, palliative care teams focus on comfort, symptom control, and supporting family goals. This may include managing pain, breathlessness, and anxiety, and planning for care at home or in hospital. Palliative care can be combined with active treatments and is not the same as “giving up.” -
Structured, low-intensity exercise training
In carefully selected mitochondrial patients, supervised, low-intensity aerobic and resistance training can improve exercise tolerance and mitochondrial efficiency. In severe COXPD7, programs must be extremely gentle, closely monitored, and stopped immediately if symptoms worsen. Exercise is seen as a “treatment” for deconditioning, not a cure for the gene defect. -
Avoidance of mitochondrial-toxic drugs
Some medicines can further harm mitochondrial function, such as valproate in certain genetic backgrounds, or high cumulative doses of some antibiotics. Valproic acid products carry specific warnings about increased risk of liver failure in patients with mitochondrial disease, highlighting the need for caution and specialist input when choosing medications.
Drug treatments
Important: none of these medications is specifically approved by the FDA to treat severe C12orf65-related combined oxidative phosphorylation defect. They are used off-label in mitochondrial disease based on small studies, case reports, or theoretical mechanisms.
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Coenzyme Q10 (ubiquinone / ubiquinol)
Coenzyme Q10 helps move electrons along the mitochondrial respiratory chain and acts as an antioxidant. Many experts include it in mitochondrial “cocktails,” even though trials show mixed benefit. Typical oral doses in mitochondrial disease may be 5–30 mg/kg/day divided, but exact dose varies. Side effects are usually mild (stomach upset, headache). CoQ10 is designated as an orphan product for certain heart conditions, not specifically for this gene defect. -
Riboflavin (vitamin B2)
Riboflavin is a cofactor for complex I and II and helps several mitochondrial enzymes work properly. Some complex I deficiencies improve clinically and biochemically on high-dose riboflavin. In practice, doses like 50–400 mg/day by mouth are used in mitochondrial disease, usually in divided doses with food. Side effects are minimal (bright yellow urine, rare stomach upset). It is often combined with CoQ10. -
Thiamine (vitamin B1)
Thiamine is a cofactor for pyruvate dehydrogenase and other enzymes that link glycolysis to the Krebs cycle. High doses may help some mitochondrial disorders, especially those with lactic acidosis or thiamine-responsive variants. Doses can range from 50–300 mg/day orally. It is generally safe, with occasional nausea or allergic reactions in parenteral use. Thiamine is part of several IV multivitamin products used in hospital care. -
Levocarnitine (CARNITOR®)
Levocarnitine helps transport long-chain fatty acids into mitochondria for oxidation. In mitochondrial disease, it may support energy production and help remove toxic acyl groups, especially if blood carnitine is low. Typical oral doses are about 50–100 mg/kg/day divided; IV forms are used acutely. Side effects include diarrhea and fishy body odor. Levocarnitine is FDA-approved for carnitine deficiency, not for C12orf65 deficiency, but it is widely used in mitochondrial patients. -
Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant and enzymatic cofactor in mitochondrial dehydrogenase complexes. It may reduce oxidative stress and support residual mitochondrial function. Doses used in practice (not specific to C12orf65) often range from 100–600 mg/day. Side effects can include stomach upset and rare low blood sugar in diabetics. It is commonly included in mitochondrial supplement regimens, but robust trial data are limited. -
Arginine
Arginine is a precursor for nitric oxide and may improve blood flow in some mitochondrial disorders, especially MELAS with stroke-like episodes. In severe C12orf65 disease, it is sometimes used to support vascular function, though specific evidence is lacking. Doses vary (for example, 150–500 mg/kg/day orally or IV during acute events in MELAS). Possible side effects include diarrhea and high potassium. -
Folinic acid (reduced folate)
Folinic acid supports one-carbon metabolism and DNA repair, and may help some mitochondrial conditions with cerebral folate deficiency. Doses like 0.5–3 mg/kg/day (max 50 mg/day) are used. Side effects are generally mild (GI upset, rare allergic reaction). Its role in severe C12orf65-related disease is theoretical but it is sometimes added to broad mitochondrial regimens. -
Vitamin E (tocopherol)
Vitamin E is a fat-soluble antioxidant that can protect cell membranes, including mitochondrial membranes, from oxidative damage. Doses may be 100–400 IU/day in children, adjusted by weight. High doses can increase bleeding risk, especially with anticoagulants. It is often used together with CoQ10 in mitochondrial patients, although clear benefit for this specific defect is not proven. -
Vitamin C (ascorbic acid)
Vitamin C is a water-soluble antioxidant and cofactor in many enzymatic reactions. It may help reduce oxidative stress in mitochondrial disorders. Doses vary (for example 100–500 mg/day in children, higher in adults). High doses can cause stomach upset or kidney stones in at-risk people. It is often included because it is inexpensive and generally safe. -
Parenteral multivitamin preparations (e.g., INFUVITE)
In hospital, patients who cannot eat may receive IV multivitamins that include thiamine, riboflavin, niacinamide, pyridoxine, folic acid, vitamin B12, and fat-soluble vitamins. These products prevent vitamin deficiency during parenteral nutrition but are not specific mitochondrial drugs. They ensure that no treatable vitamin deficiency is missed in a child with severe C12orf65-related disease. -
Vatiquinone (EPI-743)
Vatiquinone (EPI-743) is a small-molecule redox modulator studied as an orphan drug for mitochondrial diseases such as Leigh syndrome. It targets the oxidoreductase system and aims to rebalance cellular redox state. Doses and long-term safety are still being studied; it is not widely available and is used only in trials or specialized centers. -
Idebenone
Idebenone is a synthetic analogue of CoQ10 that can shuttle electrons and act as an antioxidant. It is best known for use in Leber hereditary optic neuropathy, but some clinicians consider it in mitochondrial optic neuropathies more broadly. Dosing regimens vary (for example 300–900 mg/day in divided doses). Evidence in C12orf65-related optic atrophy is currently lacking. -
Nicotinamide or niacin derivatives
Nicotinamide helps build NAD⁺, a key cofactor in many mitochondrial redox reactions. Some preclinical and early clinical studies in mitochondrial and neurodegenerative disease suggest possible benefit from NAD⁺ boosters, but data are limited. Typical supplement doses are modest; high doses can affect liver function. Use in children with severe COXPD7 must be specialist-guided. -
Levetiracetam (for seizures)
If seizures occur, levetiracetam is often chosen because it has relatively low mitochondrial toxicity compared with some older antiepileptic drugs. Dosing follows standard epilepsy guidelines (for example, starting around 10 mg/kg twice daily and increasing as needed). Behavioral side effects like irritability can occur. It treats seizures but does not correct the mitochondrial defect. -
Lamotrigine (for seizures)
Lamotrigine is another antiseizure medicine often considered “mitochondria-friendly.” Doses are increased slowly to reduce the risk of rash. It can help control generalized and focal seizures seen in some mitochondrial encephalomyopathies. Again, it is symptomatic, not disease-modifying, and must be monitored carefully. -
Baclofen (for spasticity)
Baclofen relaxes skeletal muscle by acting on GABA receptors in the spinal cord. In children with spastic paraparesis from C12orf65-related disease, it can reduce stiffness and improve comfort and function. Doses start low and are slowly increased. Side effects include drowsiness and weakness, so dose must be balanced carefully. -
Proton pump inhibitors (e.g., omeprazole) for reflux
Severe neurological impairment can lead to reflux and risk of aspiration. Proton pump inhibitors reduce stomach acid and can protect the esophagus. They do not treat the mitochondrial disease itself but can improve comfort and reduce feeding-related pain, helping the child maintain nutrition. -
Anti-emetics (e.g., ondansetron)
Nausea and vomiting, whether from the disease or from treatments, can cause dehydration and metabolic stress. Ondansetron is commonly used to control vomiting. Side effects can include constipation and, rarely, heart rhythm changes. Careful vomiting control helps maintain oral intake and reduces hospital admissions. -
Analgesics (e.g., paracetamol/acetaminophen)
Pain from muscle cramps, contractures, or procedures is common. Simple painkillers like acetaminophen are often preferred because they are generally safe for the liver at recommended doses and do not affect mitochondria directly. They improve comfort and sleep but should not be overused. -
Careful avoidance of high-risk drugs (e.g., valproate)
Valproate has specific FDA label warnings about increased risk of liver failure and death in patients with mitochondrial disorders due to POLG mutations. While C12orf65 is a different gene, these warnings remind clinicians that some drugs may be particularly risky in mitochondrial disease. Alternative antiepileptics are usually preferred.
Dietary molecular supplements
(All supplements must be checked with a mitochondrial specialist and pediatrician before use.)
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Coenzyme Q10 supplement – often given as an oil-based capsule or liquid to improve absorption and support electron transport and antioxidant defenses.
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Riboflavin supplement – high-dose vitamin B2 tablets used to support complex I and II activity and improve muscle symptoms in responsive mitochondrial conditions.
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Alpha-lipoic acid – antioxidant and mitochondrial cofactor used to reduce oxidative stress in mitochondrial disease “cocktails.”
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Acetyl-L-carnitine – a carnitine form that may improve mitochondrial energy production and has been studied by FDA scientists for safety and bioenergetic effects.
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Creatine monohydrate – acts as a phosphate energy buffer in muscle and brain; sometimes used to support short bursts of energy in mitochondrial myopathies.
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Omega-3 fatty acids (fish oil) – support cell membrane health and may reduce inflammation and cardiovascular risk in chronic mitochondrial disease.
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Vitamin D and calcium – support bone health, especially important in children with limited mobility or long-term anticonvulsant use.
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Magnesium – helps nerve and muscle function and may ease cramps; deficiency is common in children with feeding difficulties or certain medications.
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B-complex supplements – provide a broad mix of B vitamins (B1, B2, B3, B6, B12, folate) that support many mitochondrial enzymes and reduce the chance of missing a treatable deficiency.
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Probiotic preparations – may help maintain gut health in children receiving frequent antibiotics or tube feeds, improving nutrient absorption and comfort, though evidence in mitochondrial disease is still limited.
Immune-supportive, regenerative and stem-cell-related drugs
There are no approved stem-cell or gene therapies specifically for severe C12orf65-related combined oxidative phosphorylation defect yet. The items below describe general directions of research and supportive immune care.
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Standard childhood vaccinations – Routine vaccines do not “regenerate” mitochondria but protect against infections that can trigger metabolic crises. Keeping vaccines up to date is strongly recommended in mitochondrial disease care, unless there is a specific contraindication.
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Experimental redox-modulating drugs (e.g., vatiquinone/EPI-743) – These drugs aim to improve cellular redox balance and protect mitochondria from oxidative injury. Early studies in Leigh syndrome suggest some benefit, but they remain investigational and are not routine care.
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Mitochondria-targeted antioxidants (e.g., MitoQ, elamipretide) – These molecules are designed to concentrate in mitochondria and neutralize reactive oxygen species. Clinical trials in several mitochondrial conditions are ongoing, but use in C12orf65 disease is not established and should only occur in research settings.
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Agents promoting mitochondrial biogenesis (e.g., bezafibrate – research use) – Some drugs stimulate PPAR pathways and may increase mitochondrial number and enzyme activity. Studies are experimental and not disease-specific; long-term safety in children with primary mitochondrial disorders is still uncertain.
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Hematopoietic or mesenchymal stem-cell approaches (experimental)
Stem-cell therapy has been explored in other mitochondrial and metabolic diseases, aiming to replace or support affected cells. At present there is no established protocol or proven benefit for C12orf65 deficiency, and such treatments should be considered only inside well-regulated clinical trials. -
Future gene therapy targeting mitochondrial translation factors
Research into gene therapy for nuclear-encoded mitochondrial proteins is progressing, with animal and early human studies for some disorders. For C12orf65, gene therapy is a theoretical future option but not yet available. Families may hear about gene-editing technologies, but at this time they remain experimental and should be discussed with specialists.
Surgeries and procedures
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Gastrostomy tube placement
If swallowing is unsafe or oral intake is too low, a feeding tube placed through the abdominal wall (PEG or surgical gastrostomy) can provide secure access for nutrition and medicines. This helps maintain weight, reduces aspiration risk, and simplifies care during illness. -
Anti-reflux surgery (e.g., Nissen fundoplication)
In selected children with severe reflux and aspiration that do not respond to medicines, fundoplication around the lower esophagus can reduce vomiting and reflux. This protects the lungs and may make tube feeds safer. Surgery risks must be carefully weighed in fragile mitochondrial patients. -
Orthopedic surgery for contractures or scoliosis
Progressive spasticity and weakness can cause joint contractures and spinal curvature. Orthopedic procedures such as tendon lengthening or scoliosis correction aim to improve sitting balance, ease care, and reduce pain. Pre-operative anesthesia plans must consider mitochondrial vulnerability to stress. -
Tracheostomy in severe respiratory failure
In rare, advanced cases with chronic respiratory failure, a tracheostomy may be considered to allow long-term ventilation and airway management. This is a major decision that must balance potential benefits with quality-of-life goals and family wishes. -
Eye or eyelid surgery for ophthalmoplegia or ptosis
If severe eyelid droop (ptosis) or eye movement problems cause functional visual disability, ophthalmic surgery may help improve the visual field. This does not treat optic atrophy or the underlying mitochondrial defect but can support daily activities.
Prevention and long-term strategies
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Avoid prolonged fasting; offer small, frequent meals and extra carbohydrates during illness.
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Keep vaccinations up to date to reduce serious infections.
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Have a written “sick day” plan for fever, vomiting, or poor intake.
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Avoid known mitochondrial-toxic drugs when safer alternatives exist.
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Treat infections promptly and aggressively with medical guidance.
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Maintain good nutrition and prevent vitamin deficiencies.
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Encourage gentle physical activity within safe limits to avoid severe deconditioning.
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Plan anesthesia and surgery only in experienced centers familiar with mitochondrial disease.
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Use genetic counseling to plan future pregnancies and identify at-risk relatives.
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Arrange regular specialist follow-up to detect complications early.
When to see a doctor
Families should seek urgent medical help if a child with severe C12orf65-related combined oxidative phosphorylation defect develops any of the following: new seizures, severe or repeated vomiting, dehydration, high fever, rapid breathing or breathing pauses, sudden loss of skills, new weakness, trouble swallowing, or signs of infection such as cough and chest pain. Early treatment can sometimes prevent a major metabolic crisis or permanent regression.
Regular, planned visits to a metabolic or mitochondrial clinic are also important even when the child seems stable. These visits allow monitoring, updating therapies, and reviewing school and family support.
What to eat and what to avoid
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Eat small, frequent meals rich in complex carbohydrates (rice, pasta, bread, potatoes) to provide steady energy.
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Eat enough protein from sources like eggs, fish, chicken, lentils, and dairy to support muscles and growth.
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Eat plenty of fruits and vegetables for vitamins, minerals, and natural antioxidants.
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Eat healthy fats in moderation (olive oil, nut butters, avocado) for extra calories when intake is limited.
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Eat oral nutritional supplements or special formulas if recommended by the dietitian to prevent weight loss.
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Avoid long periods without food, especially overnight when ill; bedtime snacks or continuous feeds may be needed.
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Avoid very high-fat ketogenic diets unless supervised in a research or specialist setting, as effects in this specific disease are unclear.
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Avoid fad supplements or mega-doses bought online without medical guidance, because interactions and contaminants are possible.
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Avoid excessive caffeine or energy drinks, which can disturb sleep, heart rhythm, and hydration.
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Avoid extreme dieting, weight-loss plans, or prolonged fasting for religious or cultural reasons without first discussing safe adaptations with the care team.
Frequently asked questions
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Is severe C12orf65-related combined oxidative phosphorylation defect curable?
At present, there is no cure that fixes the C12orf65 gene or fully restores mitochondrial function. Treatment focuses on support, symptom control, and reducing complications, using approaches similar to those for other mitochondrial encephalomyopathies. -
How is this condition inherited?
Most reported cases follow an autosomal recessive pattern. Parents are usually healthy carriers with one changed copy each. When both are carriers, each pregnancy has a 25% chance of an affected child, a 50% chance of a carrier, and a 25% chance of an unaffected non-carrier. -
What symptoms are typical?
Common features across reported patients include developmental delay or regression, optic atrophy with visual loss, peripheral neuropathy, spastic paraparesis, ataxia, and sometimes a Leigh-like pattern on brain MRI. Severity varies from intermediate to very severe. -
How is the diagnosis made?
Doctors combine clinical signs, brain and spine MRI, muscle biopsy and respiratory chain enzyme studies, and genetic testing. Disease-causing variants in both copies of C12orf65, plus combined deficiencies of OXPHOS complexes in muscle, strongly support the diagnosis. -
Why is it called “combined oxidative phosphorylation defect”?
“Combined” means more than one mitochondrial respiratory chain complex (such as I and IV) is reduced in activity. “Oxidative phosphorylation” is the process that makes ATP in mitochondria. Enzyme testing in early reports showed deficiencies in several complexes, leading to the COXPD7 label. -
Are there disease-specific drugs for C12orf65 deficiency?
No disease-specific drug has been approved yet. Treatments like CoQ10, riboflavin, L-carnitine, and others are used based on general mitochondrial disease experience, but strong trial data in this exact condition are lacking. -
Do “mitochondrial cocktails” work?
Many patients worldwide receive combinations of vitamins and antioxidants, and some families report improvement in energy or function. However, controlled studies show mixed results, and there is no guarantee of benefit. Doctors weigh possible gains against cost and pill burden. -
Can exercise help or harm?
Well-planned, low-intensity exercise under expert supervision can improve fitness and mitochondrial efficiency in some patients. Over-exercise, especially during illness or in very severe disease, can worsen fatigue. Programs must be highly individualized. -
What is the long-term outlook (prognosis)?
Prognosis ranges from intermediate to severe. Some children stabilize for periods, while others have progressive neurological decline. Age at onset, mutation type, and level of respiratory chain deficiency all influence outcome. Because only a small number of families have been described, it is hard to predict for any individual child. -
Can siblings be tested?
Yes. Genetic counseling can arrange carrier testing for parents and older siblings, and diagnostic testing for younger children who show suggestive symptoms. Early diagnosis can allow closer monitoring and earlier supportive care. -
Are pregnancy and future children possible?
Parents who are carriers can consider options such as prenatal diagnosis or pre-implantation genetic testing with in-vitro fertilization, depending on local laws and availability. These discussions should happen with a genetics specialist before conception whenever possible. -
Is anesthesia safe in this disease?
Many people with mitochondrial disorders undergo anesthesia safely, but they may be more sensitive to certain drugs and to fasting, hypotension, and hypothermia. Anesthesia should be planned with teams who know mitochondrial disease and use careful monitoring and supportive measures. -
Do alternative or herbal treatments help?
There is very little evidence that unregulated herbal products improve C12orf65-related disease, and some may be harmful or interact with medicines. Because coenzyme Q10 and other supplements are sold as dietary products rather than drugs, quality can vary. Always discuss any product with the care team before starting it. -
Can this condition affect adults, or only children?
Most reported severe cases begin in infancy or childhood. Milder or intermediate phenotypes can present later, sometimes with spastic paraparesis and optic atrophy as the main features. The full age spectrum is still being defined as more patients are identified. -
Where can families find support?
Families can seek help from local rare disease networks and international mitochondrial disease organizations, which offer information, support groups, and research updates. These groups also help connect patients to experienced centers and clinical trials when appropriate.
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.
