Combined oxidative phosphorylation deficiency caused by mutation in MARS2 is a very rare inherited mitochondrial disease. In this condition, a mistake (variant) in both copies of the MARS2 gene stops the cell’s “energy factory” (mitochondria) from working properly. Because mitochondria make most of the body’s energy, many organs can be affected, especially the brain, muscles, heart, ears, and sometimes bones.
The MARS2 gene gives instructions to make an enzyme called mitochondrial methionyl-tRNA synthetase. This enzyme helps start and build proteins inside mitochondria. When this enzyme does not work well, the mitochondria cannot build several important proteins that are needed for the oxidative phosphorylation (OXPHOS) system, which is the main chain for energy production. This leads to “combined” deficiency of several respiratory chain complexes (often complexes I and IV) and low energy in the cells.
Doctors group these diseases under “combined oxidative phosphorylation deficiencies.” In many medical catalogs, the form linked to MARS2 is called combined oxidative phosphorylation deficiency 25 (COXPD25), even though some older papers may use different numbers. The number is mainly for classification; the important point is that the disease is caused by harmful changes in the MARS2 gene and leads to a mitochondrial translation defect.
Other names
Doctors and researchers may use several names for this same or very similar condition:
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MARS2-related combined oxidative phosphorylation deficiency
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MARS2-related mitochondrial translation deficiency
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Combined oxidative phosphorylation deficiency 25 (COXPD25)
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MARS2-related leukodystrophy or autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL) when brain white matter and movement problems are most obvious
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MARS2-related mitochondrial disease with developmental delay, poor growth, and sensorineural hearing loss
These names describe the same basic problem: MARS2 mutations causing poor mitochondrial protein building and energy failure.
Because only a small number of patients have been described, “types” are not officially fixed, but we can group the clinical patterns seen in reports into simple forms:
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Neurologic-dominant type – main problems are delayed development, low muscle tone, ataxia (unsteady movements), and spasticity (stiff muscles), with changes in brain white matter (leukoencephalopathy) on MRI.
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Hearing-loss and poor-growth type – main signs are global developmental delay, failure to gain weight and height well, and sensorineural hearing loss in childhood.
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Leukodystrophy / ARSAL type – movement problems, spastic ataxia, and white-matter disease in the brain, sometimes with slow progression in older children or young adults.
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Skeletal-involvement type – in some children, MARS2 variants are linked with growth failure and spine or bone changes, such as mild spondylar dysplasia (flattened vertebrae) and abnormal pelvis on X-ray.
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Multisystem mitochondrial type – features from the patterns above together, sometimes including heart, liver, or other organ involvement as seen in many combined OXPHOS disorders.
Causes (why it happens)
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Biallelic MARS2 variants
The basic cause is having harmful changes (variants) in both copies of the MARS2 gene, one inherited from each parent. This pattern is called autosomal recessive inheritance. The abnormal gene copies together reduce the function of the mitochondrial methionyl-tRNA synthetase enzyme. -
Missense mutations
In some patients, a single “letter change” in the DNA changes one amino acid in the enzyme (missense mutation). This can slightly change the shape of the enzyme so it cannot bind methionine or tRNA correctly, lowering its activity. -
Nonsense mutations
Other patients have mutations that create a “stop” signal too early in the gene (nonsense mutation). This makes a shorter, incomplete enzyme that is quickly destroyed by the cell, leading to very low MARS2 protein levels. -
Frameshift or small insertion/deletion mutations
Small insertions or deletions of DNA bases can shift the reading frame of the gene (frameshift). This usually produces a faulty protein and often causes the cell to break down the abnormal messenger RNA, again reducing enzyme amount. -
Complex genomic rearrangements of MARS2
Some families with ARSAL have large rearrangements involving MARS2, such as partial gene duplications. These structural changes disturb important control regions or 3′ UTR of the gene and lead to abnormal regulation and reduced enzyme function. -
Compound heterozygous mutations
Many described patients have two different harmful variants in MARS2 (compound heterozygosity). Each parent is healthy but carries one variant. The child gets both different variants, and together they are enough to cause disease. -
Homozygous mutations (often with parental relatedness)
In some populations, parents may be related (consanguineous). This raises the chance that a child receives the same harmful variant from both parents, so both MARS2 copies are identical and faulty. -
Loss of mitochondrial methionyl-tRNA synthetase activity
All these genetic changes reduce or change the MARS2 enzyme, so methionine cannot be attached correctly to mitochondrial tRNA. This step is essential to start and elongate many proteins inside mitochondria, so protein building slows or fails. -
Defective mitochondrial protein translation
When MARS2 activity is low, global mitochondrial translation is impaired. Many proteins encoded by mitochondrial DNA, especially those that begin with methionine, are not made in normal amounts. This disrupts the assembly of the oxidative phosphorylation complexes. -
Combined deficiency of respiratory chain complexes I and IV
Studies of patient cells have shown reduced activities of complex I (NADH dehydrogenase) and complex IV (cytochrome c oxidase). These complexes are central to the electron transport chain, so their failure lowers ATP production and increases lactic acid. -
Reduced levels of complex subunits (NDUFB8, COXII)
In fibroblasts and lymphoblasts from affected patients, the protein levels of NDUFB8 (a complex I subunit) and COXII (a complex IV subunit) are reduced. This shows that faulty MARS2 leads directly to poor assembly of these complexes. -
Increased oxidative stress in brain glial cells
Experimental work suggests that MARS2 defects can cause higher levels of reactive oxygen species (ROS) in glial cells. Too many ROS can damage cell membranes, proteins, and DNA, increasing injury to brain tissue. -
Vulnerability of brain white matter (leukoencephalopathy)
White matter in the brain has long nerve fibers that need a lot of energy to keep their myelin and signaling. Energy failure from combined OXPHOS defects makes this tissue fragile, leading to leukoencephalopathy and ataxia. -
Vulnerability of growing brain and ears
During childhood, the brain and inner ear are rapidly developing and need constant energy. Mitochondrial translation defects in MARS2 especially harm these tissues, explaining developmental delay and sensorineural hearing loss in several patients. -
Possible heart muscle energy shortage
In many combined OXPHOS deficiencies, heart muscle is affected, leading to hypertrophic cardiomyopathy. Even though only limited data exist for MARS2, the same mechanism of low ATP and lactic acidosis can potentially weaken or thicken heart muscle. -
Skeletal growth disturbance
In at least one child with MARS2 variants, abnormal spine and pelvis development (spondylar dysplasia) were reported. Poor energy supply in growth plates and bone-forming cells may disturb normal bone shaping. -
Modifier genes in mitochondrial pathways
Reviews of mitochondrial aminoacyl-tRNA synthetase disorders suggest that other genes in mitochondrial translation and quality-control pathways may modify the severity and pattern of disease. This may explain why patients with similar MARS2 variants can look quite different. -
General triggers: infection and metabolic stress
As in other mitochondrial diseases, fever, infection, fasting, or dehydration can temporarily worsen the energy crisis. These stress events may uncover the underlying MARS2 defect or cause sudden worsening of symptoms. -
Autosomal recessive inheritance in families
The pattern of affected siblings and healthy carrier parents shows that this condition follows autosomal recessive inheritance. This means each pregnancy of two carriers has a 25% chance to produce an affected child. -
Extreme rarity and under-diagnosis
Only a small number of patients with clearly confirmed MARS2-related disease have been reported. Many children with mitochondrial symptoms may not yet have had full genetic testing, so the condition is probably under-recognized.
Symptoms and signs
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Global developmental delay
Many affected babies and children sit, stand, walk, and talk later than expected. They may need extra help to reach milestones and may show slow learning in school because their brain does not get enough steady energy. -
Poor growth and failure to thrive
Children with MARS2 mutations may have trouble gaining weight and height. They can look smaller and thinner than other children of the same age, partly because they use more energy to keep basic body functions going. -
Low muscle tone (hypotonia)
Babies may feel “floppy” when picked up. Their muscles are soft, and they cannot hold their head or body up for a long time. This comes from weak energy production in muscle cells and nerves that control movement. -
Ataxia (unsteady movements)
Some children and young adults develop ataxia. They may walk with a wide base, sway, or fall easily. This is linked to damage in the cerebellum and white matter pathways, which need high energy to coordinate movements. -
Spasticity and stiffness
Instead of being floppy, some muscles can later become stiff and tight. Legs may scissor, and reflexes can be brisk. This “spastic ataxia” combination is well described in MARS2-related ARSAL. -
Easy fatigue and weakness
Because energy is low, children may tire quickly with physical activity. Simple actions like climbing stairs, running, or even long sitting can make them exhausted, and they may need frequent rest. -
Sensorineural hearing loss
In some families, affected siblings have hearing loss due to damage in the inner ear or auditory nerve (sensorineural). They may need hearing aids or other support to understand speech and environmental sounds. -
Seizures or epilepsy
Many combined OXPHOS deficiencies, including some MARS2-related cases, can present with seizures. These can be focal or generalized and often appear in infancy or early childhood, especially during illness or fever. -
Lactic acidosis episodes
Blood lactate may rise due to impaired oxidative phosphorylation. Clinically, this can show as fast breathing, vomiting, tiredness, or confusion during stress or infection, because the body switches to less efficient anaerobic metabolism. -
Feeding difficulties in infancy
Some babies have poor sucking, frequent vomiting, or difficulty swallowing. They may need feeding support or tube feeding to get enough calories and prevent low blood sugar or weight loss. -
Learning difficulties or intellectual disability
Because energy supply to the developing brain is limited, some children show learning problems. They may need special education services, and their IQ can range from mild to moderate impairment. -
Behavior and mood problems
Some patients can show irritability, attention problems, or mood swings. These may be related to chronic illness, brain involvement, or frustration from hearing and movement problems. -
White-matter brain changes
MRI often shows leukoencephalopathy: damaged or abnormal white matter. This may not cause visible symptoms at first but is closely linked with ataxia, spasticity, and developmental delay. -
Skeletal abnormalities
At least one child with MARS2 variants had changes in the spine and pelvis, such as platyspondyly and anterior vertebral beaking. This can lead to short trunk, posture problems, or back pain later. -
Possible heart involvement
Though not fully defined in MARS2 patients, combined OXPHOS defects in general may cause hypertrophic cardiomyopathy. Signs include shortness of breath, rapid heartbeat, or poor exercise tolerance, so the heart should be monitored.
Diagnostic tests
Physical examination (at the bedside)
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General physical and growth exam
The doctor checks weight, height, head size, body proportions, and any abnormal chest or spine shape. Slow growth, thin body, abnormal spine curve, or pectus changes can point toward a chronic genetic or mitochondrial condition. -
Neurological examination
The doctor tests muscle tone, power, reflexes, coordination, and gait. Findings such as hypotonia, spasticity, ataxia, and brisk reflexes help show that the brain and spinal cord are involved, which is typical in MARS2-related disease. -
Cardiovascular examination
The heart is checked by listening with a stethoscope, feeling pulses, and observing for signs of heart failure like swelling or breathlessness. This can raise suspicion of hypertrophic cardiomyopathy, a known risk in combined OXPHOS disorders. -
Eye and ear examination
Simple checks of eye movements, pupils, and fundus (with an ophthalmoscope), plus basic hearing assessment, can suggest optic nerve problems or hearing loss. Abnormal results lead to more detailed tests with specialists.
Manual and bedside functional tests
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Developmental milestone assessment
Tools like basic developmental screening check sitting, walking, speech, and social skills. When several areas are delayed, especially motor and language, doctors suspect a global neurodevelopmental disorder such as a mitochondrial disease. -
Bedside hearing tests (whisper and tuning fork tests)
The doctor may speak softly behind the child or use tuning forks near the ears. If the child cannot hear well, this suggests sensorineural hearing loss and prompts formal audiology tests. -
Manual muscle strength testing
Using simple resistance tests, the clinician grades muscle strength in arms and legs. Symmetric, mild weakness with fatigue may point toward a metabolic or mitochondrial myopathy rather than a primary nerve or muscle fiber disease. -
Gait and coordination testing
The patient is asked to walk, run, stand on one leg, or touch finger-to-nose. Wide-based gait, poor balance, or mis-targeting movements indicate cerebellar and white-matter involvement, as seen in ARSAL and other MARS2-related phenotypes.
Laboratory and pathological tests
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Blood lactate and pyruvate levels
High lactate (with or without high pyruvate) is a common clue for OXPHOS defects. It shows that cells are making energy without enough oxygen use and that the respiratory chain is not working efficiently. -
Basic blood tests (full blood count, liver and kidney function)
These tests help look for anemia, infection, or liver problems. In mitochondrial disease they may be normal or show non-specific changes, but they are important to rule out other common causes of the symptoms. -
Serum creatine kinase (CK)
CK is an enzyme released when muscle cells are damaged. It may be normal or mildly raised in mitochondrial disease. A high CK would support muscle involvement but does not by itself prove MARS2-related disease. -
Plasma amino acids and acylcarnitine profile
These blood tests help exclude other inborn errors of metabolism (for example, organic acidemias or fatty-acid oxidation defects). In MARS2 disease, they are often non-specific but are part of a standard metabolic work-up. -
Urine organic acid and lactate analysis
Urine tests can show increased lactic acid or other abnormal organic acids that point toward mitochondrial or metabolic dysfunction. They support the idea of a systemic energy problem rather than a localized brain issue alone. -
Respiratory chain enzyme activity in fibroblasts or muscle
In some patients, skin fibroblasts or muscle tissue are studied in specialized labs. Activities of complexes I and IV can be measured and are often reduced in MARS2-related disease, matching the translation defect. -
Muscle biopsy with histology and mitochondrial staining
A small piece of muscle may be taken to look at muscle fibers under the microscope. Features such as abnormal mitochondria, ragged-red fibers, or combined complex deficiencies support a diagnosis of mitochondrial myopathy. -
Genetic testing focused on MARS2 and related genes
Definitive diagnosis usually comes from DNA testing. This can be a targeted mitochondrial gene panel, whole exome sequencing, or specific MARS2 sequencing. Finding two harmful variants in MARS2 in the right clinical context confirms the diagnosis.
Electrodiagnostic tests
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Electroencephalogram (EEG)
EEG records the brain’s electrical activity. In children with seizures or suspected encephalopathy, EEG can show abnormal patterns and help classify the seizure type. It supports the idea that the brain is affected by a diffuse metabolic problem. -
Electromyography (EMG) and nerve conduction studies
EMG and nerve tests check how muscles and nerves conduct signals. They can help distinguish a primary neuropathy from a central cause and sometimes show features compatible with mitochondrial myopathy or mixed involvement.
Imaging tests
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Brain MRI
MRI is one of the most important tests. In MARS2-related disease it may show white-matter changes (leukoencephalopathy), cerebellar atrophy, or other structural abnormalities. These changes match the clinical signs of ataxia and spasticity and help exclude other leukodystrophies. -
Echocardiogram (heart ultrasound)
Because combined OXPHOS deficiencies can involve the heart, an echocardiogram is often done to check for hypertrophic cardiomyopathy or reduced pumping function. Early detection helps guide treatment and monitoring.
Non-pharmacological treatments (Therapies and other measures)
There is no cure that fixes the MARS2 gene today. Treatment is supportive and aims to maximize function, prevent complications, and improve quality of life. Most recommendations come from expert guidelines for primary mitochondrial disease in general.
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Multidisciplinary mitochondrial clinic care – Regular follow-up with a team including neurology, genetics, cardiology, audiology, physiotherapy and dietetics helps coordinate complex needs and detect problems early (for example, growth or hearing changes) before they cause permanent damage.
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Individualized physiotherapy – Gentle, regular stretching and strengthening exercises can help maintain muscle tone, joint range and motor skills, and reduce contractures, while avoiding over-exertion that can worsen fatigue in mitochondrial disease.
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Occupational therapy – Occupational therapists teach energy-saving techniques, help adapt daily tasks (dressing, feeding, writing), and recommend supportive devices (splints, adapted cutlery) so the child can be as independent as possible at home and school.
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Speech and feeding therapy – Speech-language therapists support safe swallowing, prevent aspiration, and help with chewing difficulties or speech delay, sometimes recommending texture-modified diets or feeding strategies.
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Hearing rehabilitation – Early use of hearing aids or, in severe cases, cochlear implants can improve language development and social interaction in children with sensorineural hearing loss due to COXPD25.
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Individualized exercise program – Carefully supervised low-to-moderate intensity aerobic and resistance exercise can improve mitochondrial function, muscle strength and endurance, as long as it is increased slowly and balanced with rest.
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Energy conservation and fatigue management – Planning activities, using wheelchairs or walkers for long distances, and scheduling rest breaks reduces energy crises and allows participation in school and family life without exhausting the child.
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Nutritional optimization – A high-energy, balanced diet with enough protein and frequent small meals helps prevent fasting and catabolism, which can worsen mitochondrial dysfunction; dietitians may use oral supplements or tube feeds if intake is poor.
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Respiratory physiotherapy – For children with weak breathing muscles, airway clearance techniques, assisted coughing and sometimes nighttime non-invasive ventilation can reduce infections and improve sleep quality and energy level.
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Developmental and special education support – Early intervention programs, individualized education plans, speech therapy, and classroom accommodations support cognitive and behavioral challenges and maximize learning potential.
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Psychological support and family counseling – Counseling helps families cope with chronic illness, uncertainty and stress, and can reduce anxiety and depression in both parents and older children living with mitochondrial disease.
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Vaccination and infection prevention – Staying up-to-date with routine vaccines and promptly treating fevers and infections helps avoid metabolic decompensation episodes triggered by illness in mitochondrial disorders.
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Avoidance of mitochondrial “toxin” medicines where possible – Some drugs (for example, certain aminoglycoside antibiotics or valproate in specific mitochondrial backgrounds) can worsen mitochondrial function, so clinicians choose safer alternatives when they can.
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Sleep hygiene and breathing assessment – Good sleep routines and checking for sleep-disordered breathing can improve daytime energy, mood and cognition, which is particularly important in children with neurological disease.
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Genetic counseling for the family – Genetic counselors explain inheritance patterns, carrier status, options for future pregnancies and testing of siblings, helping families make informed decisions.
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Assistive devices and orthotics – Ankle-foot orthoses, walkers or wheelchairs can improve safety, mobility and participation; customized seating can also reduce spine and hip deformities in children with low tone.
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Emergency plans – Written emergency letters and hospital care plans guide rapid management during acute illness (for example, IV glucose, avoiding prolonged fasting and careful fluid management).
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Palliative and supportive care when needed – For severe disease, palliative care focuses on comfort, symptom control and family quality of life, alongside or instead of aggressive interventions.
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Regular cardiac and endocrine screening – Even if no heart or hormonal problems are obvious, screening allows early detection of cardiomyopathy, arrhythmia, diabetes or thyroid issues, which can be treatable.
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Participation in registries and research – Enrolling in mitochondrial disease registries and natural-history studies helps researchers understand COXPD25 better and may give families access to future clinical trials.
Drug treatments
Important note: there is no specific drug approved to cure MARS2-related COXPD25. Medicines are used to treat symptoms (such as seizures or spasticity) or to support mitochondrial function, often extrapolated from experience in other primary mitochondrial diseases. All dosing must be individualized by a specialist; this information is educational only and not for self-treatment.
Below are examples of drug strategies that may be considered:
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Levetiracetam – An antiepileptic drug used widely to treat focal and generalized seizures; it is often preferred in mitochondrial disease because it does not strongly interfere with mitochondrial enzymes. FDA labels describe typical starting doses and safety profile in children and adults.
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Other “mito-friendly” antiseizure medicines – Agents such as lamotrigine, clobazam or benzodiazepines may be chosen when seizures are resistant, while avoiding drugs like valproate in settings where it may worsen mitochondrial function or liver disease.
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Baclofen or tizanidine for spasticity – For children who develop spasticity or painful muscle tightness, oral antispasticity drugs can improve comfort and function, often combined with physiotherapy and splinting.
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Proton pump inhibitors or reflux medicines – If severe reflux and vomiting interfere with feeding and weight gain, acid-suppressing drugs may protect the esophagus and make feeding more comfortable, supporting overall nutrition.
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Levocarnitine (Carnitor) – Levocarnitine helps transport long-chain fatty acids into mitochondria and is used if the child has documented carnitine deficiency or is on treatments that lower carnitine. FDA labeling describes indications, dosing ranges and diarrhea as a main side effect.
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L-arginine (IV or oral) in selected situations – In some mitochondrial diseases with stroke-like episodes (for example MELAS), IV and/or oral L-arginine may improve symptoms and NO (nitric oxide) production; while COXPD25 is different, this principle shows how nitrogen-handling drugs may sometimes be used in mitochondrial medicine.
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Coenzyme Q10 supplements (ubiquinone/ubiquinol) – CoQ10 is a key part of the electron transport chain and acts as an antioxidant. Although not specifically FDA-approved for mitochondrial disease, it is frequently used off-label as part of a “mito-cocktail”, and has orphan designation for related indications.
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High-dose riboflavin (vitamin B2) – Riboflavin is a cofactor for complex I and II; in some mitochondrial complex deficiencies, patients show clinical improvement with high-dose riboflavin therapy, so many specialists include it in the treatment cocktail.
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Thiamine (vitamin B1) and other B-complex vitamins – Thiamine is essential for pyruvate dehydrogenase and energy metabolism, and B-complex supplements are widely used to support mitochondrial enzymes, especially when deficiencies are suspected.
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Alpha-lipoic acid – This antioxidant cofactor participates in mitochondrial dehydrogenase complexes and may reduce oxidative stress; it is sometimes added to mitochondrial supplement regimens, with dosing guided by expert fact sheets.
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Vitamin C and vitamin E – These water- and fat-soluble antioxidants help neutralize free radicals produced by a stressed respiratory chain; small studies and expert experience support their use in combination with other supplements.
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Creatine – Creatine can buffer cellular energy by storing high-energy phosphate groups; some guidelines suggest it as part of combination therapy to improve exercise tolerance in mitochondrial myopathies.
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Elamipretide (FORZINITY) – Elamipretide is a mitochondrial cardiolipin-binding peptide recently approved to improve muscle strength in Barth syndrome, another mitochondrial disease; it stabilizes mitochondrial membranes and may represent the first generation of mitochondria-targeted drugs, though it is not approved for COXPD25.
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Supportive cardiac medicines – If a child develops cardiomyopathy or rhythm problems, standard heart failure or rhythm drugs (for example ACE inhibitors or beta-blockers) may be used, following pediatric cardiology guidelines, to protect heart function.
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Endocrine treatments – If diabetes, thyroid disease or adrenal insufficiency appear, standard hormone replacement (insulin, levothyroxine, hydrocortisone) is used to stabilize metabolism and reduce extra energy stress on mitochondria.
(Specialists may combine several of these into an individualized plan; exact doses and timing depend on age, weight, kidney function and other medical issues.)
Dietary molecular supplements
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Coenzyme Q10
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Riboflavin (vitamin B2)
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Thiamine (vitamin B1)
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L-carnitine
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Alpha-lipoic acid
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Creatine
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Vitamin C
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Vitamin E
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Folinic acid
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Arginine / citrulline
These “mito-cocktail” components aim to support electron transport, improve antioxidant defenses, and optimize cofactor levels; surveys show many mitochondrial patients use multiple supplements and often report benefit, although high-quality trials are limited. Dosing must follow specialist guidance and monitoring.
Immune-boosting, regenerative and stem-cell-related approaches
At present, there are no established immune-booster or stem-cell drugs specifically approved for COXPD25. Research in mitochondrial medicine is exploring: mitochondria-targeted peptides (such as elamipretide), redox-modifying drugs (like EPI-743/vatiquinone), and experimental gene or cell-based therapies in laboratories and early trials, but these are not standard care for MARS2 disease yet.
Immune health in COXPD25 is usually supported with routine vaccinations, good nutrition, prompt infection treatment and, only in special cases with proven immune defects, therapies like immunoglobulin replacement. Any participation in regenerative or gene-therapy trials must be within regulated clinical trials run by experienced mitochondrial centers.
Surgical options
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Gastrostomy tube placement – A feeding tube directly into the stomach can be considered when oral intake is insufficient or unsafe, helping maintain nutrition and reduce the risk of aspiration.
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Fundoplication for severe reflux – In children with severe gastro-esophageal reflux not controlled by medicines, a surgery to tighten the valve at the top of the stomach can reduce vomiting and aspiration risk.
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Cochlear implantation – For profound bilateral sensorineural hearing loss, cochlear implants can improve hearing and language, especially when done early in childhood.
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Orthopedic surgery for contractures or scoliosis – Tendon-lengthening, hip or spine surgery may be needed if severe deformities interfere with sitting, standing, walking or breathing.
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Tracheostomy or long-term ventilation procedures (rare) – In exceptional cases with severe respiratory failure, these procedures may be considered to support breathing, always weighed carefully against overall prognosis and family goals.
Prevention and risk-reduction tips
Prevention here means preventing crises and complications, not preventing the genetic disease itself:
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Avoid prolonged fasting; use frequent meals and snacks.
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Treat fevers and infections promptly; have an emergency plan.
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Keep vaccinations up-to-date according to pediatric guidelines.
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Avoid known mitochondrial “toxic” drugs when alternatives exist.
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Maintain good hydration, especially during illness or hot weather.
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Build a consistent sleep schedule and manage sleep apnea if present.
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Use a graded, regular exercise plan rather than very sudden intense effort.
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Ensure regular follow-up with a mitochondrial specialist team.
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Monitor growth, nutrition and hearing regularly to catch changes early.
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Seek genetic counseling for family planning and carrier testing.
When to see a doctor urgently
Families should seek urgent medical care if a child with COXPD25 has:
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New or rapidly worsening weakness, feeding refusal, dehydration, or difficulty breathing.
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New seizures, altered consciousness, unusual sleepiness, or confusion.
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Sudden loss of skills (regression), especially after infection or vaccination.
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Persistent vomiting, severe abdominal pain, or blood in stools.
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Sudden worsening of hearing or vision.
In these situations, emergency evaluation allows doctors to give IV fluids or glucose, monitor lactate and acid–base balance, treat infections and seizures, and prevent further organ damage.
What to eat and what to avoid
Helpful dietary habits
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Eat frequent small meals rich in complex carbohydrates to avoid low blood sugar and catabolic stress.
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Include adequate high-quality protein (fish, eggs, legumes, lean meat) to support muscle maintenance and enzyme production.
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Use healthy fats (olive oil, nuts, seeds) in moderation as energy sources, unless the specialist suggests a specific fat-modified diet.
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Ensure enough vitamins and minerals through fruits, vegetables and prescribed supplements.
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Encourage good fluid intake (water, oral rehydration solutions during illness) to avoid dehydration.
Things usually discouraged
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Avoid prolonged fasting (for example, skipping breakfast or long overnight fasts) without medical guidance.
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Avoid fad crash diets or very low-carbohydrate diets unless a metabolic specialist specifically prescribes them.
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In older teens and adults, limit or avoid alcohol and tobacco, which can worsen overall health and mitochondrial stress.
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Avoid unregulated, high-dose supplements purchased without medical advice, especially products claiming “miracle mitochondrial cures”.
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Avoid sudden large caffeine doses or energy drinks, which may disturb sleep and heart rhythm in sensitive individuals.
FAQs
1. Is COXPD25 the same as “combined oxidative phosphorylation deficiency”?
COXPD25 is one specific type of combined oxidative phosphorylation deficiency, caused by changes in the MARS2 gene; there are many other COXPD types caused by other genes affecting mitochondrial protein synthesis or function.
2. Can COXPD25 be cured now?
No cure exists today. Treatment focuses on supportive care, symptom control and optimizing mitochondrial function with nutrition, exercise, supplements and targeted medicines.
3. How rare is this condition?
COXPD25 is extremely rare; only a small number of families have been reported worldwide, so most knowledge comes from case reports and generalized mitochondrial disease guidelines.
4. Does every child with MARS2 mutation have the same symptoms?
No. Even with the same gene, symptoms can vary widely in severity and combination, from mainly hearing loss and ataxia to more complex multi-system disease.
5. Can this disease affect adults?
Most reported cases start in childhood, but some MARS2-related problems (like spastic ataxia 3) can appear later. Adult presentations may be milder or misdiagnosed.
6. Is pregnancy possible for someone with COXPD25?
This depends on disease severity, heart and respiratory status and overall health. High-risk obstetric and mitochondrial specialists should counsel individually before pregnancy.
7. Can brothers or sisters also have COXPD25?
Yes. Each full sibling of an affected child has a 25% chance of being affected, 50% chance of being a carrier, and 25% chance of having two normal copies, if both parents are carriers.
8. Should relatives be tested?
Genetic counseling can help decide who should be offered carrier or diagnostic testing, based on family structure and wishes.
9. Will my child’s condition always get worse?
Some children remain relatively stable with good supportive care, while others may worsen over time. Long-term outcome is still poorly understood because the condition is so rare.
10. Are vaccines safe for children with COXPD25?
Guidelines generally recommend routine vaccination, because infections often trigger metabolic crises and are more dangerous than vaccine side effects for most mitochondrial patients.
11. Is exercise safe?
Yes, if it is gentle, supervised and increased slowly. Over-exertion should be avoided, but regular appropriate exercise can actually help mitochondrial function and strength.
12. Do supplements really help?
Many patients report feeling better on mitochondrial cocktails, but evidence from large clinical trials is limited. Benefits and side effects should be reviewed regularly with the treating specialist.
13. Is there a special hospital I should go to?
Whenever possible, care in or linked to a center with experience in primary mitochondrial disease is ideal, because specialists there know how to coordinate testing and treatment.
14. Are clinical trials available?
Some trials for mitochondrial disease or mitochondrial drugs (like CoQ10 or elamipretide) may be open at certain times. Families can discuss registries and trials with their mitochondrial center.
15. What is the most important thing families can do right now?
The most important steps are to work closely with a knowledgeable care team, support good nutrition and safe activity, prevent infections and follow regular monitoring. These basics often make the largest day-to-day difference in comfort and quality of life.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: February 20, 2025.
