Combined Oxidative Phosphorylation Deficiency Caused by Mutation in CARS2

Combined oxidative phosphorylation deficiency caused by mutation in CARS2 (also called combined oxidative phosphorylation deficiency 27, COXPD27) is a very rare genetic disease that affects how the tiny “power plants” of the cell, the mitochondria, make energy. In this condition, there are harmful changes (mutations) in a gene called CARS2, which is needed for normal protein building inside mitochondria. Because of this, several energy-making enzyme groups (respiratory chain complexes) do not work properly at the same time, so the brain and other organs do not get enough energy. Children usually show developmental delay, seizures, and movement problems because their brain cells need a lot of energy and are very sensitive to this defect. [1]

Combined oxidative phosphorylation deficiency caused by mutation in the CARS2 gene is an ultra-rare genetic mitochondrial disease that mainly affects the brain, nerves, and muscles. It is also called combined oxidative phosphorylation deficiency 27 (COXPD27) in medical databases.[1] In this condition, both copies of the CARS2 gene (one from each parent) are changed (autosomal recessive), which damages tiny “energy factories” in cells called mitochondria and lowers the ability to make energy using oxidative phosphorylation.[1] Children often have early-onset hard-to-treat seizures, developmental delay, muscle stiffness (spasticity), abnormal movements, and sometimes high lactic acid in blood.[1] There is no single cure; treatment focuses on controlling symptoms, supporting development, and protecting remaining mitochondrial function as much as possible.[1]

The CARS2 gene gives instructions for a mitochondrial enzyme (cysteinyl-tRNA synthetase 2) that helps build proteins inside mitochondria.[2] When this enzyme does not work properly, many mitochondrial proteins are not made correctly, which damages several parts of the respiratory chain complexes at the same time, leading to a “combined oxidative phosphorylation defect.”[2] This widespread energy failure explains why the brain (which needs constant energy), the nerves, and the muscles can all be affected very severely and very early in life.[2] Because the condition is extremely rare, most knowledge comes from a few case reports and small series, so doctors usually apply general principles from mitochondrial medicine rather than disease-specific trials.[2]

This disease is autosomal recessive. This means a child becomes sick only when they receive one faulty CARS2 gene from each parent. Parents are usually healthy “carriers.” Only a small number of families have been reported in the medical literature, which is why doctors classify it as an ultra-rare disorder. [2]

Other names

Doctors and researchers may use several names for the same condition. Knowing these helps when reading reports or searching on the internet: [3]

• Combined oxidative phosphorylation deficiency 27

• Combined oxidative phosphorylation defect type 27

• COXPD27

• CARS2-combined oxidative phosphorylation deficiency

• CARS2-related mitochondrial disease

• CARS2-associated neurodevelopmental disorder with epileptic encephalopathy and movement disorder

All these terms point to the same basic problem: mutations in CARS2 causing a combined defect of mitochondrial energy production. [4]

How the CARS2 gene and mitochondria work

The CARS2 gene gives the instructions to make a protein called mitochondrial cysteinyl-tRNA synthetase. This enzyme “loads” the amino acid cysteine onto a small helper molecule called tRNA. That tRNA is then used to build proteins inside the mitochondria. If CARS2 does not work, mitochondrial protein building (mitochondrial translation) is slowed or blocked. As a result, many parts of the respiratory chain complexes (I, III, IV, V) are missing or weak, so oxidative phosphorylation (OXPHOS) does not run properly and less ATP (energy) is made. [5]

The brain, muscles, liver, and heart are some of the organs that need very high and constant energy. When energy supply is low, these organs show problems such as seizures, low muscle tone, movement disorders, and sometimes heart or liver involvement. [6]

Types

Doctors sometimes describe types or patterns based on how early symptoms start and which problems are strongest. These are not strict official subtypes but helpful ways to think about the illness: [7]

• Neonatal-onset severe encephalopathy type
  Symptoms start in the first weeks of life with very early seizures, poor feeding, fast regression, and often a very serious course.

• Infant-onset epileptic encephalopathy with movement disorder type
  Symptoms appear in late infancy or early childhood with developmental delay, seizures, and a complex movement disorder such as dystonia, chorea, and spasticity.

• Childhood-onset progressive myoclonic epilepsy type
  Children may have a period of slower but ongoing development before they begin to show myoclonic jerks, seizures, and worsening movement problems over time.

• Neurodevelopmental disorder with mainly movement and tone problems type
  In some reported individuals, seizures are less prominent, and problems with muscle tone (hypotonia, spasticity), posture, and movement are more in front.

These patterns all share the same root cause: a CARS2 mutation and combined oxidative phosphorylation deficiency, but the exact symptoms and speed of progression can differ between people. [8]

Causes

Here, “causes” means the genetic reasons and biological factors that lead to or influence this disease. The main proven cause is a harmful change in both copies of the CARS2 gene. Other points below describe different ways this can happen and what can modify the severity. [9]

1. Autosomal recessive CARS2 mutation (main cause)
   The core cause is an autosomal recessive pattern: the child inherits one faulty CARS2 gene from each parent. With two faulty copies, the CARS2 enzyme cannot work properly, leading to defective mitochondrial protein building and combined oxidative phosphorylation deficiency. [10]

2. Homozygous missense variants in CARS2
   Some patients have the same missense mutation (one amino acid changed) in both copies of CARS2. This change can reduce enzyme activity, disturb mitochondrial translation, and cause the disease. [11]

3. Compound heterozygous CARS2 variants
   In other families, each parent passes a different harmful variant, so the child has two different CARS2 mutations (compound heterozygosity). Together they still stop normal enzyme function and lead to the same clinical picture. [12]

4. Splice-site mutations in CARS2
   Some variants sit at or near splice sites, the regions where the gene is cut and joined when making RNA. Splice-site mutations can lead to missing or abnormal pieces in the CARS2 message, so the resulting protein is shortened or unstable and cannot do its job well. [13]

5. Variants that change key functional domains of CARS2
   Certain mutations lie in domains that bind ATP, cysteine, or tRNA. If these regions are altered, the enzyme cannot attach cysteine to tRNA(Cys) correctly, so mitochondrial protein building slows or stops. [14]

6. Reduced amount (expression) of CARS2 protein
   Some gene changes may not fully destroy the protein but cause the cell to make much less of it. Even partially reduced levels can be enough to disrupt mitochondrial translation in tissues that need very high activity, such as the brain. [15]

7. Mitochondrial translation failure
   When CARS2 is defective, many mitochondrial proteins that form parts of the respiratory chain cannot be made correctly. This global failure of mitochondrial translation is a direct biological step that causes combined oxidative phosphorylation deficiency. [16]

8. Combined respiratory chain complex deficiency
   Because several complexes (mainly I and IV, and sometimes others) depend on mitochondrial protein synthesis, they show reduced activity together. This combined complex deficiency underlies lactic acidosis and energy failure in cells. [17]

9. High energy demand of the developing brain
   The immature brain needs constant, high ATP production. When oxidative phosphorylation is weak, brain cells cannot maintain normal signaling, which contributes to seizures, developmental delay, and regression. So the energy need of the brain is a major factor in how the gene defect causes symptoms. [18]

10. Possible modifying variants in other mitochondrial genes
    In some individuals, additional variants in other genes related to mitochondrial function may influence how severe the CARS2 disease becomes. These modifiers do not cause the disease by themselves but can change its course. [19]

11. Consanguinity increasing the chance of homozygosity
    When parents are related (for example, cousins), they are more likely to carry the same rare CARS2 variant. This makes homozygous mutations and disease in their children more likely. Several reported families with COXPD27 have consanguineous parents. [20]

12. Founder effects in small populations (possible)
    In small or isolated populations, one CARS2 mutation carried by a common ancestor may spread through the group. This “founder effect” can increase the local frequency of the disease although it remains rare worldwide. [21]

13. Mitochondrial DNA background
    Although CARS2 is a nuclear gene, it acts in mitochondria. Some studies suggest that different mitochondrial DNA backgrounds can change how strongly nuclear mitochondrial defects present, so they might subtly influence the severity of CARS2-related disease. [22]

14. Metabolic stress from infections or fever
    Illnesses that increase body temperature and metabolic demand can unmask or worsen symptoms in children with CARS2 mutations, because their cells already struggle to make enough ATP. Parents often notice regression or seizure worsening after infections. [23]

15. Poor energy reserve in muscle and heart
    Muscles and heart also depend on strong mitochondrial function. When oxidative phosphorylation is weak, these tissues fatigue easily and may sometimes show cardiomyopathy or reduced exercise tolerance, adding to overall disease burden. [24]

16. Accumulation of lactate (lactic acidosis)
    Because cells cannot use the respiratory chain well, they shift toward anaerobic metabolism and produce more lactate. High blood lactate (lactic acidosis) both reflects and worsens the underlying energy crisis in tissues. [25]

17. Oxidative stress inside mitochondria
    When the respiratory chain is disrupted, more reactive oxygen species may form. This oxidative stress can injure mitochondrial membranes and proteins further, creating a vicious cycle that deepens the energy failure. [26]

18. Age-related vulnerability of developing nervous system
    The timing of brain development steps (such as myelination and synapse formation) may make certain ages more sensitive to the CARS2 defect. This helps explain why some children present in the neonatal period while others show problems later in childhood. [27]

19. Delayed diagnosis and lack of targeted support
    Because this disease is ultra-rare, diagnosis can be late. During this time, seizures may be poorly controlled and nutrition or therapies may be sub-optimal. While this does not cause the gene defect, it can worsen the final level of disability. [28]

20. General mitochondrial disease risk factors in the family
    A family history of mitochondrial or unexplained neurodevelopmental disorders may point to shared underlying variants, including CARS2 or related genes. This shared genetic background can raise the chance that another child will also be affected. [29]

Symptoms

Not every person has all symptoms, and severity can differ a lot, even inside the same family. These are common or reported features of combined oxidative phosphorylation deficiency 27 due to CARS2 mutation: [30]

1. Global developmental delay
   Children may sit, stand, walk, or talk later than usual. They may need extra help to learn basic skills such as holding up the head, using the hands, or speaking words.

2. Developmental regression
   Some children lose skills they previously had, such as being able to sit, speak, or walk. This often happens around the time seizures or other brain symptoms get worse.

3. Seizures and epileptic encephalopathy
   Many children have repeated seizures of different types (for example, myoclonic jerks, generalized seizures). When seizures are very frequent and hard to control, they can disturb brain function all the time, which doctors call epileptic encephalopathy.

4. Myoclonic jerks and other movement problems
   Quick, shock-like jerks of the muscles (myoclonus) are common. Some children also have dystonia (twisting movements or abnormal postures) or chorea (irregular, dance-like movements).

5. Abnormal muscle tone (hypotonia and spasticity)
   Muscles may be very floppy (low tone or hypotonia), especially in babies. Later, some children develop stiffness and tightness of the muscles (spasticity), which makes movement and walking difficult.

6. Areflexia or reduced reflexes
   In some patients, deep tendon reflexes (like knee jerk) are weak or absent, which can suggest involvement of peripheral nerves or spinal pathways.

7. Vision problems or blindness
   Some cases show severe visual impairment or blindness, sometimes linked to damage of the visual pathways in the brain or optic nerve.

8. Speech delay or absent speech
   Many children say few words or do not develop speech. This may be due to both brain involvement and problems with muscle control needed for speech.

9. Feeding difficulties and failure to thrive
   Babies may have trouble sucking or swallowing, may vomit often, or may not gain weight as expected. Some need feeding by tube to keep up nutrition.

10. Exercise intolerance and easy fatigue
    Older children may become tired very quickly when moving, playing, or walking, because their muscles cannot make enough energy during activity.

11. Lactic acidosis symptoms
    High lactate levels can cause fast breathing, vomiting, and a generally unwell feeling, especially during illness or stress. Blood tests often show raised lactate.

12. Abnormal brain imaging
    MRI scans may show changes in deep brain structures such as the basal ganglia or brainstem, or more general brain atrophy (shrinkage). These findings reflect chronic energy shortage in sensitive regions.

13. Behavioral or sleep disturbances
    Some children have irritability, poor sleep, or periods of extreme restlessness, which can be linked to seizures, discomfort, or brain dysfunction.

14. Possible heart involvement (cardiomyopathy)
    In some mitochondrial disorders, including combined oxidative phosphorylation deficiencies, the heart muscle may become thickened or weak (cardiomyopathy), though this seems less commonly reported for CARS2 than for some other genes.

15. Early death in severe forms
    In the most severe neonatal or infantile cases, the combination of uncontrolled seizures, infections, breathing problems, and metabolic crisis can sadly lead to early death despite treatment.

These features come mainly from small case series and reports, so future patients may show additional symptoms as more is learned. [31]

Diagnostic tests

Because this is a rare mitochondrial disease, doctors use a step-by-step approach. They start with clinical examination, then lab tests, brain and other organ studies, and finally detailed genetic testing to confirm CARS2 mutations. [32]

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Physical exam tests

1. General physical and growth examination
   The doctor measures weight, height, and head size and compares them with normal charts. They look for poor growth, small head size (microcephaly), or other physical features that might point to a long-standing neurologic or metabolic problem. [33]

2. Neurological examination (muscle tone, strength, reflexes)
   The neurologist gently moves the child’s arms and legs to feel if muscles are floppy or stiff, tests muscle strength against resistance, and checks reflexes with a hammer. This helps to confirm hypotonia, spasticity, and abnormal reflexes that are typical in CARS2-related disease. [34]

3. Developmental and cognitive assessment at the bedside
   Using simple tasks (tracking a toy, sitting balance, copying shapes, simple questions), the clinician estimates the child’s developmental level. Delays or regression in milestones raise suspicion of a neurodevelopmental or mitochondrial disorder. [35]

4. Vision and eye examination
   The doctor checks if the child can fix and follow objects, reacts to light, and examines the eyes with an ophthalmoscope to look at the optic nerve and retina. Poor visual responses or optic nerve changes can support the picture of a severe brain or mitochondrial disease. [36]

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Manual tests (functional bedside tests)

5. Manual muscle strength testing
   In older children, the doctor asks them to push or pull against the examiner’s hands. This simple test checks for weakness in arms and legs, which can come from central or peripheral nervous system involvement and from poor energy supply in muscles. [37]

6. Assessment of muscle tone and range of motion
   By moving joints slowly and quickly, the doctor can feel if the muscles resist movement (spasticity or rigidity) or are very floppy. Contractures (fixed tight joints) may show long-standing spasticity or dystonia in children with CARS2 mutations. [38]

7. Gait and posture observation
   If the child can stand or walk, the doctor watches posture, balance, and walking pattern. A scissoring gait, toe-walking, or difficulty starting movement can reflect spasticity and other movement-disorder features related to the brain energy problem. [39]

8. Simple coordination tests (finger–nose, heel–shin)
   In cooperative patients, tests like touching the nose and then the doctor’s finger help to see if there is cerebellar or sensory ataxia. Poor coordination may result from brain regions damaged by the chronic mitochondrial energy deficit. [40]

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Lab and pathological tests

9. Blood lactate and pyruvate
   A key screening test is the level of lactate and pyruvate in the blood. Many children with combined oxidative phosphorylation deficiencies, including CARS2-related disease, show elevated lactate, especially during illness or after feeding, because their mitochondria cannot clear lactate efficiently. [41]

10. Serum creatine kinase (CK)
    CK is an enzyme released from damaged muscle. It may be mildly raised in some mitochondrial disorders if muscle fibers are under constant stress. While not specific, an elevated CK can support the idea of a systemic neuromuscular condition. [42]

11. Liver function tests and basic metabolic panel
    Tests of liver enzymes, blood sugar, kidney function, and electrolytes can show if organs other than the brain are also affected. Some combined oxidative phosphorylation deficiencies involve the liver, though this appears less prominent in many CARS2 cases. [43]

12. Blood gas and acid–base status
    Measuring pH and bicarbonate levels helps detect metabolic acidosis from high lactate. This is important during acute episodes, such as infections, when children with mitochondrial disease are especially at risk of metabolic decompensation. [44]

13. Plasma amino acids and acylcarnitine profile
    These tests check for other inborn errors of metabolism that can mimic mitochondrial diseases. Normal results help rule out other conditions, while certain patterns may still suggest a wider mitochondrial or metabolic problem. [45]

14. Genetic panel for mitochondrial and epileptic encephalopathy genes
    Many centers now use next-generation sequencing panels that include CARS2 and other mitochondrial genes. Finding two likely harmful variants in CARS2 in a child whose symptoms fit the disease strongly supports the diagnosis. [46]

15. Whole-exome or whole-genome sequencing with CARS2 analysis
    If a panel is negative or not available, doctors may order wider tests like exome or genome sequencing. These methods have identified new CARS2 variants and helped classify them as the cause of combined oxidative phosphorylation deficiency 27. [47]

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Electrodiagnostic tests

16. Electroencephalogram (EEG)
    EEG records brain electrical activity. In CARS2-related disease, EEG often shows abnormal background slowing and many epileptic discharges, reflecting epileptic encephalopathy. The EEG pattern can help guide seizure treatment and confirm that events seen by parents are true seizures. [48]

17. Nerve conduction studies and electromyography (EMG)
    These tests measure how well signals travel along nerves and how muscles respond. Some patients with combined oxidative phosphorylation deficiencies have peripheral neuropathy or myopathy. Finding such changes can further support a systemic mitochondrial disorder, even though not all CARS2 cases show them. [49]

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Imaging tests

18. Brain MRI
    MRI often shows abnormalities in deep gray matter structures, white matter, or general brain volume loss in children with CARS2 mutations. These patterns are typical of mitochondrial encephalopathies and help distinguish them from other causes of seizures or developmental delay. [50]

19. Magnetic resonance spectroscopy (MRS)
    MRS is a special type of MRI that can detect chemicals like lactate in the brain. A lactate peak on MRS is a strong clue that mitochondrial energy metabolism is disturbed, which fits with combined oxidative phosphorylation deficiency. [51]

20. Echocardiography (heart ultrasound)
    An ultrasound of the heart looks for cardiomyopathy or other structural problems. While not present in every child with CARS2 mutation, checking the heart is part of a safe work-up, because many mitochondrial disorders can affect the heart muscle. [52]

Non-pharmacological treatments (therapies and other supports)

1. Physiotherapy and regular stretching
Specialist physiotherapy keeps muscles as flexible and strong as possible and helps prevent contractures in children with spasticity or movement problems.[1] The purpose is to keep joints moving, improve posture, and reduce pain by using gentle stretches, guided exercises, and positioning techniques.[1] The main mechanism is mechanical: moving the limbs, training balance, and strengthening weaker muscles to slow down stiffness that comes from abnormal muscle tone and low movement.[1] For many families, home exercise programs taught by the therapist are as important as clinic visits.[1]

2. Occupational therapy (OT) for daily activities
Occupational therapists help the child or young person learn practical skills like sitting, feeding, dressing, and playing using adaptive tools and simple step-by-step training.[1] The purpose is to keep as much independence as possible and reduce the burden on caregivers.[1] Mechanistically, OT breaks tasks into small parts, uses repetition, and adds supportive equipment (special chairs, adapted cutlery, splints) so that the child can participate even with muscle weakness or coordination problems.[1] This support also protects mental health by letting the child feel more included in family life.[1]

3. Speech, language, and swallowing therapy
Speech-language therapists support children who have delayed speech, low tone in mouth muscles, or swallowing problems (dysphagia).[1] The purpose is safer feeding and better communication, using strategies like texture modification of food, postural changes, and communication aids.[1] The mechanism is partly motor training (strengthening tongue and swallowing muscles) and partly teaching new ways to communicate, such as picture boards or speech-generating devices, which is crucial when movement disorders make speech unclear.[1] Early intervention can reduce the risk of choking and aspiration pneumonia.[1]

4. Nutritional counselling and feeding support
Dietitians with mitochondrial-disease experience assess calories, protein, fluid, and vitamins to prevent malnutrition, which can quickly worsen weakness and fatigue.[1] The purpose is to give enough energy without long periods of fasting and to avoid both under-nutrition and harmful extreme diets.[1] The mechanism is simple: regular small meals, sometimes higher-energy foods, and management of swallowing difficulties; if needed, tube feeding may be recommended so that the child gets reliable nutrition.[1] Good nutrition also helps the body cope better with infections and other stresses.[1]

5. Respiratory physiotherapy and breathing support
Some patients develop weak breathing muscles or recurrent chest infections, so chest physiotherapy techniques (like assisted coughing or airway-clearance devices) are used.[1] The purpose is to move mucus out of the lungs, improve oxygen levels, and lower the chance of pneumonia.[1] Mechanistically, vibration, positioning, and mechanical cough-assist devices create pressure changes that help clear secretions that the patient cannot cough up alone.[1] In more advanced cases, non-invasive ventilation (like BiPAP) during sleep can support breathing and reduce fatigue in the daytime.[1]

6. Special education and developmental programs
Because combined oxidative phosphorylation deficiency due to CARS2 often causes developmental delay and learning difficulties, early intervention and special education services are very important.[1] The purpose is to offer a structured environment with adapted teaching techniques so the child can learn at their own pace.[1] The mechanism is educational, not biological: frequent repetition, visual supports, predictable routines, and one-to-one help can build skills even when memory or movement are affected.[1] This approach also supports social interaction and reduces isolation.[1]

7. Psychological support and family counselling
Living with a severe rare disease can be emotionally exhausting for the child, siblings, and parents, so psychological counselling is often needed.[1] The purpose is to help families process grief, fear, guilt, and stress, and to build coping skills and resilience.[1] The mechanism involves talking therapies, support groups, and sometimes behavioural strategies to manage anxiety, sleep problems, or challenging behaviour caused by frustration or neurological symptoms.[1] Emotional support can also improve cooperation with physical and medical treatments.[1]

8. Mobility aids, orthotics, and seating systems
Wheelchairs, walkers, standing frames, ankle-foot orthoses, and custom seating can greatly improve safety and comfort when balance and muscle control are poor.[1] The purpose is to allow mobility with less fatigue and to prevent secondary complications such as joint dislocations, scoliosis, or pressure sores.[1] The mechanism is mainly mechanical: devices stabilise joints, redistribute pressure, and support upright posture so that the child can participate in school and family outings despite severe motor symptoms.[1] Regular review is needed as the child grows.[1]

9. Seizure first-aid training and safety planning
Because epileptic seizures are a major feature of CARS2-related disease, caregivers and teachers need careful training in seizure first aid.[1] The purpose is to keep the person safe during a seizure, know when to use rescue medicines, and understand when emergency care is needed.[1] Mechanistically, this is education rather than a biological treatment: simple steps like protecting the head, turning the person on their side, and timing the seizure can prevent injuries and guide medical decisions.[1] Written seizure action plans can be shared with school and emergency teams.[1]

10. Structured daily routine and energy management
Fatigue is common in mitochondrial disease, so planning daily life to include rest periods is important.[1] The purpose is to balance activity and rest so the child can still attend school or therapy without becoming exhausted and unwell.[1] The mechanism is behavioural: using pacing, planning important tasks for times of best energy, and avoiding sudden big bursts of effort helps match energy use to limited energy production in mitochondria.[1] Families often learn to watch for early signs of over-tiredness and adjust the schedule.[1]

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Drug treatments (symptom-based medicines)

There is currently no medicine approved specifically to cure CARS2-related combined oxidative phosphorylation deficiency. Doctors use medicines that are already approved for problems such as seizures, spasticity, reflux, and infections, and doses are based on standard FDA prescribing information, not on this rare disease alone.[1] Always follow your specialist’s instructions and never use these examples to self-dose.[1]

1. Antiseizure medicine: levetiracetam
Levetiracetam is a widely used antiseizure drug that can help control generalized and focal seizures in many mitochondrial disorders and is less likely to harm mitochondria than some older drugs.[1] It belongs to the class of “second-generation antiepileptic drugs” and is given as tablets, liquid, or injection in doses adjusted to body weight and age.[1] The main mechanism is binding to the synaptic vesicle protein SV2A, which reduces abnormal electrical discharges in the brain and stabilizes neuronal activity.[1] Common side effects include sleepiness, irritability, mood changes, and sometimes loss of appetite, so close monitoring is important.[1]

2. Other antiseizure medicines (for combination therapy)
When seizures remain hard to control, neurologists may add other antiseizure drugs such as clobazam, topiramate, lamotrigine, or others, chosen carefully to avoid strong mitochondrial toxicity.[1] These drugs come from different pharmacological classes (for example, benzodiazepines, sodium-channel blockers, GABA-modulating agents) and doses are set using official drug labels and epilepsy guidelines.[1] Mechanisms include enhancing inhibitory GABA signals or reducing excessive excitatory firing in the brain, which lowers seizure frequency and severity.[1] Side effects can include drowsiness, behaviour changes, and effects on liver or blood counts, so regular blood tests and clinic visits are needed.[1]

3. Rescue benzodiazepines for prolonged seizures
Medicines such as diazepam or midazolam may be prescribed in special forms (buccal or nasal) for emergency use when a seizure lasts too long or clusters occur.[1] They belong to the benzodiazepine class and are used only according to a written seizure action plan, often in school or at home.[1] The mechanism is quick enhancement of GABA (the main calming neurotransmitter), which helps stop dangerous prolonged seizures.[1] Side effects include drowsiness and slowed breathing, so caregivers must know when to call emergency services after giving a rescue dose.[1]

4. Baclofen for muscle stiffness and spasticity
Baclofen is a muscle-relaxant drug, used orally or sometimes via a spinal pump, to reduce severe spasticity and painful muscle spasms in conditions with central nervous system damage.[1] It is in the class of GABA-B receptor agonists, and doses are slowly increased from a low starting level according to official prescribing information and the child’s response.[1] The mechanism is to reduce the release of excitatory neurotransmitters in the spinal cord, which decreases abnormal muscle tone and can make it easier to sit, transfer, or sleep.[1] Side effects can include sleepiness, low muscle tone, and withdrawal symptoms if stopped suddenly, so dose changes must always be supervised.[1]

5. Medicines for reflux and stomach protection
Children with severe neurological problems often have gastro-oesophageal reflux, vomiting, or poor weight gain, so doctors may prescribe proton-pump inhibitors (like omeprazole) or H2 blockers to reduce stomach acid.[1] These drugs belong to classes that block acid-producing enzymes or receptors in the stomach lining, and doses are based on weight according to pediatric labelling.[1] The mechanism is simple: less acid means less heartburn, less damage to the oesophagus, and sometimes better comfort for feeding and sleeping.[1] Possible side effects include diarrhoea, headache, and in long-term use possible effects on mineral absorption, so regular review is wise.[1]

6. Laxatives and stool softeners for constipation
Low mobility, muscle weakness, and some drugs can cause constipation, so osmotic laxatives (like polyethylene glycol) or stool softeners are often used.[1] These medicines are not specific to mitochondrial disease but are important to keep bowel movements regular and comfortable.[1] The mechanism is to pull more water into the stool or to lubricate it, making it easier to pass and reducing pain and the risk of faecal impaction.[1] Side effects can include bloating, cramps, or diarrhoea if the dose is too high, so doctors adjust the dose step by step.[1]

7. Antibiotics and antivirals for infections
Because infections can seriously worsen mitochondrial symptoms and trigger seizures or regression, doctors treat bacterial or viral infections quickly with appropriate antibiotics or antivirals.[1] The purpose is to clear infection fast, reduce fever, and avoid dehydration and metabolic stress.[1] The mechanism depends on the drug class (for example, beta-lactam antibiotics damaging bacterial cell walls, or antivirals blocking viral replication).[1] Some medicines (such as aminoglycoside antibiotics) are known to have mitochondrial toxicity and are used very cautiously or avoided if possible, so specialist advice is always required.[1]

8. Pain-relief medicines
Common analgesics like paracetamol (acetaminophen) or ibuprofen may be used for pain, fever, or discomfort from muscle spasms, contractures, or infections.[1] They belong to different classes (paracetamol is a central analgesic; ibuprofen is a non-steroidal anti-inflammatory drug) and are dosed by weight and age according to standard labels.[1] The mechanism is reduction of pain-signalling chemicals and fever, which can also reduce energy demands on an already stressed body.[1] Over-use can cause liver or kidney problems, so maximum daily doses and intervals must be respected.[1]

9. Sleep and behaviour medicines (used cautiously)
Some children with severe neurological disease have sleep disturbance or behaviour problems that do not respond to environmental changes alone, so doctors may sometimes use melatonin or other carefully chosen medicines.[1] The purpose is better night-time sleep, which improves daytime function and reduces carer strain.[1] Melatonin works by adjusting the body’s sleep–wake clock, while other drugs may calm overactive brain circuits; all are chosen with special care because of possible interactions with antiseizure medicines.[1] Side effects may include daytime sleepiness or paradoxical agitation, so close monitoring is essential.[1]

10. Medicines for excessive drooling and secretions
If drooling or thick secretions cause choking, skin irritation, or social problems, anticholinergic drugs such as glycopyrrolate or other agents may be used in small doses.[1] These medicines block certain nerve signals to salivary glands, reducing saliva production and making mouth care easier.[1] The mechanism can also dry other secretions, which may help some children but may worsen constipation or cause urinary retention.[1] Therefore, doctors balance benefits and side effects very carefully and may adjust dose many times.[1]

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Dietary molecular supplements

Supplements are often used in mitochondrial disease, but evidence is mixed and doses must be individualized. They are not a substitute for prescribed medicines, and some may interact with drugs.[1]

1. Coenzyme Q10 (ubiquinone or ubiquinol)
Coenzyme Q10 is a key part of the mitochondrial respiratory chain and is one of the most commonly used supplements in mitochondrial disorders.[1] The purpose is to support electron transport and improve energy production in cells that still have some mitochondrial function.[1] Mechanistically, CoQ10 carries electrons between complexes I/II and III, and supplemental forms may slightly boost ATP production or reduce oxidative stress.[1] Clinical studies show mixed but sometimes encouraging results; typical doses are weight-based and divided across the day under specialist supervision.[1]

2. L-carnitine
L-carnitine helps shuttle long-chain fatty acids into mitochondria so they can be used for energy, and low levels are common in some mitochondrial diseases.[1] The purpose of supplementation is to support fat metabolism, reduce toxic acyl compounds, and possibly improve endurance and muscle strength.[1] The mechanism is to act as a carrier for fatty acids and to form acyl-carnitines that can be excreted when certain pathways are blocked.[1] Doses are usually given several times per day and may cause fishy odour or loose stools; levels and safety should be monitored.[1]

3. Riboflavin (vitamin B2)
Riboflavin is a water-soluble vitamin that forms part of flavin co-enzymes (FAD, FMN) used by many mitochondrial enzymes, including some respiratory-chain components.[1] The purpose of high-dose riboflavin in mitochondrial disease is to support these enzymes and sometimes improve symptoms in specific flavoprotein-related defects.[1] The mechanism is to provide more building blocks for flavoenzymes, which may improve electron transfer in pathways that still have partial function.[1] Doses are usually higher than standard vitamin needs and often turn urine bright yellow; serious side effects are rare but should still be checked by a doctor.[1]

4. Thiamine (vitamin B1)
Thiamine is essential for enzymes involved in carbohydrate metabolism and the citric acid cycle, and deficiency can worsen neurological symptoms.[1] The purpose of supplementation is to support energy production from glucose and to prevent secondary deficiency in children with poor intake or high metabolic demand.[1] Mechanistically, thiamine acts as a co-factor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, helping convert nutrients into usable energy.[1] High-dose thiamine is usually well tolerated; doctors may adjust dose based on diet, blood levels, and overall clinical response.[1]

5. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant and co-factor for mitochondrial enzyme complexes, sometimes used in mitochondrial or neuropathic conditions.[1] The purpose is to reduce oxidative stress and support metabolic pathways that are under strain when mitochondria work poorly.[1] The mechanism includes direct antioxidant effects and recycling of other antioxidants such as glutathione and vitamins C and E, which may protect cell membranes and DNA.[1] Possible side effects include gastrointestinal upset or low blood sugar, so dosing and monitoring should be handled by a clinician.[1]

6. Creatine
Creatine acts as an energy buffer in muscle and brain by forming phosphocreatine, which can quickly donate phosphate groups to regenerate ATP.[1] In mitochondrial disease, supplementation aims to support short bursts of energy for movement and possibly reduce fatigue.[1] The mechanism is biochemical: creatine and phosphocreatine form a “reserve” energy system, helping cells cope when ATP production is limited or fluctuates.[1] Some people experience weight gain, cramps, or stomach discomfort, so dosing is individual and usually avoided in those with kidney disease.[1]

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Immune-boosting and regenerative / stem-cell-related approaches

There is no approved immune-booster or stem-cell drug specifically for CARS2-related combined oxidative phosphorylation deficiency, and unregulated “stem-cell clinics” can be dangerous.[1] Most regenerative ideas are still in research laboratories or highly specialized centres, often for other mitochondrial or genetic diseases.[1]

1. Optimised standard vaccinations and infection prevention
The safest and most effective way to “boost” immunity in this disease is to follow up-to-date vaccination schedules and infection-control advice.[1] Vaccines work by training the immune system to recognise germs before they cause severe infection, which is very important because infections can trigger regressions in mitochondrial disease.[1] This is an immune-modulating strategy, not a drug course, but it protects fragile patients from extra stress on already weak mitochondria.[1] Doctors may sometimes recommend extra pneumococcal or influenza vaccines where guidelines allow.[1]

2. Experimental mitochondrial and gene therapies (research only)
Researchers are exploring gene therapy using viral vectors (like AAV) and other methods to treat various mitochondrial disorders, but these are still experimental.[1] The purpose is to correct or bypass the genetic defect at the DNA or mitochondrial level, which in theory could restore more normal oxidative phosphorylation.[1] Mechanistically, gene therapy can deliver working copies of genes or modify cells to improve mitochondrial function, but trials so far mostly involve other genes (for example, NDUFS6, SURF1, or mtDNA-related diseases), not CARS2.[1] Participation in clinical trials, if ever offered, must only occur through reputable academic centres with strict safety oversight.[1]

3. Hematopoietic stem cell and mitochondrial augmentation research
In a few other mitochondrial conditions (such as MNGIE), allogeneic haematopoietic stem cell transplantation has been tried to correct a metabolic defect by replacing blood-forming cells.[1] More recently, mitochondrial augmentation of a patient’s own stem cells has been explored in small groups of children with selected mitochondrial diseases.[1] The mechanism is to infuse stem cells with healthier mitochondria or correct enzyme activity, hoping they will repopulate tissues and improve metabolism, but these procedures carry serious risks and remain experimental.[1] At present, such approaches are not standard care for CARS2 deficiency and should only be considered within formal clinical research.[1]

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Surgical and procedural treatments

1. Gastrostomy (feeding tube) placement
When swallowing is unsafe or oral intake is too low, surgeons may place a feeding tube directly into the stomach (gastrostomy) through a small operation.[1] The purpose is to provide safe, reliable nutrition and fluids without the constant risk of choking, especially in children with severe movement disorders or frequent seizures.[1] Mechanistically, this bypasses weak mouth and throat muscles and allows precise control of calories, water, and medicines, which can stabilise weight and reduce hospital admissions for dehydration.[1] Families are trained carefully in tube care after the procedure.[1]

2. Anti-reflux surgery (fundoplication) in selected cases
If very severe reflux does not improve with medicines and is causing lung damage or repeated hospitalizations, surgeons may consider a fundoplication, where the top of the stomach is wrapped around the lower oesophagus to reduce reflux.[1] The purpose is to protect the lungs from aspiration, make feeding more comfortable, and reduce vomiting.[1] The mechanism is mechanical tightening of the valve area between oesophagus and stomach, which stops acid and food moving upwards as easily.[1] Because surgery carries risks, the decision is taken by a multidisciplinary team who know the child’s overall condition well.[1]

3. Orthopaedic surgery for contractures or scoliosis
Over time, untreated spasticity and muscle imbalance can lead to joint contractures or spinal curvature (scoliosis) that cause pain and make care more difficult.[1] In some children, orthopaedic surgery (such as tendon lengthening or spinal fusion) is considered to improve sitting balance, ease care, and reduce pain.[1] Mechanistically, surgery changes bone or soft-tissue alignment and then is followed by physiotherapy and bracing to maintain the new position.[1] Because recovery is demanding, careful risk–benefit analysis is essential in a child with limited energy reserves.[1]

4. Vagus nerve stimulation (VNS) or other neuromodulation for refractory epilepsy
If many antiseizure drugs fail, some patients with severe epilepsy may be considered for devices such as vagus nerve stimulation, which sends regular electrical pulses to brain pathways through a small implanted stimulator.[1] The purpose is to reduce seizure frequency and severity when medicines alone are not enough.[1] The mechanism is neuromodulation of brain networks involved in seizure generation; although the exact mechanism is not fully understood, VNS has shown benefit in many refractory epilepsy syndromes.[1] It requires surgery to implant the device and regular follow-up to fine-tune settings.[1]

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Prevention and risk reduction

Because CARS2-related combined oxidative phosphorylation deficiency is genetic, it cannot be fully prevented after conception, but several steps can reduce risk in families and limit complications in affected individuals.[1]

1. Genetic counselling for parents and relatives – Carrier testing, prenatal diagnosis, or pre-implantation genetic testing can help families understand recurrence risk and plan future pregnancies.[1]

2. Early diagnosis and specialist follow-up – Recognising the disease early allows early seizure control, nutritional support, and physiotherapy, which may improve quality of life.[1]

3. Avoiding long fasting and dehydration – Regular meals, extra fluids during illness, and early treatment of vomiting and diarrhoea prevent metabolic decompensation.[1]

4. Avoiding clearly mitochondrial-toxic medicines where possible – Certain drugs (for example, high-dose valproate or some antibiotics) can worsen mitochondrial function and should be used only with expert advice.[1]

5. Prompt treatment of infections – Fast management of fever and infections can avoid sudden deterioration and hospitalization.[1]

6. Safe exercise and activity pacing – Gentle, regular activity chosen with physiotherapists helps maintain function without pushing the child into exhaustion.[1]

7. Fall and injury prevention – Adapting the home and school environment (rails, non-slip floors, helmets if needed) reduces the risk of fractures and head injury during seizures or falls.[1]

8. Regular monitoring of heart, lungs, and nutrition – Routine check-ups help detect silent problems early so they can be treated promptly.[1]

9. Clear emergency plans – Written seizure and emergency plans tell caregivers when to give rescue medicine and when to call an ambulance.[1]

10. Psychosocial support and respite care – Supporting caregiver mental health helps them continue good day-to-day care for the child.[1]

Each of these steps reduces risk; none replaces specialist medical care.[1]

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When to see a doctor

You should contact a doctor urgently or go to emergency services if there are new or worsening seizures, long seizures, or seizures that are different from usual.[1] Sudden breathing problems, very fast or very slow breathing, blue lips, or repeated choking episodes also need emergency attention.[1] Other warning signs include high fever that does not respond to usual treatment, repeated vomiting, no urine for many hours, or sudden loss of skills such as sitting, speaking, or making eye contact.[1] Routine follow-up with a neurologist, metabolic specialist, dietitian, and therapist team should be kept even when the child seems stable, because small changes can be picked up early.[1]

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Diet: what to eat and what to avoid

Helpful patterns (what to eat)
A balanced diet that includes carbohydrates, proteins, healthy fats, vitamins, and minerals is usually recommended for mitochondrial disease, adjusted by a specialist dietitian.[1] Regular meals and snacks, rather than long fasts, help keep blood sugar stable and give a steady energy supply to the brain and muscles.[1] Many clinicians encourage whole grains, fruits, vegetables, and lean protein (fish, poultry, legumes, eggs) plus adequate fluids to avoid dehydration.[1] In underweight children, calorie-dense but nutritious foods (like nut butters, cheese, and healthy oils) or tube feeds may be used to reach energy needs.[1]

Things usually avoided or used only with specialist guidance
Very restrictive fad diets, crash diets, or unsupervised extreme high-fat or high-protein diets can be risky in mitochondrial disease and should not be started without a metabolic specialist.[1] Fasting for long hours, especially during illness, can drain energy and trigger metabolic decompensation.[1] Older teenagers are advised to avoid smoking, alcohol, and recreational drugs, as these can further damage organs and interact with medicines.[1] Herbal products and “energy boosters” advertised online may contain unknown substances that stress the liver or mitochondria, so always discuss them with the medical team before use.[1]

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Frequently asked questions (FAQs)

1. Is combined oxidative phosphorylation deficiency due to CARS2 always severe?
Reported cases usually show severe early-onset disease with hard-to-control seizures and marked developmental delay, so it is generally considered a serious condition.[1] However, because only a small number of patients have been described, the full spectrum is not yet known, and some genetic variants may cause milder problems.[1]

2. Can this disease be cured?
At present, there is no cure that can fully fix the underlying CARS2 gene problem or completely restore normal mitochondrial function.[1] Treatment is supportive and symptom-based, focusing on seizures, movement, nutrition, breathing, and comfort, while research continues into genetic and mitochondrial therapies.[1]

3. Do supplements like CoQ10 or L-carnitine always help?
Many patients with mitochondrial disease take CoQ10, L-carnitine, and vitamins, and some report better energy or fewer hospitalizations, but scientific evidence is mixed and benefits are often modest.[1] Because supplements can be costly and sometimes cause side effects, their use should be guided by a mitochondrial specialist who can review response over time.[1]

4. Is a special “mitochondrial diet” needed?
There is no single proven “mitochondrial diet” for CARS2 deficiency, but general rules such as regular meals, adequate calories, and avoidance of long fasting are widely accepted.[1] Any major diet change, including high-fat or ketogenic diets, must be planned by an experienced team because it can interact with seizures and metabolism.[1]

5. Will every sibling have the disease?
Because this condition is usually autosomal recessive, when both parents are carriers every pregnancy has a 25% chance of an affected child, a 50% chance of a carrier child, and a 25% chance of a non-carrier child.[1] Genetic testing and counselling can clarify risks for each family and discuss testing options for future pregnancies.[1]

6. Can children with this disease go to school?
Many children can attend school with suitable supports such as special education services, classroom aides, medical plans, and assistive technology.[1] The exact level of participation depends on the severity of seizures, movement disorder, and learning difficulties, and is reviewed regularly by the care team and educators.[1]

7. Is physiotherapy still useful in very severe disease?
Yes. Even when a child cannot walk, physiotherapy and positioning can prevent painful contractures, reduce pressure sores, and improve comfort.[1] Therapy goals may shift from gaining new skills to maintaining comfort and ease of caregiving.[1]

8. Are experimental gene or stem-cell treatments available now?
Gene and cell-based therapies are being studied in some mitochondrial conditions, but they are not standard treatments for CARS2 deficiency at this time.[1] Families should be cautious of unproven treatments advertised online and discuss any research offers only with trusted specialists at recognised centres.[1]

9. How can families cope emotionally?
Rare, severe diseases place huge emotional and practical strain on families, so psychological support, respite care, and connection with rare-disease groups are very important.[1] Talking with others who have similar experiences and working with counsellors can reduce isolation and help families find practical strategies for day-to-day life.[1]

10. What should be done during an illness like a cold or stomach bug?
Illness can quickly reduce energy and fluid levels, so many metabolic teams give families “sick-day rules,” such as offering extra fluids, not missing medicines, and seeking early medical review.[1] Any signs of dehydration, uncontrolled fever, or increased seizures need prompt medical attention.[1]

11. Can adults have CARS2-related disease?
Most reported patients have childhood onset, but milder or later-onset forms might be under-diagnosed because genetic testing is not always done.[1] Adults with long-standing unexplained epilepsy, movement disorder, and developmental history may sometimes be diagnosed later through gene panels.[1]

12. Does this condition affect the heart?
Some mitochondrial diseases can involve the heart (cardiomyopathy or rhythm problems), and regular screening is often advised even if no symptoms are obvious.[1] If heart involvement appears, cardiologists will use standard heart-failure or rhythm treatments adapted to the patient’s overall condition.[1]

13. Are there international guidelines for treatment?
There are general consensus guidelines for mitochondrial disease management, but there are no large, disease-specific guidelines for CARS2-related combined oxidative phosphorylation deficiency because it is so rare.[1] Most specialists adapt broader mitochondrial recommendations and epilepsy standards to the individual child.[1]

14. How can families find research studies?
Families can look at clinical-trial registries, mitochondrial-disease foundations, or academic centre websites, but must discuss any trial with their own doctors first.[1] Not every study will be suitable or safe, and careful review of risks and benefits is essential.[1]

15. What is the most important message for caregivers?
The most important message is that you are not alone and that good supportive care—controlling seizures, protecting nutrition, preventing infections, and providing therapies—can still make a meaningful difference, even without a cure.[1] Working closely with a team that understands mitochondrial disease, and asking for emotional and practical support, is just as important as any medicine or supplement.[1]

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 21, 2025.