Combined Oxidative Phosphorylation Defect Type 27 (COXPD27)

Combined oxidative phosphorylation defect type 27 (COXPD27) is a very rare inherited disease where the “power stations” of the cell, called mitochondria, cannot make enough energy because several energy-making protein complexes do not work properly. [1] In this disease, harmful changes (mutations) in a gene called CARS2 stop the cell from building one of the helper enzymes needed for normal mitochondrial protein production, so many parts of the oxidative phosphorylation chain are affected at the same time. [2] In simple words, COXPD27 is a mitochondrial energy shortage disease. [2] The body needs a constant supply of energy to run the brain, muscles, liver, and other organs. When the CARS2 gene does not work, the mitochondria in these organs cannot make enough energy, so cells become weak and can slowly get damaged, especially in the nervous system. [1]

COXPD27 is a very rare genetic mitochondrial disease. It happens when both copies of the CARS2 gene are changed (mutated). This gene makes an enzyme that helps load the amino acid cysteine onto a transfer RNA (tRNA) inside the mitochondria. When this enzyme does not work well, the mitochondria cannot build normal proteins for the respiratory chain, and the cell cannot make enough energy (ATP). This energy failure mainly harms the brain and muscles and can cause early-onset seizures, movement problems, developmental delay, and lactic acidosis.

In COXPD27, the faulty CARS2 enzyme slows mitochondrial protein production and disrupts oxidative phosphorylation in several complexes at the same time. This lowers ATP and increases toxic by-products like lactate and reactive oxygen species. Tissues that need a lot of energy, such as the brain, muscles, heart, and sometimes liver, are most affected. Children often show seizures (including myoclonic epilepsy), dystonia or other movement disorders, low muscle tone (hypotonia), failure to thrive, hearing loss, and global developmental delay.

Other names

Doctors and researchers may use several names for the same condition: [1]

1. Combined oxidative phosphorylation deficiency 27

2. Combined oxidative phosphorylation defect type 27

3. COXPD27

4. CARS2-related mitochondrial disease

5. CARS2-related epileptic encephalopathy / movement disorder

All these names describe the same disorder that comes from disease-causing changes in the CARS2 gene and leads to problems in many mitochondrial respiratory chain complexes. [2]

In every cell, mitochondria act like tiny batteries. They use a process called oxidative phosphorylation to turn food into usable energy (ATP). [1] In COXPD27, the CARS2 gene that helps build one of the enzymes for mitochondrial protein making is damaged. [2] Because of this, many “steps” in the oxidative phosphorylation chain are weak, so the cell’s batteries cannot keep up with the energy demand. [3]

The brain, muscles, and liver use a lot of energy, so they are hit hardest. [1] Many children with this condition have seizures, movement problems, low muscle tone, and slow development. Some also have liver problems, hearing or vision loss, and high lactic acid levels in blood, which is a sign that cells are trying to make energy in a less efficient way. [2]

How the CARS2 gene and mitochondria are involved

The CARS2 gene tells the cell how to make an enzyme called mitochondrial cysteinyl-tRNA synthetase. [1] This enzyme “loads” the amino acid cysteine onto a special RNA (tRNA) so that mitochondria can build many of their own proteins correctly. [2] If this enzyme does not work well, the mitochondria cannot produce several important proteins that form parts of the oxidative phosphorylation complexes (complex I, III, IV, and V). [3]

In COXPD27, both copies of the CARS2 gene (one from each parent) carry harmful changes. [1] This inheritance pattern is called autosomal recessive. Parents are usually healthy “carriers,” but their child can be affected if the child receives the changed gene from both sides. [2]

Types (clinical patterns)

There is no strict official subtype list, but doctors have noticed a few patterns of how the disease can appear. [1] These are not separate diseases, just different clinical pictures of the same CARS2-related disorder: [2]

1. Infantile epileptic encephalopathy type
   – Starts in early infancy with very frequent seizures, poor feeding, weak muscles, and failure to thrive. Brain scans often show atrophy (shrinking) and white matter changes. Outcome can be severe. [1]

2. Childhood-onset myoclonus epilepsy and movement-disorder type
   – Starts later in childhood with severe jerks (myoclonus), epilepsy, abnormal movements like dystonia or chorea, and slowly worsening walking and limb control. [2]

3. Multisystem early-onset type with liver involvement
   – Along with brain problems, there is clear liver disease, such as raised liver enzymes or liver dysfunction, plus high blood lactate as a marker of mitochondrial stress. [3]

4. Progressive neurologic regression type
   – A child first develops somewhat normally, then slowly loses skills such as walking, talking, or using hands as seizures and movement problems become worse over time. [4]

These forms overlap, and one child may fit more than one pattern during life. [5]

Causes

The main direct cause is harmful changes (mutations) in both copies of the CARS2 gene. All of the following “causes” are ways this genetic problem can happen or factors linked to how the disease appears and behaves: [1]

1. Biallelic CARS2 mutation
   – The child inherits one damaged CARS2 gene from each parent, so both copies in the child’s cells are faulty, leading to COXPD27. [1]

2. Missense mutation in CARS2
   – A single “letter change” in the DNA makes the enzyme shape slightly wrong. The enzyme may still work a little but not enough, causing milder or later-onset disease in some cases. [2]

3. Nonsense or frameshift mutation in CARS2
   – The mutation stops the protein too early or shifts the reading frame, so almost no normal enzyme is made. This can lead to more severe, early-onset disease. [3]

4. Compound heterozygous mutations
   – The child has two different harmful CARS2 mutations (one on each copy). Each alone is not enough to cause disease in carriers, but together they remove enough enzyme activity to cause COXPD27. [4]

5. Homozygous mutation from consanguineous parents
   – When parents are related (for example, cousins), they can both pass down the same rare CARS2 variant, so the child gets two identical mutant copies. [5]

6. Autosomal recessive inheritance pattern
   – This genetic pattern means there is a 25% chance in each pregnancy that a carrier couple will have an affected child. The inheritance pattern is a cause of how the disease appears in families. [6]

7. Loss of mitochondrial cysteinyl-tRNA synthetase activity
   – The functional cause inside the cell is decreased or absent activity of the CARS2 enzyme, so mitochondria cannot charge tRNA with cysteine as needed. [7]

8. Defective mitochondrial protein synthesis
   – When tRNA charging fails, mitochondria cannot make several of their own proteins, especially those that form parts of oxidative phosphorylation complexes. This directly lowers energy production. [8]

9. Combined respiratory-chain complex deficiency
   – Multiple enzyme complexes (I, III, IV, and sometimes V) become weak. This combined complex defect is the hallmark “cause” of poor ATP production in COXPD27. [9]

10. Secondary lactic acidosis
    – Because oxidative phosphorylation is weak, cells switch more to anaerobic metabolism, producing extra lactic acid. High lactate levels then worsen cell stress and symptoms. [10]

11. High energy demand in brain tissue
    – The brain needs constant energy. Mitochondrial failure in neurons leads to seizures, regression, and movement disorders, so high brain energy demand is a key background cause of symptoms. [11]

12. High energy demand in muscles
    – Skeletal muscles also need a lot of ATP. When mitochondrial function is poor, muscles become weak and floppy (hypotonia) and tire easily. [12]

13. High energy demand in liver
    – The liver performs many chemical tasks for the body. Mitochondrial dysfunction can therefore cause liver injury and abnormal liver tests in some patients. [13]

14. Modifiers in other mitochondrial genes
    – In some families, variants in other mitochondrial or nuclear genes may change how severe the disease is, even though CARS2 is the main affected gene. [14]

15. Oxidative stress in mitochondria
    – Weak oxidative phosphorylation can increase production of reactive oxygen species, which further damage mitochondrial components and worsen the energy defect. [15]

16. Delayed diagnosis and lack of early supportive care
    – The genetic defect is present from birth, but if diagnosis is late, seizures and nutritional problems may cause extra brain injury, acting as a secondary worsening cause. [16]

17. Fever and infections
    – Illnesses with fever raise energy demand and can trigger more seizures or regression in children with COXPD27, making infections important practical triggers. [17]

18. Poor nutritional intake
    – Failure to thrive, feeding problems, and vomiting can reduce calorie and protein intake, which in turn reduces the raw material the body needs to make energy, making symptoms worse. [18]

19. Metabolic decompensation episodes
    – During stress (illness, fasting, surgery), the limited mitochondrial reserve can fail, causing acute worsening with severe lactic acidosis or liver dysfunction. [19]

20. Lack of curative therapy
    – There is currently no cure that can correct the CARS2 gene or fully restore oxidative phosphorylation, so the ongoing mitochondrial defect continues to drive disease over time. [20]

Symptoms

Symptoms can vary from child to child, but many share a group of common problems related to brain, muscle, and liver function. [1]

1. Global developmental delay
   – The child learns to roll, sit, stand, walk, or talk later than expected for age. Skills may improve slowly or sometimes stop or go backward (regression). [1]

2. Seizures (epilepsy)
   – Repeated fits, jerks, staring spells, or stiffening episodes are common. Seizures often start in infancy or early childhood and may be hard to control with medicine. [2]

3. Epileptic encephalopathy
   – This means that the seizures themselves and the underlying brain disease together damage brain function, causing poor awareness, slow thinking, and loss of skills. [3]

4. Myoclonus (sudden jerks)
   – Sudden brief muscle jerks can affect the arms, legs, or whole body. These jerks may be triggered by movement, noise, or light, and can be very disabling. [4]

5. Dystonia and other movement disorders
   – Some children have twisting, abnormal postures, chorea (dance-like movements), or athetosis (slow writhing), making it hard to walk or use their hands. [5]

6. Progressive spastic tetraparesis
   – Over time, stiffness and weakness in all four limbs can appear. The child may lose the ability to walk and may need a wheelchair or full support. [6]

7. Hypotonia (low muscle tone)
   – Babies may feel “floppy” when held. They may have poor head control and difficulty sitting or standing due to weak and soft muscles. [7]

8. Failure to thrive and poor growth
   – Many children do not gain weight or height as expected because of feeding difficulties, frequent illness, and high energy needs of the body. [8]

9. Feeding problems
   – Babies may have trouble sucking or swallowing, may choke on feeds, or may not tolerate enough food, sometimes needing a feeding tube. [9]

10. Cognitive decline or learning difficulties
    – Some children show slow learning, and others lose previously gained abilities like speaking or understanding language as the disease progresses. [10]

11. Hearing loss
    – Progressive sensorineural hearing loss can occur because the auditory nerve and inner ear cells need high energy to work normally. [11]

12. Vision problems or visual loss
    – The optic pathways and retina can be affected, leading to poor visual tracking, reduced visual acuity, or even blindness in severe cases. [12]

13. Liver involvement
    – Some patients have abnormal liver blood tests, enlarged liver, or signs of liver dysfunction. This reflects mitochondrial disease inside liver cells. [13]

14. Microcephaly and brain atrophy
    – The head may be smaller than expected, and brain scans may show loss of brain volume, especially in the cortex and white matter. [14]

15. Elevated lactic acid and metabolic crises
    – Episodes of high blood lactate, sometimes with vomiting, rapid breathing, or lethargy, show that the body is under metabolic stress and cannot meet its energy needs. [15]

Diagnostic tests

There is no single simple test that alone confirms COXPD27, but a combination of clinical exam, blood and urine tests, brain and muscle studies, and genetic testing usually leads to the diagnosis. [1] The most specific test is DNA testing that shows pathogenic variants in both copies of the CARS2 gene. [2]

Physical exam tests

1. General pediatric physical examination
   – The doctor checks growth (weight, height, head size), body proportions, muscle bulk, and any visible abnormalities. In COXPD27, this exam may show poor growth, microcephaly, and thin or weak muscles, giving the first clues that there is a serious multisystem disorder. [1]

2. Neurological examination
   – The neurologist tests muscle tone, strength, reflexes, coordination, and gait. In COXPD27, the exam may find hypotonia in early stages and later spasticity or abnormal movements, helping separate this disease from purely muscle disorders or purely brain malformations. [2]

3. Developmental assessment in clinic
   – Using simple tools and observation, the doctor checks how the child moves, speaks, understands, and interacts. Delays or regression in several areas support the idea of encephalopathy linked to mitochondrial disease rather than isolated motor delay. [3]

4. Systemic organ exam (heart, liver, abdomen)
   – The clinician listens to the heart and lungs, feels the abdomen for liver size, and checks for organ enlargement or tenderness. Signs of hepatomegaly (enlarged liver) or other organ problems warn that the mitochondrial defect is affecting more than just the brain. [4]

Manual (bedside) tests

5. Gross motor function tests (sitting, standing, walking)
   – The child is asked to roll, sit, stand, and walk if possible. The doctor watches for balance problems, falls, abnormal movements, or stiffness. These simple bedside tasks show how strongly the motor system is affected and how fast it is worsening. [1]

6. Fine motor and hand use tests
   – The child is asked to reach for toys, pick up small objects, and draw or stack blocks. Difficulty with these tasks, especially when combined with jerks or dystonia, hints at a central (brain) movement disorder rather than only weak muscles. [2]

7. Bedside hearing and vision checks
   – Simple tests like calling the child’s name from behind, clapping, shining a light, or showing bright toys help screen for hearing and vision problems. Abnormal responses suggest that formal hearing tests and eye exams are needed to look for mitochondrial damage in these senses. [3]

8. Bedside coordination tests
   – Touching the doctor’s finger, touching the nose, or heel-to-shin movements can be tried in older children. Clumsy, shaky, or poorly aimed movements may show cerebellar involvement, which is common in mitochondrial disorder–related movement disease. [4]

Laboratory and pathological tests

9. Serum lactate and pyruvate levels
   – Blood tests for lactate and pyruvate show how the body is handling energy metabolism. Many children with COXPD27 have elevated lactate, especially during illness, confirming that mitochondria are struggling to make energy by oxidative phosphorylation. [1]

10. Basic metabolic panel and liver function tests
    – Blood chemistry, liver enzymes, and coagulation tests help detect liver involvement and general metabolic stress. Abnormal liver enzymes or low clotting factors may indicate mitochondrial-related liver disease, which is reported in some COXPD27 patients. [2]

11. Creatine kinase (CK) and muscle enzymes
    – CK and related enzymes show whether there is significant muscle breakdown. They may be normal or mildly raised in COXPD27, but results help rule out primary muscle diseases and guide further testing. [3]

12. Plasma amino acids and urine organic acids
    – These metabolic screens can show secondary changes due to mitochondrial dysfunction, such as elevated lactate-related metabolites or unusual organic acids, which support a diagnosis of mitochondrial disease even if they are not specific to CARS2. [4]

13. Muscle biopsy with histology and histochemistry
    – A small piece of muscle is taken and examined under the microscope. In mitochondrial disease, doctors may see ragged-red fibers, abnormal mitochondria, or reduced staining for oxidative phosphorylation enzymes, confirming that the energy chain is defective in muscle. [5]

14. Respiratory chain enzyme analysis in muscle or fibroblasts
    – Special biochemical tests measure the activity of each mitochondrial complex (I to V). In COXPD27, several complexes may show reduced activity, giving the “combined oxidative phosphorylation deficiency” pattern that matches the genetic diagnosis. [6]

Electrodiagnostic tests

15. Electroencephalogram (EEG)
    – EEG records brain electrical activity. Children with COXPD27 usually have abnormal EEGs with epileptic discharges, background slowing, or patterns of epileptic encephalopathy. EEG findings help classify seizure type, guide anti-seizure drug choices, and support the presence of diffuse brain dysfunction from mitochondrial disease. [1]

16. Electromyography (EMG) and nerve conduction studies (NCS)
    – These tests look at how well nerves and muscles transmit electrical signals. They may be normal or show non-specific myopathic changes, but they are useful to exclude primary neuropathies or neuromuscular junction disorders, helping focus attention on central mitochondrial disease. [2]

Imaging tests

17. Brain MRI (magnetic resonance imaging)
    – MRI is the key imaging test in COXPD27. Many patients show brain atrophy, white-matter abnormalities (leukodystrophy-like changes), or signal changes in deep brain structures. These patterns are common in mitochondrial diseases and support a diagnosis of CARS2-related encephalopathy when combined with clinical and genetic findings. [1]

18. MRI spectroscopy (MRS)
    – MRS can detect lactate peaks and other metabolic markers in the brain. A lactate peak supports mitochondrial dysfunction in brain tissue and helps distinguish COXPD27 from some other neurodegenerative conditions. [2]

19. Liver ultrasound or MRI
    – These imaging studies look at liver size, texture, and blood flow. They may show an enlarged or abnormal liver in patients with liver involvement, confirming that the mitochondrial defect affects this organ as well. [3]

20. Ophthalmologic imaging (OCT, fundus photography)
    – Eye specialists may use optical coherence tomography (OCT) or retinal photos to look at the retina and optic nerve. Damage in these highly energy-demanding tissues can explain visual problems and fits with a diagnosis of mitochondrial oxidative phosphorylation disorder. [4]

Non-pharmacological treatments (Therapies and other measures)

1. Multidisciplinary mitochondrial clinic care
Description, purpose, mechanism: A team including neurologists, metabolic specialists, dietitians, physiotherapists, speech therapists, and psychologists works together. The purpose is to look at the whole child and treat all problems early. This team approach helps coordinate tests, manage emergencies, adjust therapies, and support caregivers, which can reduce hospitalizations and improve quality of life.

2. Individualized physiotherapy and stretching
Description, purpose, mechanism: Regular gentle exercises, stretching, and positioning help maintain joint movement, muscle strength, and balance. The purpose is to slow contractures, scoliosis, and loss of mobility common in neuromuscular mitochondrial disease. Exercise, when carefully dosed, can stimulate mitochondrial biogenesis and improve endurance, but must be monitored to avoid fatigue and metabolic stress.

3. Occupational therapy for daily living skills
Description, purpose, mechanism: Occupational therapists teach easier ways to dress, feed, write, and use the bathroom, and may suggest splints, seating, or special tools. The purpose is to preserve independence and reduce caregiver burden. By adapting tasks to the child’s energy level and motor abilities, they reduce muscle overuse and secondary pain.

4. Speech, language, and feeding therapy
Description, purpose, mechanism: Speech therapists support understanding and expression, and also help with chewing and swallowing. The goal is to improve communication, reduce aspiration risk, and support safe eating. Simple strategies like texture modification, posture, pacing, and communication devices can prevent pneumonia and improve social participation.

5. Nutritional support and high-energy diet planning
Description, purpose, mechanism: A dietitian plans meals that give enough calories and protein while avoiding long fasting periods. The purpose is to prevent weight loss, failure to thrive, and metabolic crises. Frequent small meals with complex carbohydrates help stabilize blood sugar and reduce catabolism, supporting mitochondrial function and growth.

6. Gastrostomy tube (G-tube) feeding when needed
Description, purpose, mechanism: If a child cannot safely eat enough by mouth, a feeding tube directly into the stomach can be placed surgically. The purpose is to secure safe nutrition, medications, and water, reduce aspiration, and lessen the stress of long mealtimes. Studies in neurologically impaired children show tube feeding can improve weight and sometimes reduce complications linked to malnutrition.

7. Energy conservation and pacing strategies

Description, purpose, mechanism: Families are taught to plan the day so heavy activities happen when the child feels strongest, with built-in rest periods. The purpose is to avoid “crash” fatigue and metabolic overload. By pacing, using wheelchairs or strollers when needed, and simplifying tasks, energy demand stays closer to what damaged mitochondria can supply.

8. Structured, low-to-moderate exercise training

Description, purpose, mechanism: Carefully supervised aerobic exercise (such as slow walking or cycling) and light resistance training may be used in stable patients. The aim is to improve endurance and muscle efficiency without triggering crises. Research in mitochondrial disease suggests modest training can increase mitochondrial content and function in muscle when tailored to the patient’s capacity.

9. Respiratory physiotherapy

Description, purpose, mechanism: Techniques like chest physiotherapy, cough-assist devices, and breathing exercises help clear secretions and strengthen respiratory muscles. The goal is to prevent pneumonia and respiratory failure, especially in patients with weak cough or scoliosis. Better airway clearance reduces infection-driven metabolic decompensation.

10. Orthopedic management of contractures and scoliosis

Description, purpose, mechanism: Bracing, seating systems, and sometimes surgical correction of scoliosis or contractures can be needed. The purpose is to improve sitting, breathing, comfort, and caregiving. Correcting severe spinal curves can improve lung mechanics and reduce pain, although surgery carries higher risk in neuromuscular disease.

11. Vision and hearing support

Description, purpose, mechanism: Regular audiology and ophthalmology checks can find hearing loss or visual problems early. Devices like hearing aids, glasses, and low-vision tools help communication and learning. This support reduces sensory overload and improves participation in school and social life despite mitochondrial involvement of eyes and ears.

12. Assistive communication technologies

Description, purpose, mechanism: Tablets, picture boards, or eye-gaze devices can be used when speech is limited. The purpose is to give the child a voice and reduce frustration. These tools work by replacing or augmenting speech output, making it easier to express needs, pain, or choices, which leads to better care and mental health.

13. Psychological and family counseling

Description, purpose, mechanism: Chronic, progressive illnesses cause stress, anxiety, and grief for patients and families. Psychologists and social workers offer coping skills, behavioral strategies for difficult symptoms, and emotional support. Therapy may reduce depression and help families navigate complex decisions, improving resilience and adherence to care plans.

14. Educational support and special schooling

Description, purpose, mechanism: Many children with COXPD27 need individualized education plans, classroom accommodations, or special schools. The aim is to maximize learning while considering fatigue, seizures, and sensory issues. Adjustments such as shorter days, extra breaks, and assistive technology help match school demands to the child’s energy and cognitive profile.

15. Sleep hygiene and night-time monitoring

Description, purpose, mechanism: A regular sleep schedule, quiet sleep environment, and safe positioning reduce night-time seizures, breathing problems, and caregiver exhaustion. Good sleep supports brain function, mood, and seizure threshold. In selected cases, home pulse oximetry or apnea monitoring can pick up dangerous events early.

16. Infection prevention and vaccination

Description, purpose, mechanism: Routine vaccines (and sometimes extra ones, as advised by specialists), flu shots, and strict hand hygiene reduce infections that can trigger metabolic crises. Avoiding exposure to sick contacts and quick treatment of fevers help prevent decompensation and regression.

17. Avoidance of mitochondrial toxins

Description, purpose, mechanism: Some drugs and exposures (for example, certain aminoglycoside antibiotics, valproate in some contexts, and tobacco smoke) can further damage mitochondria. Doctors try to avoid or carefully control these in people with primary mitochondrial disease. This reduces the risk of liver failure, worsening myopathy, and sudden clinical deterioration.

18. Genetic counseling for the family

Description, purpose, mechanism: Genetic counselors explain inheritance, carrier risks, and options such as prenatal testing or IVF with mitochondrial donation. For autosomal recessive CARS2 disease, each future pregnancy has a 25% chance of being affected when both parents are carriers. Counseling helps informed family planning and early diagnosis.

19. Palliative care and symptom-focused support

Description, purpose, mechanism: Palliative care teams help with pain, breathlessness, feeding difficulties, and complex decisions at any stage. This is not only for end-of-life care. Their aim is to improve comfort and quality of life and support the family’s emotional and spiritual needs.

20. Patient and caregiver support groups

Description, purpose, mechanism: Joining mitochondrial disease support groups or rare-disease networks allows families to share experiences and coping tips. The purpose is emotional support, practical advice, and easier access to information about research. Feeling less alone can reduce anxiety and depression and strengthen long-term engagement with care.

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Drug treatments

Important: No medicine is currently approved specifically for COXPD27. All drugs below are examples used to control symptoms such as seizures or dystonia in mitochondrial diseases. Doses must always be individualized by a specialist; do not start or change medicines without your doctor.

1. Levetiracetam (e.g., KEPPRA, SPRITAM)
Class and purpose: Antiepileptic drug used to control focal and generalized seizures with relatively low mitochondrial toxicity. FDA labels describe adult doses of 1000–3000 mg/day in divided doses for partial-onset seizures.
Mechanism and side effects: It binds to synaptic vesicle protein SV2A and modulates neurotransmitter release, helping stabilize neuronal firing and sometimes offering neuroprotective mitochondrial effects in models. Common side effects include sleepiness, irritability, mood changes, dizziness, and sometimes behavioral problems.

2. Zonisamide
Class and purpose: Antiepileptic that blocks sodium and T-type calcium channels and has carbonic anhydrase–inhibiting effects. It is considered in some mitochondrial epilepsies where drugs with higher mitochondrial toxicity are avoided.
Mechanism and side effects: By decreasing repetitive neuronal firing, zonisamide can reduce seizure frequency. Side effects may include weight loss, kidney stones, metabolic acidosis, sleepiness, and rarely serious skin reactions; careful monitoring of bicarbonate and kidney function is needed.

3. Clobazam
Class and purpose: Benzodiazepine used as adjunct for refractory seizures and epileptic encephalopathy. It enhances the effect of the inhibitory neurotransmitter GABA.
Mechanism and side effects: Clobazam increases chloride entry into neurons, making them less likely to fire abnormally. Sedation, drooling, behavioral changes, tolerance, and dependence can occur; sudden stopping may provoke withdrawal seizures.

4. Diazepam (rescue medication)
Class and purpose: Fast-acting benzodiazepine used for acute seizure clusters or status epilepticus (for example, as rectal gel or nasal spray) under emergency protocols.
Mechanism and side effects: It strongly boosts GABAergic inhibition, quickly stopping many seizures. Risks include excessive sleepiness, slowed breathing, and low blood pressure, so it is used under medical direction with careful observation.

5. Lamotrigine
Class and purpose: Antiepileptic that blocks voltage-gated sodium channels; sometimes chosen when mood-stabilizing and antidepressant benefits are also helpful. It is viewed as a relatively “mitochondria-friendlier” option compared with valproate.
Mechanism and side effects: Lamotrigine reduces glutamate release and stabilizes neuronal membranes. Side effects include rash (rarely Stevens–Johnson syndrome), dizziness, nausea, and insomnia; doses must be slowly increased to lower rash risk.

6. Topiramate

Class and purpose: Broad-spectrum antiepileptic sometimes used in mitochondrial epilepsy, though it can cause weight loss and acidosis. It blocks sodium channels, enhances GABA, and inhibits carbonic anhydrase.
Mechanism and side effects: By dampening excitatory transmission, topiramate may reduce seizure frequency and migraines but can worsen fatigue, cause kidney stones, cognitive slowing, and metabolic acidosis; bicarbonate and growth should be monitored.

7. Baclofen

Class and purpose: Antispasticity agent and GABA_B agonist used for dystonia, spasticity, and painful muscle spasms. It can be given orally or by intrathecal pump in severe cases.
Mechanism and side effects: Baclofen reduces excitatory transmission in the spinal cord, lowering muscle tone and involuntary movements. Side effects include drowsiness, weakness, low blood pressure, and serious withdrawal symptoms if high-dose therapy is stopped abruptly.

8. Botulinum toxin injections

Class and purpose: Locally injected neurotoxin that blocks acetylcholine release at the neuromuscular junction. It is used to treat focal dystonia, spasticity, or painful contractures that interfere with care.
Mechanism and side effects: By weakening overactive muscles for several months, botulinum toxin can improve posture, hygiene, and pain. Side effects are usually localized weakness; systemic spread is rare but can cause swallowing or breathing difficulties.

9. Proton pump inhibitors (for severe reflux)

Class and purpose: Drugs like omeprazole reduce stomach acid, protecting the esophagus and lungs from reflux-related injury in neurologically impaired children with feeding problems.
Mechanism and side effects: They block the proton pump in stomach parietal cells, cutting acid production. Long-term use may slightly increase risks of infections, low magnesium, or bone issues, so doctors use the lowest effective dose.

10. L-arginine (IV or oral in selected mitochondrial crises)
Class and purpose: Amino acid used in some mitochondrial encephalopathy syndromes (like MELAS) to treat or prevent stroke-like episodes; in COXPD27 it is experimental and individualized.
Mechanism and side effects: Arginine is a substrate for nitric oxide synthesis, which may improve blood vessel dilation and cerebral blood flow. Side effects include nausea, diarrhea, low blood pressure, and electrolyte changes; safety must be monitored carefully.

11. Thiamine (vitamin B1, high-dose)
Class and purpose: A cofactor for several mitochondrial enzymes, given as part of mitochondrial “vitamin cocktails.” It is sometimes tried in high doses in energy-metabolism disorders.
Mechanism and side effects: Thiamine supports pyruvate dehydrogenase and other enzymes, which may improve ATP generation. It is generally well tolerated; very high doses rarely cause allergic reactions when given IV.

12. Riboflavin (vitamin B2, high-dose)
Class and purpose: Another key mitochondrial cofactor used in many mitochondrial syndromes and sometimes in complex I or II deficiencies.
Mechanism and side effects: Riboflavin participates in redox reactions in the respiratory chain. High doses are usually safe but can cause bright yellow urine and mild stomach upset.

13. Coenzyme Q10 (ubiquinone/ubiquinol)
Class and purpose: A lipid-soluble antioxidant and electron carrier in the respiratory chain, widely used off-label in mitochondrial disease. It is often considered a “core” supplement in mitochondrial cocktails.
Mechanism and side effects: CoQ10 shuttles electrons between complexes I/II and III, helping ATP production and reducing oxidative damage. Side effects are usually mild (nausea, diarrhea, insomnia); evidence of benefit is mixed but it is generally well tolerated.

14. L-carnitine

Class and purpose: A carrier molecule that moves long-chain fatty acids into mitochondria for beta-oxidation, frequently used in mitochondrial disease cocktails.
Mechanism and side effects: Supplemental carnitine may support energy production and help clear toxic acyl compounds. It can cause fishy body odor, diarrhea, and, rarely, seizures at high doses; it must be used carefully in patients with seizure disorders.

15. Alpha-lipoic acid

Class and purpose: Antioxidant and mitochondrial cofactor sometimes used in mitochondrial cocktails to reduce oxidative stress.
Mechanism and side effects: It works in redox cycles and may regenerate other antioxidants like vitamins C and E. Side effects can include heartburn, nausea, and rarely low blood sugar or allergic skin reactions.

16. Folinic acid (5-formyl-tetrahydrofolate)
Class and purpose: A reduced folate used in some mitochondrial and neurometabolic disorders, sometimes combined with other vitamins.
Mechanism and side effects: It supports one-carbon metabolism and DNA repair, which may indirectly help mitochondrial function. It is generally well tolerated; rare side effects include nausea and allergic reactions.

17. Creatine monohydrate (as a “drug-like” supplement)
Class and purpose: A high-energy phosphate buffer used to support muscle power and reduce fatigue in some mitochondrial myopathies.
Mechanism and side effects: Creatine stores high-energy phosphate groups and can help regenerate ATP in muscle. Common side effects are weight gain from water retention and stomach upset; kidney function should be monitored in long-term use.

18. Biotin (vitamin B7, high-dose)
Class and purpose: Coenzyme for carboxylases; sometimes included in mitochondrial cocktails and in specific carboxylase deficiencies.
Mechanism and side effects: By supporting fatty acid and amino acid metabolism, biotin may help energy production. It is usually very safe, but high doses can interfere with some lab tests (especially thyroid and troponin).

19. Vitamin E (tocopherols/tocotrienols)
Class and purpose: Fat-soluble antioxidant included in many mitochondrial cocktails, sometimes in combination with vitamin C and CoQ10.
Mechanism and side effects: Vitamin E protects cell membranes from lipid peroxidation, which may be increased in oxidative phosphorylation defects. Very high doses may increase bleeding risk, especially with anticoagulants, so dosing should be supervised.

20. Vitamin C (ascorbic acid)
Class and purpose: Water-soluble antioxidant given with vitamin E or CoQ10 as a redox pair, helping balance oxidative stress.
Mechanism and side effects: Vitamin C donates electrons to neutralize free radicals and regenerates oxidized vitamin E. High doses can cause diarrhea and increase kidney stone risk in susceptible people, so large doses should be monitored.

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Dietary molecular supplements

These are not cures, but are often combined as a “mitochondrial cocktail” under specialist guidance.

1. Coenzyme Q10 – Typical oral doses in mitochondrial studies range roughly from 5–30 mg/kg/day, divided. It supports electron transport and acts as an antioxidant, which may slightly improve exercise tolerance or fatigue in some patients, though trial results are mixed.

2. L-carnitine – Doses often fall around 50–100 mg/kg/day in divided doses, adjusted by the metabolic physician. Carnitine transports long-chain fatty acids into mitochondria and helps remove toxic acyl groups, potentially reducing fatigue and muscle pain.

3. Riboflavin (vitamin B2) – High-dose riboflavin (for example 50–400 mg/day in adults) is used in some respiratory chain defects. It functions as a precursor for FAD and FMN, which are essential in complexes I and II, supporting electron transfer.

4. Thiamine (vitamin B1) – Doses may be in the range of 50–300 mg/day, often divided. Thiamine assists pyruvate dehydrogenase and other dehydrogenase complexes, helping move carbohydrates into the Krebs cycle and supporting ATP generation.

5. Alpha-lipoic acid – Frequently used at 300–600 mg/day in adults in other conditions, it acts as both a cofactor and antioxidant. It helps regenerate other antioxidants and may improve mitochondrial redox balance, but evidence in primary mitochondrial disease is still limited.

6. Creatine monohydrate – Oral doses around 3–5 g/day in adults are common in neuromuscular trials. Creatine stores high-energy phosphate in muscle and may improve short-burst strength, though not all patients notice benefit.

7. Folinic acid – Doses vary widely and are individualized. It supplies reduced folate, supporting DNA repair and methylation, and may be especially useful when folate transport or metabolism is impaired along with mitochondrial function.

8. Vitamin E (mixed tocopherols/tocotrienols) – Doses are adjusted by weight and diet. As a fat-soluble antioxidant, it protects cell membranes and may work best when combined with vitamin C and CoQ10 in a balanced redox “team.”

9. Vitamin C – Dosing is usually kept within recommended upper limits for age unless under strict supervision. It supports collagen, iron absorption, and antioxidant defense and helps recycle vitamin E and possibly CoQ10.

10. Combined “mitochondrial cocktail” – Many specialists use a customized mix of 3–6 of these supplements, adjusted to genetics, symptoms, and tolerance. Observational studies show many patients report better stamina and fewer crises, but strong controlled trial evidence is still limited.

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Regenerative / immune-modulating / stem-cell-related drugs

These options are research-stage for mitochondrial disease and not standard care for COXPD27. They should only be considered in clinical trials.

1. Elamipretide (Forzinity and investigational forms)
Elamipretide is a mitochondria-targeted peptide designed to bind cardiolipin in the inner mitochondrial membrane and stabilize it. Trials in primary mitochondrial myopathy and other disorders have shown mixed efficacy, but it recently gained approval for Barth syndrome, a rare mitochondrial cardiomyopathy. Its potential benefit is to improve ATP production and reduce oxidative damage, but long-term effects in COXPD27 are unknown.

2. Vatiquinone (EPI-743, PTC-743)
Vatiquinone is a vitamin-E-related small molecule that targets 15-lipoxygenase and pathways involved in oxidative stress and ferroptosis. Early and ongoing trials explore its use in various mitochondrial and neurodegenerative diseases, including mitochondrial epilepsy, but key studies have failed primary endpoints. It may enhance cellular glutathione and reduce oxidative injury, yet its exact place in therapy remains uncertain.

3. Experimental mitochondrial transplantation and stem-cell-based therapies
Researchers are studying how mesenchymal stem cells and isolated mitochondria can transfer healthy mitochondria into damaged cells. Animal and early translational studies suggest that mitochondrial donation can improve cellular respiration and survival, but human protocols are still experimental and not routine for COXPD27.

4. Gene-therapy and mitochondrial DNA editing approaches
New enzyme and nucleic-acid technologies are being developed to change mutated mitochondrial DNA or nuclear genes in stem cells and then re-introduce corrected cells. This work is still early and carries important safety questions, but it offers long-term hope for some mitochondrial disorders.

5. Mitochondrial donation (three-person IVF) for future pregnancies
For mothers who carry mitochondrial DNA mutations, IVF with mitochondrial donation can prevent passing faulty mitochondria to the baby. Although COXPD27 is nuclear (CARS2) rather than mitochondrial DNA, this technique illustrates the broader concept of regenerative reproductive strategies for mitochondrial disease prevention.

6. Immune-modulating and antioxidant strategies in trials
Some studies are exploring how anti-inflammatory agents, advanced antioxidants, or metabolic modulators can protect mitochondria from ongoing damage. These include agents that influence ferroptosis, redox balance, or mitochondrial biogenesis. Results so far are mixed and mainly from small studies or animal models, so they cannot yet be recommended as routine COXPD27 treatments.

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Surgeries and interventional procedures

1. Gastrostomy tube (PEG or surgical G-tube) placement
Procedure and reason: A small opening is created into the stomach, and a feeding tube is placed under endoscopic or surgical guidance. It is done when a child’s swallowing is unsafe or too slow, or when they cannot meet energy needs by mouth. The goal is to improve nutrition, medication delivery, and quality of life while reducing aspiration risk.

2. Spinal fusion for neuromuscular scoliosis
Procedure and reason: In progressive scoliosis with poor sitting balance or lung compression, surgeons may straighten and fuse the spine using rods, screws, and bone grafts. This is done to stop curve progression, improve sitting posture, and support breathing, even though surgery carries higher risk in medically fragile mitochondrial patients.

3. Deep brain stimulation (DBS) for severe dystonia or movement disorder
Procedure and reason: Neurosurgeons implant electrodes into deep brain structures such as the globus pallidus internus, connected to a pacemaker in the chest. In rare mitochondrial cases with disabling dystonia not controlled by medication, DBS may reduce abnormal movements and improve comfort and care, although evidence is limited to case reports.

4. Vagus nerve stimulator (VNS) implantation for refractory epilepsy
Procedure and reason: A small stimulator is implanted under the skin of the chest with a wire wrapped around the left vagus nerve in the neck. It sends regular electrical pulses that can reduce seizure frequency in some patients. In mitochondrial epilepsies, results are mixed, and careful cardiac and respiratory monitoring is needed.

5. Tracheostomy and long-term airway support (selected cases)
Procedure and reason: When respiratory muscle weakness or central control problems cause repeated respiratory failure, a tracheostomy (surgical airway in the neck) and sometimes long-term ventilatory support may be required. This can make suctioning easier, improve comfort, and support survival, but it is a major decision that involves palliative care discussions.

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Prevention and risk reduction

Many aspects of COXPD27 cannot be fully prevented, but risks and complications can be lowered:

1. Genetic counseling and carrier testing for parents and family members to understand recurrence risk and options such as preimplantation or prenatal genetic diagnosis.

2. Avoiding consanguineous marriages (close-relative marriages) in families with known CARS2 mutations to reduce the chance that both parents carry the same recessive mutation.

3. Routine vaccinations and infection control, including flu shots, good hand washing, and early treatment of fevers to prevent metabolic crises triggered by infections.

4. Avoidance of known mitochondrial toxins, such as certain aminoglycoside antibiotics, linezolid, and valproate where possible, under specialist guidance.

5. Careful planning of anesthesia and surgery in experienced centers, using protocols designed for mitochondrial patients and close temperature and glucose monitoring.

6. Good nutrition and avoidance of prolonged fasting, especially during illness, to prevent hypoglycemia and catabolism.

7. Early recognition and treatment of seizures and movement disorders to reduce repeated brain injury from uncontrolled electrical activity or severe dystonia.

8. Regular monitoring of heart, hearing, and vision, so that problems like cardiomyopathy, deafness, or optic neuropathy can be treated early.

9. Healthy lifestyle for the whole family, including smoke-free homes, good sleep, and stress reduction, to limit additional strain on the child’s energy system.

10. Participation in registries or research studies, when available, to help improve understanding and future treatments for COXPD27 while gaining access to expert centers.

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When to see a doctor urgently

You should seek urgent medical care (emergency or immediate clinic visit) if a person with suspected or known COXPD27 has any of the following:

• New or worsening seizures, especially if they last more than 5 minutes or cluster together.

• Sudden loss of previously gained skills (such as walking, sitting, or speaking) or very fast developmental regression.

• Difficulty breathing, rapid breathing, or blue coloration of lips or fingers.

• Poor feeding, repeated vomiting, or signs of dehydration or low blood sugar (sleepiness, sweating, shakiness).

• High fever, drowsiness, or unusual behavior that could signal infection or encephalopathy.

For non-urgent concerns like slow development, mild weakness, or family history of mitochondrial disease, a referral to a neurologist or genetic/metabolic specialist is also important.

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What to eat and what to avoid

1. Prefer whole foods – Encourage fruits, vegetables, whole grains, and lean proteins to provide steady energy, vitamins, and minerals.

2. Use small, frequent meals – Many mitochondrial patients feel better with smaller meals every 3–4 hours to avoid long fasting periods and energy crashes.

3. Include complex carbohydrates – Foods like oats, brown rice, and lentils release glucose slowly and may support more stable energy than sugary drinks or sweets.

4. Adequate protein – Eggs, fish, poultry, and legumes help maintain muscle mass and repair tissues in children with chronic illness.

5. Healthy fats – Use moderate amounts of olive oil, nuts, and seeds for calories, but avoid very high-fat crash diets unless prescribed for specific reasons (for example, ketogenic diet under strict epilepsy protocols).

6. Avoid long fasting and skipping breakfast – Long periods without food can trigger metabolic stress, especially during illness.

7. Limit ultra-processed foods and sugary drinks – These can cause blood sugar spikes followed by crashes, which are not ideal for fragile energy metabolism.

8. Avoid alcohol and smoking exposure – In older patients and adults, alcohol and tobacco add oxidative stress and damage mitochondria further; in children, second-hand smoke should be avoided.

9. Discuss special diets – Ketogenic or modified Atkins diets for epilepsy, or specific low-fat diets for fatty-acid oxidation disorders, must only be used under an experienced metabolic team.

10. Always coordinate supplements and diet with the care team – Even “natural” supplements can interact with medicines or lab tests, so regular review with the mitochondrial clinic is essential.

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Frequently asked questions (FAQs)

1. Is COXPD27 curable?
At present there is no cure that can correct the underlying CARS2 mutation. Treatment focuses on controlling symptoms, improving quality of life, and preventing complications. Research into gene therapy, mitochondrial-targeted drugs, and stem-cell approaches is ongoing.

2. How is COXPD27 diagnosed?
Doctors look at the clinical picture (seizures, developmental delay, hypotonia), MRI and metabolic tests (such as lactate), and then confirm the diagnosis with genetic testing that finds two pathogenic variants in CARS2. Sometimes muscle or fibroblast studies show combined respiratory chain deficiency.

3. What is the outlook (prognosis)?
Because COXPD27 is very rare, prognosis can vary widely. Many reported patients have significant neurodevelopmental impairment and epilepsy; some cases progress quickly, while others are more stable with good supportive care. Close follow-up in an experienced center is important.

4. Does every child with COXPD27 have seizures?
Most reported patients have seizures or epileptic encephalopathy, but there are rare cases with mainly dystonia or other movement problems. Seizure type and severity can differ even between patients with similar mutations.

5. Can siblings be tested before they show symptoms?
Yes. Once the family’s CARS2 variants are known, siblings can be tested through genetic counseling services. Early diagnosis allows closer monitoring and quicker treatment of problems like seizures or feeding issues.

6. Is pregnancy safe for a mother who already has a child with COXPD27?
A mother who is a carrier usually does not have COXPD27 symptoms, but each pregnancy with a carrier partner has a 25% chance of an affected child. Genetic counseling before pregnancy can explain options like carrier testing of the partner, prenatal diagnosis, or IVF with embryo testing.

7. Are there special precautions for anesthesia and surgery?
Yes. Patients with mitochondrial disease may be sensitive to fasting, temperature changes, and some anesthetic drugs. Anesthesiologists should follow mitochondrial-specific protocols, maintain glucose, prevent hypothermia, and monitor closely during and after surgery.

8. Can regular exercise help or harm?
Carefully planned, low-to-moderate exercise can help strength and endurance, but over-exercise can worsen fatigue and cause metabolic stress. Exercise programs must be individualized, starting very gently and adjusting based on symptoms.

9. Why do doctors recommend so many vitamins and supplements?
Mitochondrial “cocktails” combine several vitamins and cofactors (like CoQ10, carnitine, riboflavin) that support energy pathways or act as antioxidants. Evidence for benefit is mixed, but they are usually safe and sometimes improve stamina or reduce crisis frequency.

10. Are these vitamins enough as treatment?
No. Supplements are only one part of care. Seizure control, nutrition, physiotherapy, infection prevention, and family support are just as important, and sometimes more important, than vitamins alone.

11. Does COXPD27 always get worse with time?
Many mitochondrial diseases are progressive, but the speed and pattern of progression differ a lot. Some children decline quickly, while others remain relatively stable for years with good supportive care. Regular assessment helps adjust treatment as needs change.

12. Can children with COXPD27 go to school?
Yes, many can, but they often need special education plans, shortened days, assistive communication tools, or physical supports. Working with teachers and school nurses helps create a safe and supportive environment.

13. Are there international guidelines for treating mitochondrial epilepsy?
Expert groups have published consensus statements for seizure management in primary mitochondrial disease. They recommend avoiding highly mitochondria-toxic antiepileptic drugs when possible and favor options like levetiracetam, lamotrigine, and zonisamide, plus careful use of rescue medications.

14. How can families keep up with new research?
Families can follow mitochondrial foundations, research centers, and clinical trial registries. Joining registries or support groups can help them hear about trials of new drugs, gene therapy, or regenerative treatments that may one day benefit nuclear-encoded disorders like COXPD27.

15. Is this information a substitute for medical advice?
No. This overview is for education and SEO-friendly explanation only. Every child with COXPD27 is unique. Diagnosis, medicines, diet, and therapies must always be planned and changed by qualified healthcare professionals who know the patient’s full history.

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.