Combined Oxidative Phosphorylation Defect Type 23 (COXPD23)

Combined oxidative phosphorylation defect type 23 (COXPD23) is a very rare genetic mitochondrial disease. It happens when both copies of a gene called GTPBP3 do not work properly. This gene normally helps mitochondria make energy by helping to build special parts of the energy chain. When GTPBP3 is damaged, the body cannot make enough energy, especially in the heart and brain. Children usually show heart muscle thickening (hypertrophic cardiomyopathy), weak muscles, slow development, and high lactic acid in the blood. [1][2]

Combined oxidative phosphorylation defect type 23 (often written as COXPD23) is a very rare mitochondrial disease. In this condition, tiny “power plants” in the cell, called mitochondria, do not work well. Because of this, many organs that need a lot of energy, like the heart, muscles, and brain, can be affected. Children usually show problems early in life, such as weak muscles, trouble feeding, delayed development, and heart muscle thickening (hypertrophic cardiomyopathy). Blood tests often show high lactic acid because the body cannot make energy in the normal way. [1]

COXPD23 is usually inherited in an autosomal recessive way. This means a child gets one non-working copy of the gene from each parent. The disease has been linked to changes (mutations) in a gene called GTPBP3, which is important for proper function of the mitochondrial protein-making system. When GTPBP3 does not work, the mitochondrial “energy chain” (oxidative phosphorylation) cannot run smoothly, especially complexes I and IV. [2]

Other names

Doctors and researchers use several names for the same condition. All of them describe the same basic disease: an inherited problem with mitochondrial energy production due to changes in the GTPBP3 gene. [1][3]

• Combined oxidative phosphorylation deficiency 23 – often shortened to COXPD23. [1]

• Combined oxidative phosphorylation defect type 23 – the same disease, just a different word (“defect” instead of “deficiency”). [1]

• GTPBP3-related combined oxidative phosphorylation deficiency – a name that highlights the exact gene involved. [2]

• GTPBP3 mitochondrial disease with cardiomyopathy and neurologic symptoms – a descriptive name that focuses on heart and brain problems in this condition. [2]

Types

Researchers have not created strict “official” subtypes of COXPD23. Instead, case reports show patterns based on age when symptoms start and which organs are most affected. These patterns help doctors think about severity and prognosis, but they are still the same underlying disease. [1][2]

• Neonatal-onset severe form – symptoms start soon after birth with very weak muscles, feeding problems, severe lactic acidosis, and often early death if support is not possible. [1]

• Infantile cardiomyopathy-dominant form – babies mainly show thickened heart muscle, fast breathing, and signs of heart failure, sometimes before strong brain symptoms appear. [1][2]

• Infantile neuro-cardiac mixed form – many children show both heart disease and neurologic problems, such as low muscle tone, seizures, and developmental delay. [2][4]

• Childhood-onset neurologic-predominant form – some children have milder or managed heart findings but more obvious learning problems, seizures, or movement problems. [2][5]

• Survivor form into later childhood – a few children survive into the second decade with chronic muscle weakness, intellectual disability, and heart problems that may be stable or slowly progressive. [1][2]

Causes

1. Pathogenic variants in the GTPBP3 gene
The main direct cause of COXPD23 is having harmful changes (pathogenic variants) in both copies of the GTPBP3 gene. This gene helps modify special mitochondrial tRNA molecules needed to build proteins for the energy chain. When both copies are faulty, mitochondria cannot work properly, and the disease appears. [1][2]

2. Autosomal recessive inheritance
COXPD23 follows an autosomal recessive pattern. This means each parent usually carries one silent faulty copy of GTPBP3, but they are healthy. A child who inherits the faulty copy from both parents (two variants) will have the disease. This inheritance pattern explains why the condition often appears in siblings. [1][3]

3. Homozygous missense mutations
Some patients have the same missense change (one incorrect amino acid) in both copies of GTPBP3. This small change can still seriously damage how the GTPBP3 protein folds or works, so mitochondrial tRNA modification and energy production are impaired. [2][4]

4. Compound heterozygous mutations
Other patients have two different GTPBP3 variants, one from each parent (compound heterozygous). Each variant partially damages the protein, and together they reduce mitochondrial function enough to cause the full clinical picture of COXPD23. [2][5]

5. Nonsense (truncating) mutations
Nonsense mutations in GTPBP3 create a “stop” signal too early and cut off the protein, so it is shortened or destroyed. These truncating variants lead to a serious loss of function, and they are strongly linked with severe mitochondrial energy failure and lactic acidosis. [2][4]

6. Splice-site mutations affecting pre-mRNA splicing
Some variants in GTPBP3 affect how the gene’s RNA is spliced. These splice-site mutations can remove or add extra pieces to the RNA, producing abnormal proteins that cannot carry out their normal tRNA-modifying job in mitochondria. [4][5]

7. Impaired taurine modification of mitochondrial tRNAs
GTPBP3 normally helps add a taurine-related chemical change to certain mitochondrial tRNAs (for glutamine, glutamate, and lysine). When GTPBP3 is defective, this modification is missing, so the protein-building process inside mitochondria becomes slow and error-prone. [2][4]

8. Defective mitochondrial protein translation
Because mitochondrial tRNAs are not correctly modified, the ribosome in mitochondria cannot translate many energy-chain proteins properly. This defective mitochondrial translation lowers the amount of vital respiratory chain proteins, especially in high-energy organs. [1][2]

9. Reduced activity of respiratory chain complexes I and IV
Muscle biopsies and biochemical tests in COXPD23 often show that complexes I and IV in the respiratory chain work less than normal. These complexes are key steps in oxidative phosphorylation. Their reduced activity cuts ATP production and causes energy failure. [1][3]

10. Mitochondrial energy failure in heart muscle
Heart muscle cells need a lot of ATP. In COXPD23, damaged oxidative phosphorylation means the heart must work harder with less fuel. This contributes to thickened heart muscle (hypertrophic cardiomyopathy), heart failure, and arrhythmias in many patients. [1][2]

11. Mitochondrial energy failure in brain tissue
The brain also needs constant high energy. When mitochondrial ATP is low, neurons cannot maintain normal electrical activity and signaling. This energy failure helps cause seizures, developmental delay, and other neurologic symptoms seen in this disease. [1][5]

12. Lactic acidosis from increased anaerobic metabolism
Because oxidative phosphorylation is weak, cells switch more to anaerobic glycolysis to make energy. This pathway produces lactic acid. Overproduction and poor clearance cause lactic acidosis, which is a hallmark laboratory finding in COXPD23. [1][2]

13. Consanguinity (parents related by blood)
Several reported families with COXPD23 come from consanguineous parents. When parents are related, they are more likely to carry the same rare GTPBP3 variant, which increases the chance that a child will inherit the defective gene from both sides. [1][3]

14. Positive family history of GTPBP3-related disease
If one child in the family is affected and parents are confirmed carriers, later pregnancies have the same genetic risk. This family pattern does not cause the mutation itself but explains why the condition can repeat in siblings. [1][3]

15. Genetic modifiers in other mitochondrial genes
Published cases show wide differences in severity, even with similar GTPBP3 variants. Researchers think other mitochondrial or nuclear genes may modify how serious the disease becomes. These modifier genes can worsen or soften the effect of the main GTPBP3 defect. [2][5]

16. Metabolic stress from infections or fasting
Like many mitochondrial diseases, COXPD23 often gets worse during infections, fever, or prolonged fasting. These stresses suddenly increase energy needs. Because the mitochondria cannot respond adequately, lactic acidosis and heart or brain symptoms may suddenly worsen. [1][5]

17. Early rapid growth in infancy
The first months of life are a period of very high energy demand for growth and organ maturation. In infants with GTPBP3 mutations, this natural stress can unmask the underlying mitochondrial defect and bring out symptoms earlier. [1][2]

18. Tissue-specific vulnerability of heart and brain
Although GTPBP3 is present in many tissues, the heart and brain seem especially sensitive. Their constant high ATP needs mean that even moderate mitochondrial dysfunction due to GTPBP3 defects can lead to obvious clinical disease in these organs. [2][4]

19. Impaired GTP-binding function of GTPBP3 protein
GTPBP3 is a GTP-binding protein. Some mutations directly affect its ability to bind or hydrolyze GTP. This problem further disrupts the tRNA modification steps needed for normal mitochondrial translation, deepening the energy defect. [4][5]

20. Delayed diagnosis and lack of supportive management
The gene defect itself is the primary cause, but late recognition can allow repeated episodes of metabolic crisis, severe lactic acidosis, and heart failure. These repeated events can worsen organ damage and long-term outcome in children with COXPD23. [1][5]

Symptoms

1. Hypertrophic cardiomyopathy (thick heart muscle)
Many patients develop hypertrophic cardiomyopathy, where the heart muscle, especially the left ventricle, becomes abnormally thick. This can make it harder for the heart to pump blood and may lead to heart failure or abnormal heart rhythms. [1][2]

2. Global developmental delay
Children often sit, stand, walk, and talk later than expected. This global developmental delay reflects poor brain energy supply and can range from mild learning problems to severe disability depending on how bad the mitochondrial defect is. [1][2]

3. Generalized hypotonia (low muscle tone)
Babies with COXPD23 may feel “floppy” when held. Low muscle tone makes it hard for them to control their head, sit, or walk. Hypotonia is very common in mitochondrial diseases because muscles lack enough ATP to stay firm and strong. [1][3]

4. Intellectual disability or cognitive impairment
As children grow, many show ongoing problems with learning, memory, and thinking skills. Intellectual disability in this disease reflects chronic brain energy shortage and sometimes structural brain changes seen on MRI. [2][4]

5. Seizures
Seizures are common, especially in more severe cases. Episodes can be triggered by fever or metabolic stress. Because the brain’s energy is unstable, nerve cells fire in abnormal bursts, causing convulsions or staring spells. [2][5]

6. Lactic acidosis-related symptoms (vomiting, rapid breathing)
High lactic acid can cause vomiting, fast breathing, and feeling very unwell. Parents may notice their child breathing quickly or deeply, which is the body’s way to blow off extra acid through carbon dioxide. [1][2]

7. Feeding difficulties in infancy
Weak muscles, poor coordination, and easy fatigue can make feeding hard. Babies may take a long time to feed, cough or choke, or fail to gain weight. Sometimes tube feeding is needed to maintain nutrition and avoid aspiration. [1][2]

8. Failure to thrive and poor growth
Because energy production is low and feeding is difficult, many children do not grow as expected. They may be much smaller or lighter than peers. This “failure to thrive” is a common sign that something serious is affecting metabolism. [1][2]

9. Dyspnea or breathing trouble
Heart failure, lactic acidosis, and weak respiratory muscles can all cause shortness of breath (dyspnea). Children may breathe faster at rest, tire easily during feeding, or need oxygen or ventilatory support during episodes. [2][5]

10. Visual impairment
Some patients have reduced vision or abnormal visual behavior. This may come from damage to parts of the brain that process vision or from involvement of the optic nerve, both of which rely heavily on mitochondrial energy. [1][2]

11. Hearing impairment in some cases
A few reports describe children with GTPBP3 mutations who have hearing loss. The tiny sensory cells in the inner ear depend on good mitochondrial function, so they can be affected in this disease. [2][5]

12. Encephalopathy (general brain dysfunction)
Encephalopathy describes an overall sick brain, not just a single symptom. Children may be unusually sleepy, irritable, confused, or show loss of skills they had gained before. Brain MRI often shows lesions in deep brain structures. [1][3]

13. Movement problems or ataxia
Some patients develop jerky movements, poor balance, or difficulty controlling their limbs. These problems may reflect damage in the basal ganglia or cerebellum, areas of the brain that guide movement and are often abnormal on imaging. [1][2]

14. Fatigability and exercise intolerance
Even when older children can walk, they often tire very quickly. Simple activities such as climbing stairs or playing may cause exhaustion, because their muscles cannot make enough ATP from oxidative phosphorylation. [2][5]

15. Congestive heart failure signs
In advanced cases, the thick and weak heart may not pump blood well, leading to swelling of legs or face, enlarged liver, and poor circulation. These signs of congestive heart failure are serious and need urgent treatment. [2][4]

Diagnostic tests

Physical examination tests

1. General pediatric examination
A full head-to-toe exam helps the doctor see growth pattern, overall muscle tone, breathing, heart sounds, and signs of organ enlargement. In COXPD23, the doctor may notice poor growth, floppy muscles, or an enlarged liver due to heart failure. [1][2]

2. Cardiovascular examination
Listening with a stethoscope can show extra heart sounds, murmurs, or fast heart rate. Checking pulses, blood pressure, and signs of fluid overload helps detect hypertrophic cardiomyopathy or heart failure that are typical in this disease. [1][2]

3. Neurologic examination
The neurologic exam looks at reflexes, muscle strength, tone, coordination, and cranial nerves. In COXPD23, the doctor often finds hypotonia, abnormal reflexes, and sometimes visual or hearing problems, which point toward a mitochondrial encephalopathy. [1][3]

4. Growth and developmental assessment
Plotting weight, length, and head size on growth charts and using simple developmental checklists reveals failure to thrive and developmental delay. These findings support the suspicion of a chronic metabolic or mitochondrial problem such as COXPD23. [1][2]

Manual / bedside functional tests

5. Manual muscle strength testing
In older children, doctors can test muscle power by asking them to push or pull against resistance. Weakness in many muscle groups, together with hypotonia, supports the idea of a systemic mitochondrial myopathy rather than a local nerve injury. [2][5]

6. Tone and posture assessment in infants
For babies, clinicians gently move the limbs and watch how they hold their head and trunk. Marked head lag, “slipping through” when held under the arms, and poor antigravity movement show significant hypotonia, common in COXPD23. [1][3]

7. Simple vision and eye movement checks
Doctors can check whether the child fixes on faces, tracks objects, and has normal eye movements. Poor tracking, nystagmus, or absent visual response may indicate visual impairment from brain or optic nerve involvement in this mitochondrial disease. [1][2]

8. Bedside hearing screening
Basic bedside tests (response to sound, use of simple hearing screens, or referral for formal audiology) help detect hearing loss. Because GTPBP3 disease can include hearing problems, identifying this early is important for support and communication. [2][5]

Laboratory and pathological tests

9. Blood lactate and pyruvate levels
High blood lactate, often with an abnormal lactate-to-pyruvate ratio, is a key sign of impaired oxidative phosphorylation. In COXPD23, lactic acidosis is reported in almost all described patients and strongly points toward mitochondrial disease. [1][2]

10. Arterial or venous blood gas analysis
Blood gas tests show how acidic the blood is and whether there is respiratory compensation. In COXPD23, metabolic acidosis with low bicarbonate and sometimes respiratory alkalosis from fast breathing confirms significant lactic acidosis. [1][2]

11. Serum creatine kinase (CK)
CK is a marker of muscle damage. It can be normal or mildly raised in mitochondrial disease. While not specific, measuring CK helps rule out other muscle conditions and can support the idea of a myopathic process in some patients. [2][5]

12. Comprehensive metabolic panel (liver, kidney, electrolytes)
Tests of liver enzymes, kidney function, glucose, and electrolytes are important to see how other organs are coping. In severe COXPD23, liver involvement or kidney problems may appear, especially during metabolic crises. [2][5]

13. Urine organic acids
Urine organic acid analysis often shows increased lactic acid and other metabolites that indicate mitochondrial dysfunction. While not specific for GTPBP3, this test is part of the standard workup for suspected mitochondrial disease. [1][2]

14. Muscle biopsy with respiratory chain enzyme analysis
A muscle biopsy can measure the activity of mitochondrial respiratory complexes. In COXPD23, reduced activity of complexes I and IV is typical and provides strong biochemical evidence of combined oxidative phosphorylation deficiency. [1][2]

15. Molecular genetic testing of GTPBP3
Sequencing the GTPBP3 gene is the definitive test. Modern panels or whole-exome / whole-genome sequencing can find pathogenic variants. Confirming biallelic GTPBP3 mutations officially establishes the diagnosis of COXPD23. [2][4]

Electrodiagnostic tests

16. Electrocardiogram (ECG)
An ECG records the heart’s electrical activity. In COXPD23, ECG may show rhythm disturbances, conduction problems, or signs of left ventricular hypertrophy, all of which fit with hypertrophic cardiomyopathy and heart failure risk. [1][2]

17. Electroencephalogram (EEG)
EEG measures brain electrical activity. It helps confirm seizures and may show diffuse slowing or epileptic discharges in children with encephalopathy and seizures due to COXPD23. This supports the link between mitochondrial dysfunction and brain involvement. [2][5]

18. Nerve conduction studies and EMG (in selected cases)
In some patients, doctors may test peripheral nerves and muscles electrically. Although not always abnormal, these studies can help rule out primary nerve diseases and sometimes show myopathic or mitochondrial patterns when muscle is involved. [2][5]

Imaging tests

19. Echocardiography (heart ultrasound)
Echocardiography is the key imaging test for hypertrophic cardiomyopathy. It lets doctors see the thickness of the heart walls, pumping function, valve behavior, and any outflow obstruction. In COXPD23, echo often shows marked left ventricular hypertrophy. [1][2]

20. Brain MRI (with or without MR spectroscopy)
Brain MRI commonly reveals abnormal signals in the basal ganglia, thalamus, or brainstem in COXPD23. These lesions match the encephalopathy and movement problems. MR spectroscopy may show high lactate peaks, further proving mitochondrial dysfunction. [1][2]

Non-pharmacological treatments (therapies and others)

1. Individualized physiotherapy and stretching
Regular physiotherapy helps keep muscles strong and flexible, and can reduce joint stiffness and contractures. Exercises are chosen very carefully to avoid over-tiring the child, because too much effort can worsen fatigue or trigger lactic acidosis. Gentle stretching, positioning, and assisted movement can also improve posture and breathing. A physiotherapist with experience in neuromuscular or mitochondrial disease usually designs a program to match the child’s abilities. [4]

2. Energy-conserving occupational therapy
Occupational therapists teach the child and family how to save energy in daily life. This may include using special chairs, wheelchairs, bathing aids, or communication tools. Tasks are broken into smaller steps with rest periods in between. The goal is to increase independence while protecting the child from exhaustion. This kind of therapy also supports school participation and self-care skills. [5]

3. Speech and feeding therapy
Many children with COXPD23 have weak mouth muscles, swallowing problems, or delayed speech. Speech-language therapists can help with safe swallowing techniques, feeding positions, and exercises to improve lip, tongue, and jaw control. They may also recommend thickened fluids or special textures to reduce choking risk. If speech is delayed, they can introduce picture boards or devices so the child can communicate better. [6]

4. Cardiac rehabilitation style monitoring (for older children)
Because the heart is often affected, monitored gentle activity under cardiology supervision can help some older children keep their heart and muscles active without over-straining them. Walking on a flat surface, light cycling, or simple play activities can be adjusted based on heart rate and symptoms. This reduces de-conditioning and may improve mood and sleep. [7]

5. Structured rest and pacing plan
Families are encouraged to plan the day with “energy budgeting.” This means putting big activities earlier in the day, adding rest breaks, and avoiding long periods of walking or standing. Good pacing helps prevent sudden energy crashes, breathing problems, or worsening lactic acidosis. Written daily plans and school support can make this easier. [8]

6. Nutritional counseling and high-energy meal planning
Dietitians familiar with mitochondrial disease can suggest meals that provide enough calories and protein while avoiding long fasting periods. Small, frequent meals help keep blood sugar stable and support energy production. Nutrition plans may be adjusted when the child is sick, to prevent metabolic crises. [9]

7. Night-time and illness-day feeding support (including tube feeding if needed)
Some children cannot eat enough by mouth because of weak muscles or fatigue. In these cases, tube feeding (nasogastric or gastrostomy tube) can safely provide calories, fluids, and supplements. This is especially important overnight and during infections, when energy needs go up. The goal is to prevent weight loss and dehydration. [10]

8. Respiratory support and airway clearance
Weak respiratory muscles can cause shallow breathing, low oxygen, or trouble clearing mucus. Techniques such as chest physiotherapy, assisted coughing devices, or non-invasive ventilation (like BiPAP) can support breathing, especially during sleep or infections. Good lung care lowers the risk of pneumonia and hospital stays. [11]

9. Temperature and infection control
Fever and infections increase energy demand and can worsen lactic acidosis and heart stress. Families are taught to seek quick medical care for fevers, dehydration, or new breathing problems. Regular vaccines (when advised by specialists) and careful hygiene can help prevent severe infections. [12]

10. Psychological and family support
Living with a rare, chronic disease is stressful. Psychological support for parents and siblings, and age-appropriate counseling or play therapy for the child, can reduce anxiety and depression. Social workers can help families access services, financial support, and special education resources. [13]

11. Special education and developmental therapies
Children with COXPD23 may have delayed milestones or learning difficulties. Early intervention, special education plans, and therapies for motor and cognitive skills can help the child reach their best possible developmental level. School teams and medical teams usually work together to adapt teaching methods. [14]

12. Gentle, supervised exercise programs
In some mitochondrial conditions, carefully supervised low-intensity exercise can improve muscle strength and endurance without harming mitochondria. Activities are chosen to avoid sudden bursts or heavy lifting, and sessions are stopped if the child feels dizzy, very tired, or short of breath. [15]

(In practice, doctors will choose and combine the most suitable of these non-drug treatments for each child.)

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Drug treatments

Important safety note
There is no drug that cures COXPD23. Medicines are used to treat problems such as seizures, heart failure, lactic acidosis, or infections. Many drugs are used off-label (not specifically tested for this exact disease), based on experience in other mitochondrial diseases. Exact doses must always be set by specialists. Do not start, stop, or change any medicine without your doctor. [16]

Below are examples of drug types commonly considered; they are not a treatment plan for any individual child.

1. Levocarnitine (CARNITOR®)
Levocarnitine is a synthetic form of carnitine, a molecule that helps move fatty acids into mitochondria to be burned as fuel. In some mitochondrial and metabolic disorders with carnitine deficiency, levocarnitine can support energy production and help remove toxic acyl compounds. It is usually given by mouth or injection in weight-based doses several times a day, adjusted by the doctor. Common side effects include nausea, vomiting, or diarrhea. [17]

2. Coenzyme Q10 (ubiquinone/ubiquinol)
Coenzyme Q10 is a key part of the mitochondrial electron transport chain. Supplementing it may help cells make more ATP and reduce oxidative stress. In mitochondrial disease practice, CoQ10 is often given orally in divided daily doses with food, as part of a “mitochondrial cocktail.” It is generally well tolerated; occasional side effects include stomach upset or headache. [18]

3. Riboflavin (vitamin B2)
Riboflavin is a vitamin that helps several enzymes in the mitochondrial chain, especially complex I and II. In some mitochondrial disorders, high-dose riboflavin has been reported to improve muscle strength or reduce lactic acid levels. It is usually given once or twice daily with food. Urine may become bright yellow, which is harmless. [19]

4. Thiamine (vitamin B1)
Thiamine is needed for enzymes that link sugar breakdown to the mitochondrial energy chain. High-dose thiamine is sometimes used when lactic acidosis and neurologic symptoms suggest a thiamine-responsive mitochondrial disorder. It is usually taken by mouth one or more times daily. Side effects are rare but may include mild stomach upset or allergic reactions with injections. [20]

5. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant and a cofactor in mitochondrial dehydrogenase complexes. In some small studies, it has been combined with CoQ10 and creatine to support mitochondrial function. It is taken orally with meals. Possible side effects include nausea, skin rash, or low blood sugar, especially in people with diabetes medicines. [21]

6. Creatine monohydrate
Creatine helps store and shuttle energy in muscle cells as phosphocreatine. Supplements may improve muscle strength and reduce fatigue in some mitochondrial myopathies. It is usually taken by mouth daily, sometimes in divided doses. Side effects can include weight gain from water retention and, rarely, stomach upset. Kidney function is usually monitored. [22]

7. Arginine or citrulline
Arginine and citrulline are amino acids that help make nitric oxide, which widens blood vessels and supports blood flow. In certain mitochondrial syndromes with stroke-like episodes, arginine infusions or high-dose oral arginine have been used. For COXPD23, use would be considered case-by-case by specialists. Side effects can include stomach upset, low potassium, or blood pressure changes. [23]

8. Standard heart failure drugs (ACE inhibitors, beta-blockers, diuretics)
Because hypertrophic cardiomyopathy and heart failure are common, cardiologists may use medicines like ACE inhibitors, beta-blockers, and diuretics. These help the heart pump more efficiently, control blood pressure, and remove excess fluid. Doses are very carefully adjusted, and the child is monitored for low blood pressure, kidney problems, or electrolyte changes. [24]

9. Anti-seizure medicines chosen for mitochondrial safety
If seizures occur, doctors choose anti-seizure medicines that are less harmful to mitochondria, such as levetiracetam or lamotrigine, while trying to avoid drugs known to worsen mitochondrial function in some patients (for example, valproic acid in certain gene defects). Doses are slowly adjusted to control seizures with the fewest side effects. [25]

10. Bicarbonate or other alkali to treat acidosis (hospital use)
During severe illness with lactic acidosis, intravenous fluids and sometimes bicarbonate or other alkali may be used to correct blood acidity. This is done in hospital with close monitoring of blood gases, electrolytes, and heart function. The goal is to stabilize the child while the underlying trigger (such as infection or dehydration) is treated. [26]

(In real life, a full list of medicines may be longer, but the exact choices and doses are always individualized by a specialist team.)

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Dietary molecular supplements

1. Coenzyme Q10 (mitochondrial chain support)
As noted above, CoQ10 is one of the most common supplements used in mitochondrial disease. It supports electron transfer in the respiratory chain and acts as an antioxidant. Oral CoQ10 is usually taken with meals that contain some fat to improve absorption, in two or three doses per day. Doctors adjust the amount based on age, weight, and response. [27]

2. Riboflavin (complex I and II cofactor)
High-dose riboflavin supports flavoprotein enzymes in the mitochondrial chain. It may be given as part of a daily vitamin “cocktail” to help improve energy production. It is simple to take and generally safe, so it is often included in long-term plans for mitochondrial patients. [28]

3. Thiamine (pyruvate dehydrogenase cofactor)
Thiamine helps convert sugar into acetyl-CoA, which then enters the citric acid cycle in mitochondria. By supporting this step, thiamine may help reduce lactic acid and improve energy use. It can be given once or more daily. Doctors sometimes give higher doses at the start and then continue with a maintenance dose. [29]

4. Alpha-lipoic acid (antioxidant support)
Alpha-lipoic acid works as an antioxidant inside mitochondria and regenerates other antioxidants like vitamin C and glutathione. It may support mitochondrial enzymes involved in energy production. It is usually taken orally once or twice a day. Side effects are monitored, especially in people with diabetes who are on glucose-lowering medicines. [30]

5. L-carnitine (fatty acid transport)
As a supplement, L-carnitine increases the body’s carnitine pool, improving transport of long-chain fatty acids into mitochondria and removal of toxic acyl compounds. It is usually given by mouth several times daily with food. It can cause fishy body odor or stomach upset in some people. Blood carnitine levels are often checked. [31]

6. Folinic acid (activated folate)
Folinic acid is used in some mitochondrial and neurometabolic conditions, especially when there is concern for cerebral folate deficiency. It helps support DNA and RNA synthesis and repair. It is usually taken once or twice daily by mouth. Side effects are uncommon, but doses and need for therapy are decided by specialists. [32]

7. Vitamins C and E (antioxidant vitamins)
Vitamin C and vitamin E help neutralize free radicals and may reduce oxidative damage to mitochondrial membranes and DNA. They are often used as part of a broader antioxidant regimen. They are taken by mouth, and long-term high doses are usually avoided to reduce risk of side effects, such as diarrhea or increased bleeding risk. [33]

8. Vitamin K (support for mitochondrial and clotting functions)
Vitamin K is sometimes discussed in mitochondrial nutrition because of its role in electron transport in some models and for blood clotting. In practice, it is used mainly if there is a specific deficiency or clotting problem. It is usually given in small daily doses orally or by injection under specialist guidance. [34]

9. Selenium and zinc (trace elements)
Selenium and zinc are important for antioxidant enzymes and immune function. If tests show deficiency, supplements may be given in small, weight-based doses. Too much can be harmful, so they should only be used under dietitian or physician guidance, with periodic blood tests. [35]

10. Multivitamin with minerals
A balanced multivitamin is often used to ensure overall micronutrient intake, especially if the child eats poorly. It is not a specific treatment for COXPD23, but it can help prevent secondary vitamin and mineral deficiencies that could further worsen fatigue or immunity. [36]

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Immune-supporting and regenerative / stem-cell approaches

1. General immune support with adequate nutrition and vaccines
The strongest and safest immune “booster” for a child with COXPD23 is good nutrition, enough sleep, and appropriate vaccines, as advised by the care team. This helps the body fight infections without overstressing the mitochondria. Extra or unproven “immune boosters” bought online can be risky and should be avoided unless a specialist approves them. [37]

2. Antioxidant combinations (CoQ10, alpha-lipoic acid, vitamins)
Some researchers consider antioxidant combinations as a way to protect cells from oxidative damage and support mitochondrial function. These are not classic “immune drugs,” but better mitochondrial function may indirectly support immune health and healing. Evidence is limited, and results vary between patients. [38]

3. Experimental drugs targeting mitochondrial function
New drugs that target the mitochondrial chain, redox balance, or signaling pathways are being studied in clinical trials for mitochondrial diseases in general. Examples include novel CoQ10 analogs or compounds that alter NAD+/NADH balance. These medicines are not standard care for COXPD23 and are available only in research studies. [39]

4. Hematopoietic or mesenchymal stem-cell therapies (highly experimental)
Stem-cell based approaches are being explored for some metabolic and genetic diseases. For mitochondrial disorders like COXPD23, such treatments are still at a very early, experimental stage, often in the lab or very small trials. They carry serious risks and are not routine treatment. Families should only consider such options within approved clinical trials at expert centers. [40]

5. Gene-targeted strategies in research
Because COXPD23 involves mutations in GTPBP3, future gene-based therapies might aim to correct or bypass this defect. At present, gene therapy for this condition is not available in routine clinical care. Discussions about such options should take place at specialized mitochondrial centers and within clinical trial settings. [41]

6. Avoiding harmful “stem-cell” clinics
Many unregulated clinics advertise “stem-cell cures” for a wide range of diseases. These are usually not evidence-based, can be extremely expensive, and may be dangerous. Families should be warned to avoid them and instead talk to their specialist about real, registered clinical trials. [42]

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Surgical and device-based procedures

1. Gastrostomy tube placement (feeding tube surgery)
If swallowing is unsafe or the child cannot take enough calories by mouth, a small surgery can place a feeding tube directly into the stomach (gastrostomy). This allows safe delivery of food, fluids, and medicines. It can improve growth, reduce hospitalizations, and make daily care easier. The surgery is done under anesthesia with careful heart and breathing monitoring. [43]

2. Cardiac pacemaker or implantable cardioverter-defibrillator (ICD)
In some children, heart rhythm problems or severe cardiomyopathy may require a pacemaker or ICD. These devices help keep the heartbeat regular and prevent sudden dangerous rhythms. The procedure involves placing leads in the heart and a small device under the skin. Decisions are made by cardiologists who specialize in heart failure and inherited heart disease. [44]

3. Scoliosis or orthopedic surgery
If muscle weakness leads to severe spinal curvature (scoliosis) or joint problems that interfere with breathing or sitting, orthopedic surgery may be considered. The aim is to improve posture, comfort, and lung function. Anesthesia risk is carefully evaluated in mitochondrial patients, and surgery is only done when benefits clearly outweigh risks. [45]

4. Tracheostomy (airway surgery) in severe respiratory failure
In rare, very severe cases where long-term respiratory support is needed, a tracheostomy (a hole in the windpipe with a tube) may be done. This can make ventilation more comfortable and easier to manage at home. It is a major decision that requires detailed discussion with the family and the care team. [46]

5. Heart transplantation (exceptional cases)
For some patients with end-stage cardiomyopathy and relatively preserved function in other organs, heart transplantation may be considered. This is rare and depends on many factors, including how much the mitochondrial defect affects other systems. Transplant centers evaluate each case very carefully. [47]

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Prevention and lifestyle tips

Complete prevention of COXPD23 is not possible once a child is born with the condition. However, some steps can reduce complications and improve quality of life. [48]

1. Early diagnosis and genetic counseling – When COXPD23 is suspected, early genetic testing and counseling help families understand the condition, future pregnancy risks, and options like prenatal or pre-implantation genetic diagnosis. [49]

2. Regular follow-up at a mitochondrial or metabolic center – Ongoing care with a specialist team helps detect heart, lung, or nutritional problems early and adjust treatments in time. [50]

3. Prompt treatment of infections and fevers – Quick medical attention for fevers, vomiting, or breathing problems can prevent metabolic crises and hospitalizations. [51]

4. Avoiding prolonged fasting – Long gaps without food can trigger low blood sugar and lactic acidosis. Small, regular meals or night feeds are often recommended. [52]

5. Avoiding known mitochondrial-toxic drugs – Certain medications may worsen mitochondrial function. Specialists can provide a list of drugs to avoid and safer alternatives. [53]

6. Careful planning for anesthesia and surgery – Anesthetics can stress the heart and metabolism. Anesthesia plans should be made by teams familiar with mitochondrial disease. [54]

7. Protecting from overheating and extreme cold – Extreme temperatures can increase energy needs and stress. Comfortable room temperature, good hydration, and appropriate clothing are helpful. [55]

8. Supporting mental health and family resilience – Psychological, educational, and social support reduces stress and helps families manage long-term care. [56]

9. Vaccination as recommended by specialists – Vaccines (excluding any that the care team specifically advises against) help prevent serious infections that could trigger metabolic crises. [57]

10. Involving local doctors and schools in the care plan – Sharing clear care plans and emergency letters with local doctors, teachers, and school nurses helps keep the child safer in daily life. [58]

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What to eat and what to avoid

What to eat (general ideas)
Children with COXPD23 usually do better with a balanced diet that provides steady energy. This often includes complex carbohydrates (rice, bread, potatoes, oats), enough protein (meat, fish, eggs, beans), healthy fats (vegetable oils, nuts where safe), fruits, and vegetables. Small, frequent meals and snacks can help avoid energy “crashes.” Any special diet (such as higher-fat or higher-carb) should be guided by a mitochondrial dietitian. [59]

What to avoid (or use only under medical guidance)
Extremely strict diets, fad “detox” plans, or long fasting periods can be dangerous, because they may trigger low blood sugar or lactic acidosis. Very high-protein or very high-fat diets should only be used if a specialist recommends them. Large amounts of unproven herbal products or “miracle cures” can interact with medicines or harm the liver and kidneys. [60]

Because each child is different, detailed diet plans should always come from the medical and nutrition team that knows the child’s exact condition.

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When to see a doctor

You should contact a doctor urgently or go to emergency care if a child with COXPD23 has:

• Fast or difficult breathing, blue lips, or very pale skin

• New or worsening chest pain, very fast heartbeat, or fainting

• New seizures or sudden change in behavior or awareness

• Very poor feeding, repeated vomiting, or signs of dehydration (very little urine, dry mouth, sunken eyes)

• High fever that does not improve, or signs of serious infection

You should also see the specialist team routinely for regular heart checks, growth checks, blood tests, and medication review, even if the child seems stable. [61]

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Frequently asked questions (FAQs)

1. Is Combined oxidative phosphorylation defect type 23 curable?
At this time, there is no cure that fixes the underlying genetic problem in COXPD23. Treatment focuses on supporting the heart, muscles, brain, and general health, and on preventing or treating complications early. Research is ongoing into new medicines and gene-based therapies, but these are not yet routine treatment. [62]

2. Can children with COXPD23 go to school?
Many children can attend school with support. They may need shorter days, rest breaks, help with mobility, or special education services. A clear plan made between parents, teachers, and the medical team helps keep the child safe and involved in learning. [63]

3. Will every child with COXPD23 have severe heart disease?
No. Some children have very severe heart problems early in life, while others have milder or later-onset disease. Regular heart checks are important for all, because early changes may not cause symptoms at first. [64]

4. Why is lactic acid high in this condition?
When mitochondria do not produce enough energy, cells switch more to “backup” pathways that make lactic acid. This leads to raised lactic acid levels in blood and sometimes in the brain. Good energy supply, infection control, and careful use of medicines can help reduce severe lactic acidosis episodes. [65]

5. Are brothers and sisters at risk?
Because COXPD23 is autosomal recessive, parents usually carry one non-working copy of the gene but are healthy. Each child of the same parents has a 25% chance of having the disease, 50% chance of being a carrier, and 25% chance of having two working copies. Genetic counseling can explain this in detail. [66]

6. Can adults have COXPD23?
Most reported cases start in childhood, but milder forms could possibly appear later. Adults with unexplained cardiomyopathy plus neurological signs may be evaluated for mitochondrial disease, including rare forms like COXPD23, especially if there is a family history. [67]

7. What tests are used to diagnose COXPD23?
Doctors use a mix of clinical exam, heart tests (such as echocardiogram), brain imaging, blood and urine tests (including lactic acid), muscle biopsy in some cases, and genetic testing to look for GTPBP3 mutations. Today, next-generation sequencing panels or exome sequencing are common tools. [68]

8. Why do different patients look so different even with the same disease name?
Even with mutations in the same gene, the effect on mitochondria can vary, and the body’s ability to compensate is different in each person. Other genes, environment, and care all influence how severe the disease becomes. This is why some children are severely affected while others are milder. [69]

9. Are “mitochondrial cocktails” safe?
Most components, like vitamins and CoQ10, are generally safe at the doses used under medical supervision. However, high doses or combinations can still cause side effects or interact with drugs. Therefore, even supplements should be prescribed and monitored by a mitochondrial specialist or metabolic doctor. [70]

10. Should we try alternative or herbal treatments?
It is understandable to look for additional help, but many alternative products have not been tested in mitochondrial disease and may be harmful. Always talk to the medical team before starting any new supplement or herb, especially in a child with heart or liver problems. [71]

11. Can exercise make the disease worse?
Too much or too intense exercise can cause fatigue and lactic acidosis, but gentle, supervised activity may help maintain strength and mood. The care team can suggest a safe level of activity. Children should stop if they feel dizzy, short of breath, or very tired. [72]

12. Is pregnancy possible for women with COXPD23?
This depends on how affected the heart, lungs, and other organs are. Pregnancy puts extra load on the heart and metabolism, so it can be high risk. Women with mitochondrial disease who are considering pregnancy should talk to a high-risk obstetrician and mitochondrial specialist well in advance. [73]

13. How can families find expert centers or clinical trials?
National or regional mitochondrial disease networks, rare disease organizations, and hospital genetics or neurometabolic clinics can guide families to expert centers. They can also provide information about ongoing clinical trials, including who might be eligible. [74]

14. What is the long-term outlook (prognosis)?
Prognosis is very variable. Some children sadly have severe disease that progresses quickly, while others remain relatively stable for years with good supportive care. Early diagnosis, careful monitoring, and good management of infections and heart disease can improve outcomes. [75]

15. Where can families get emotional and practical support?
Rare disease organizations, mitochondrial disease foundations, local disability services, and online support groups can provide information, emotional support, and practical advice. Social workers in the hospital can help connect families to these resources. [76]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 20, 2025.