Combined Oxidative Phosphorylation Defect Type 24

Combined oxidative phosphorylation defect type 24 (short form: COXPD24) is a very rare genetic disease that affects the “power plants” of the cell, called mitochondria. In this disease, the cell cannot make enough energy using the normal oxidative phosphorylation process, so many organs do not work properly. [1] This disorder is autosomal recessive. This means a child becomes sick only when they receive one faulty copy of the same gene from each parent. The main gene known for COXPD24 is called NARS2, which makes a protein that helps build mitochondrial proteins needed for energy production. [2]

Combined oxidative phosphorylation defect type 24 (COXPD24) is a very rare inherited disease that affects the mitochondria, the “power stations” inside each cell that make energy. In this condition, several parts of the mitochondrial respiratory chain (oxidative phosphorylation complexes) do not work properly, so many organs that need a lot of energy – brain, muscles, ears, heart, liver and kidneys – can be affected. Children usually present in infancy with developmental delay, seizures, low muscle tone, hearing loss, visual problems and sometimes Leigh syndrome–like brain changes and lactic acidosis (too much lactic acid in the blood).[1]

Genetics (NARS2 Gene)

COXPD24 is caused by harmful changes (variants) in a nuclear gene called NARS2, which provides the instructions for an enzyme that attaches the amino acid asparagine to a special mitochondrial tRNA. When NARS2 is not working correctly, mitochondrial protein synthesis is impaired, and several respiratory chain complexes cannot be built properly, leading to combined oxidative phosphorylation deficiency. The disease is inherited in an autosomal recessive way, which means a child becomes affected when they receive one faulty NARS2 copy from each parent; parents are usually healthy carriers.[2][3]

Most children with COXPD24 become ill in early infancy or early childhood. They often have problems with development, learning, movement, muscles, and hearing. The disease can look very different from one child to another: some have very severe disease with early death, while others have milder problems and live longer. [3]

Because the mitochondria are important for many organs, COXPD24 can affect the brain, muscles, ears (hearing), eyes, liver, kidneys, and sometimes the heart. Lab tests often show lactic acidosis (too much lactic acid in the blood) and reduced activity of mitochondrial respiratory chain complexes. [4]

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Other Names and Types

COXPD24 is known in medical books by several different names. These names all point to the same or very closely related conditions. [5]

• Combined oxidative phosphorylation deficiency 24 – this is the most common name used in genetic and rare disease databases. [6]

• Combined oxidative phosphorylation defect type 24 – a slightly different wording, but it means the same disorder. [7]

• NARS2-related combined oxidative phosphorylation deficiency – used when doctors want to highlight that the NARS2 gene is involved. [8]

• MIM 616239 mitochondrial disease – this refers to the number used in the OMIM (Online Mendelian Inheritance in Man) database for this condition. [9]

Doctors describe several clinical types or patterns of COXPD24, based on which organs are most affected and how severe the symptoms are. These are not official separate diseases, but useful ways to group patients. [10]

• Severe infantile encephalomyopathic type – very early onset, with seizures, poor muscle tone, and serious brain and muscle problems, often with lactic acidosis and multi-organ involvement. [11]

• Neuro-hearing type – main problems are global developmental delay, learning problems, seizures, and hearing loss due to auditory nerve damage. [12]

• Myopathy-predominant type – muscle weakness, exercise intolerance, and sometimes mild brain signs, with less severe systemic involvement. [13]

• Hearing-loss–dominant or deafness type – some people mainly have sensorineural hearing loss linked to NARS2 variants, with mild or no obvious brain involvement. [14]

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Causes

1. Pathogenic variants in the NARS2 gene
   The main cause of COXPD24 is harmful changes (variants) in both copies of the NARS2 gene. This gene makes mitochondrial asparaginyl-tRNA synthetase, an enzyme needed to build proteins inside mitochondria. When this enzyme does not work properly, mitochondrial proteins are made incorrectly or too slowly, and energy production falls. [15]

2. Autosomal recessive inheritance
   COXPD24 happens when a child inherits one faulty NARS2 gene from each parent. The parents are usually healthy carriers, with one normal and one changed gene. When two carriers have a child, there is a 25% chance in each pregnancy that the child will have COXPD24. [16]

3. Missense variants in NARS2
   Many reported NARS2 changes are missense variants, where one amino acid in the protein is replaced by another. This small change can disturb the shape of the enzyme, making it less efficient, so mitochondrial protein synthesis becomes weak and oxidative phosphorylation is reduced. [17]

4. Nonsense or frameshift variants in NARS2
   Some variants create an early “stop” signal or shift the reading frame of the gene. These changes can result in a very short or unstable protein that is quickly destroyed by the cell. Without enough NARS2 protein, the mitochondria cannot build normal respiratory chain complexes. [18]

5. Splice-site variants in NARS2
   Certain variants affect how the gene’s RNA is cut and joined (spliced). Incorrect splicing can remove or insert pieces of the protein, leading to a mis-shaped enzyme. This abnormal enzyme cannot properly attach asparagine to mitochondrial tRNA, so mitochondrial protein translation is impaired. [19]

6. Loss of mitochondrial asparaginyl-tRNA synthetase activity
   The final common result of NARS2 variants is partial or severe loss of enzyme activity. When this enzyme is weak, the mitochondria cannot correctly assemble many proteins of respiratory chain complexes I, III, IV, and V. This “combined” loss of complex function is why the disease has its name. [20]

7. Defective mitochondrial protein synthesis
   Because NARS2 works in protein building inside mitochondria, faulty NARS2 leads directly to poor mitochondrial protein synthesis. The small protein factories in mitochondria become slow and error-prone, reducing energy output and harming cells that need high energy, such as brain, muscle, and auditory nerve cells. [21]

8. Reduced activity of respiratory chain complexes
   Studies of muscle biopsies from patients show decreased activity of several respiratory chain complexes. This means the full oxidative phosphorylation pathway is weakened, so ATP (cell energy) production falls. Cells then switch to less efficient pathways, producing lactic acid as a by-product. [22]

9. Lactic acidosis from energy failure
   When mitochondria cannot use oxygen well, cells rely more on glycolysis, which produces lactate. Over time, lactate builds up in blood and tissues, causing lactic acidosis. This is not a separate cause but a direct result of mitochondrial failure, which adds further stress to organs. [23]

10. High energy demand in the developing brain
    Babies and young children have very active brains that need a lot of energy. In COXPD24, the limited mitochondrial function cannot match this demand, so brain cells are easily injured. This is one reason why seizures, developmental delay, and regression are common. [24]

11. High energy demand in muscle tissue
    Muscles, especially when moving, need constant ATP. Defective oxidative phosphorylation makes muscles weak and easily tired. In some patients, muscle involvement (myopathy, hypotonia, or exercise intolerance) is a major part of the disease picture. [25]

12. Vulnerability of auditory neurons
    Hearing problems, often auditory neuropathy, are common. The auditory nerve and inner ear hair cells need stable energy to transmit sound signals. In COXPD24, poor mitochondrial function in these cells can cause hearing loss even when the outer ear and eardrum look normal. [26]

13. Possible modifier genes
    Some patients with similar NARS2 variants have different severity, suggesting that other genes may modify the disease course. These “modifier genes” are not primary causes but can worsen or lessen the impact of NARS2 changes on mitochondrial function. [27]

14. Parental consanguinity (related parents)
    In some reported families, the parents are related (for example, cousins). This increases the chance that both parents carry the same rare NARS2 variant, which makes autosomal recessive diseases like COXPD24 more likely in their children. [28]

15. New (de novo) variants in NARS2
    Although COXPD24 usually runs in families, in rare cases a new variant might arise for the first time in a child. The parents would not show the disease, but the child could still be affected if another inherited or new variant is present in the second NARS2 copy. [29]

16. Environmental stresses increasing energy need
    Fever, infections, or other illnesses can sharply raise the body’s energy demand. In a child with already weak mitochondrial function, these stresses can provoke sudden worsening of symptoms, such as more seizures or regression, although they are not the root genetic cause. [30]

17. Nutritional stress and fasting
    Long periods without food or poor nutrition can reduce the supply of fuels for mitochondria. In COXPD24, where energy production is already reduced, fasting can trigger low blood sugar, lactic acidosis, and increased weakness or seizures. [31]

18. Oxidative stress in mitochondria
    Mitochondrial dysfunction often increases the production of reactive oxygen species (“free radicals”). These molecules can damage mitochondrial DNA, proteins, and membranes, leading to a vicious cycle where energy production becomes even worse over time. [32]

19. Secondary organ damage (liver and kidney)
    Over time, chronic lactic acidosis and poor energy supply can hurt the liver and kidneys. Organ injury then further weakens the body’s ability to clear toxins, which may amplify metabolic problems and clinical symptoms. [33]

20. Delayed or missed diagnosis
    COXPD24 is very rare and often not recognized early. Without early supportive care and careful management of metabolic stress, the disease’s natural course may be more severe. Late diagnosis is not a genetic cause but can worsen the final outcome. [34]

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Symptoms

1. Global developmental delay
   Many children with COXPD24 sit, stand, walk, and talk later than other children. They may need extra help to learn basic skills. This delay often appears in the first year of life and reflects the brain’s struggle to function with limited energy. [35]

2. Psychomotor regression
   Some children lose skills they had already learned, such as sitting, walking, or speaking. This “going backwards” is called regression and usually occurs after periods of illness or seizure clusters, when brain cells are under extra stress. [36]

3. Intellectual disability or learning problems
   Many patients have mild to severe difficulties with thinking, understanding, memory, or school learning. This results from chronic problems in brain networks that need steady energy to grow and work properly. [37]

4. Seizures and epilepsy
   Seizures are one of the most common features. They may start in infancy and can be hard to control with medicine (refractory epilepsy). Seizures happen because energy-starved brain cells fire in an abnormal and uncontrolled way. [38]

5. Hypotonia (low muscle tone)
   Babies often feel “floppy” when picked up. Their muscles may not offer normal resistance. Hypotonia reflects poor energy supply to muscle and nerve cells, and it can make feeding, sitting, and walking more difficult. [39]

6. Myopathy and muscle weakness
   Some children tire quickly, cannot keep up with others, or have trouble standing, walking, or climbing stairs. This muscle weakness is due to reduced ATP in muscle cells and may be confirmed by raised muscle enzymes or muscle biopsy findings. [40]

7. Hearing loss / auditory neuropathy
   Many patients develop sensorineural hearing loss, often related to auditory nerve or inner ear damage. Parents may notice that the child does not respond to sounds or speech as expected. Special hearing tests often show auditory neuropathy. [41]

8. Visual problems and cortical blindness
   Some patients have poor vision or cortical blindness, where the eyes themselves may be structurally normal, but the brain areas that process vision are damaged. This can result in poor eye contact or difficulty tracking objects. [42]

9. Ataxia and coordination problems
   Children may have unsteady walking, tremor, or trouble with fine hand movements. This “ataxia” comes from damage in parts of the brain that coordinate movement, such as the cerebellum, which are sensitive to energy failure. [43]

10. Failure to thrive and poor weight gain
    Because feeding is often difficult and energy use is inefficient, many children do not gain weight or grow as expected. They may require special feeding support to maintain growth. [44]

11. Lactic acidosis-related symptoms
    High lactate levels can cause fast breathing, vomiting, tiredness, and general feeling of illness. During metabolic crises, these symptoms can become severe and may need urgent medical care. [45]

12. Liver problems
    Some children develop liver enlargement or abnormal liver blood tests. In more severe cases, liver dysfunction can resemble conditions like Alpers-like syndrome, with progressive liver damage alongside brain disease. [46]

13. Kidney involvement
    A few patients show kidney problems, such as abnormal urine tests or reduced kidney function. The kidneys are rich in mitochondria, so chronic energy shortage can gradually impair their work. [47]

14. Respiratory problems
    Weak respiratory muscles, brainstem involvement, or lactic acidosis can cause fast or shallow breathing and, in severe cases, respiratory failure. Some children may need breathing support during acute crises or long-term. [48]

15. Early death in severe forms
    In the most severe infantile forms, the combination of refractory seizures, lactic acidosis, and multi-organ failure can lead to early death despite supportive care. Other patients, especially milder forms, can survive longer and show slower progression. [49]

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Diagnostic Tests

Physical exam tests

1. General physical examination and growth assessment
   The doctor checks height, weight, head size, and overall body build and compares them with standard growth charts. They also look for dysmorphic features, organ enlargement, or other visible signs of systemic illness that may suggest a mitochondrial disorder. [50]

2. Neurological examination
   The neurologist tests muscle strength, reflexes, tone, coordination, and cranial nerves (vision, eye movements, facial muscles). Abnormal findings such as hypotonia, ataxia, or abnormal reflexes suggest brain and nerve involvement typical of COXPD24. [51]

3. Muscle tone and power assessment
   The physician gently moves the child’s arms and legs to feel how stiff or floppy the muscles are and asks older children to push or pull against resistance. Persistent low tone and weakness raise suspicion of myopathy related to mitochondrial disease. [52]

4. Ear, eye, and hearing-focused examination
   The doctor looks in the ears, checks for middle ear problems, and screens hearing and vision responses at the bedside. Normal outer ear and eardrum with poor responses to sound can suggest inner ear or auditory nerve problems seen in COXPD24. [53]

Manual (bedside) tests

5. Developmental screening scales
   Simple tools, such as questionnaires or checklists, help measure motor, language, and social skills compared with age norms. Clear delays across several areas support the possibility of a global neurodevelopmental disorder such as COXPD24. [54]

6. Bedside hearing response tests
   In infants, the clinician may clap, ring a bell, or speak at different volumes and watch for startle or head-turning. Weak or absent responses, especially when repeated, suggest hearing loss and call for more advanced hearing tests. [55]

7. Bedside visual tracking tests
   The examiner moves a light or colorful toy and watches how the child follows it with their eyes. Poor tracking or lack of fixation, especially with normal eye structures, may indicate cortical visual impairment common in mitochondrial encephalopathies. [56]

8. Coordination and gait observation
   Older children may be asked to walk, stand on one foot, or touch finger to nose. Unsteady gait, tremor, or poor coordination (ataxia) support involvement of the cerebellum or other brain regions affected by energy failure. [57]

Laboratory and pathological tests

9. Blood lactate and pyruvate levels
   Blood tests often show increased lactate, with or without raised pyruvate, reflecting impaired oxidative phosphorylation. Persistently high lactate at rest or exaggerated rise after mild stress is a key biochemical clue to mitochondrial disease. [58]

10. Blood gas and metabolic panel
    Blood gas analysis can show metabolic acidosis due to lactic acid build-up. A metabolic panel also looks at glucose, electrolytes, kidney function, and liver enzymes, which may reveal organ involvement or help rule out other metabolic disorders. [59]

11. Creatine kinase (CK) and liver enzyme tests
    CK may be mildly raised if muscle cells are damaged. Liver enzymes (AST, ALT) can be high when the liver is affected. While not specific, these tests support systemic involvement and can guide further mitochondrial evaluation. [60]

12. Urine organic acid analysis
    A specialized urine test checks for abnormal organic acids that build up when metabolism is disturbed. Some patterns, together with lactic acidosis, can support the diagnosis of a mitochondrial disorder and help exclude other metabolic diseases. [61]

13. Genetic testing for NARS2 variants
    Molecular testing, often using gene panels or whole-exome sequencing, looks for variants in the NARS2 gene. Finding disease-causing variants in both copies of NARS2 confirms the diagnosis of COXPD24 and helps with family counseling. [62]

14. Muscle biopsy with respiratory chain analysis
    In some cases, doctors take a small piece of muscle for microscopic and biochemical studies. Tests may show reduced activity of multiple respiratory chain complexes and structural mitochondrial changes, supporting a diagnosis of combined oxidative phosphorylation deficiency. [63]

Electrodiagnostic tests

15. Electroencephalogram (EEG)
    An EEG records brain electrical activity and helps detect seizures or abnormal background patterns. In COXPD24, EEG may show frequent epileptic discharges or changes consistent with epileptic encephalopathy, matching the clinical picture of refractory seizures. [64]

16. Nerve conduction studies and electromyography (EMG)
    These tests measure how fast and how strongly nerves and muscles respond to electrical signals. Results may show myopathic changes or, less often, neuropathic patterns, helping to characterize the degree and type of neuromuscular involvement. [65]

17. Auditory brainstem response (ABR) / brainstem auditory evoked potentials
    ABR measures the brain’s response to sound clicks using scalp electrodes. In COXPD24, results often show auditory neuropathy, where the nerve signal is abnormal despite normal outer ear structures, confirming the suspected hearing pathway damage. [66]

Imaging tests

18. Brain MRI (magnetic resonance imaging)
    Brain MRI often shows abnormal signal changes in areas such as the basal ganglia, thalamus, brainstem, or cortex, and sometimes overall brain atrophy. These patterns are typical of mitochondrial encephalopathy and support the diagnosis. [67]

19. Magnetic resonance spectroscopy (MRS)
    MRS is a special MRI-based test that measures brain chemicals. It may show elevated lactate peaks, reflecting local energy failure in brain tissue. This finding, together with clinical and genetic data, strengthens the evidence for mitochondrial disease. [68]

20. Echocardiogram (heart ultrasound)
    An echocardiogram uses sound waves to create moving pictures of the heart. Although cardiomyopathy is less central in COXPD24 than in some other COXPD types, heart ultrasound is often done to look for structural or pumping problems that may appear in some patients. [69]

Non-Pharmacological Treatments (Therapies and Other Measures)

There is no cure yet for COXPD24, so non-drug therapies focus on supporting development, preventing complications and improving quality of life. These measures are usually used together in a multidisciplinary mitochondrial clinic.

1. Physiotherapy and motor rehabilitation
Regular physiotherapy helps keep joints flexible, reduce contractures and improve posture, balance and mobility. Simple, gentle exercises, stretching and positioning tricks are adapted to each child’s strength and fatigue level. The main purpose is to protect function for as long as possible and to prevent pain and deformity. Physiotherapy also helps the lungs by encouraging movement and deeper breathing, which can reduce pneumonia risk in children with low tone.[6][7]

2. Occupational therapy for daily living skills
Occupational therapists teach families how to adapt daily activities like feeding, dressing and playing so that the child can participate safely with less effort. They may suggest special seats, standing frames, adapted cutlery, and communication switches. The goal is not to force independence but to make daily life easier and safer, reduce caregiver burden and support the child’s dignity and participation in school and home routines.[7]

3. Speech, language and swallowing therapy
Speech and language therapists help with communication, including using sign language, picture boards or communication devices when speech is limited. They also evaluate swallowing, give suggestions on food textures, and teach safe feeding positions to reduce choking and aspiration. The purpose is to protect nutrition, avoid chest infections and support the child’s ability to interact with others.[7][8]

4. Hearing support: hearing aids and cochlear implants
Because NARS2 mutations often cause sensorineural hearing loss, early hearing testing and timely fitting of hearing aids or cochlear implants are very important. Amplification allows better language development, social interaction and safety (for example, hearing alarms). The mechanism is simple: devices help bypass damaged inner-ear hair cells and send stronger sound signals to the brain.[5][9]

5. Vision rehabilitation and low-vision aids
If the child has visual impairment or cortical blindness, low-vision services can offer high-contrast books, large print, optimal lighting and orientation and mobility training. Although nerve damage cannot be reversed, teaching the child to use remaining vision and other senses (touch, sound) can greatly improve interaction with the environment and reduce frustration and isolation.[1][6]

6. Nutrition support and safe feeding strategies
Dietitians experienced in mitochondrial disease help plan meals that provide enough calories and protein while avoiding long fasting periods, which can worsen metabolic stress. Families learn how to give small, frequent meals and how to adjust feeding during illness. In children who aspirate or cannot meet needs by mouth, gastrostomy feeding (feeding tube to the stomach) can be considered to maintain growth and reduce hospitalizations.[6][7]

7. Respiratory physiotherapy and non-invasive ventilation
When muscle weakness affects breathing, respiratory physiotherapists may teach airway-clearance techniques and cough assist devices. Some children benefit from nighttime non-invasive ventilation (for example, BiPAP) to support breathing and reduce carbon dioxide retention. The aim is to prevent chronic lung damage, improve sleep quality and reduce episodes of respiratory failure.[6]

8. Psychological support and family counselling
Living with a severe, progressive rare disease is very stressful for parents and siblings. Psychologists and social workers can help families process grief, manage anxiety and depression, and coordinate practical support such as respite care and disability benefits. Emotional support does not change the biology of the disease, but it can greatly improve coping, family functioning and adherence to treatment plans.[6][10]

9. Special education and developmental support
Early intervention programs and individualized education plans can adapt teaching strategies to the child’s cognitive profile and sensory limitations. Teachers may use visual supports, sign language, assistive communication devices and flexible pacing. This helps the child reach their personal learning potential, even if overall intellectual disability is present, and supports inclusion in school as much as possible.[1][6]

10. Genetic counselling for the family
Genetic counselling explains the cause, inheritance pattern and recurrence risk in simple terms. Carrier testing for parents and siblings and options like prenatal or pre-implantation genetic diagnosis in future pregnancies can be discussed. The mechanism is not a treatment for the child but a way to prevent new affected pregnancies and to help family members make informed reproductive choices.[2][3]

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Drug Treatments

There is no drug approved specifically for COXPD24, so medicines are used to treat symptoms such as seizures, spasticity, reflux or infections. Many drugs are FDA-approved for those general indications (for example epilepsy), and doctors sometimes use them off-label in mitochondrial disease. Doses must be individualized by specialists; this information is only educational.

1. Levetiracetam (Keppra) – antiseizure drug
Levetiracetam is a broad-spectrum antiseizure medicine widely used in mitochondrial epilepsies because it has relatively low mitochondrial toxicity compared with some older drugs. According to the FDA label, it is approved as adjunctive therapy for focal, myoclonic and primary generalized tonic-clonic seizures in children and adults, with doses adjusted for age, weight and kidney function.[11] It works by modulating synaptic vesicle protein SV2A and reducing abnormal neuronal firing. Common side effects include irritability, mood changes and sleepiness.[11]

2. Clobazam – add-on therapy for difficult seizures
Clobazam is a benzodiazepine used as adjunctive treatment for certain epilepsies. It enhances the effect of the calming neurotransmitter GABA at its receptor, helping to reduce seizure frequency. In mitochondrial disease, it may be used when seizures remain frequent despite first-line drugs, but doctors are careful about sedation and breathing suppression. The FDA label describes dosing schedules that start low and increase gradually, as well as side effects like drowsiness, drooling and behavioural changes.[12]

3. Diazepam or midazolam rescue medication
For prolonged seizures or clusters, rescue medicines such as diazepam (rectal or nasal) or midazolam (buccal or nasal) can be lifesaving. They quickly boost GABAergic inhibition to stop seizure activity. In mitochondrial epilepsy, families are often given a written seizure plan describing when and how to use these drugs, under neurologist guidance.[12] These benzodiazepines are all FDA-approved for seizure emergencies in general, but exact formulations and dosing must follow the labelled instructions and specialist advice.[12]

4. Levocarnitine (Carnitor) – carnitine replacement
Levocarnitine helps transport long-chain fatty acids into mitochondria for energy production and helps remove toxic acyl compounds. Some patients with primary mitochondrial disorders and low carnitine levels receive levocarnitine supplementation. The FDA label for CARNITOR describes its approval for primary and secondary carnitine deficiency, with dosing based on weight and regular monitoring of levels.[13] In COXPD24, levocarnitine is used off-label to support energy metabolism; side effects can include nausea, diarrhoea and a fishy body odour.[13]

5. Riboflavin (vitamin B2)
Riboflavin is a key cofactor for flavoproteins in the mitochondrial respiratory chain. In some mitochondrial disorders, high-dose riboflavin has shown benefit, and it is often part of the “mitochondrial cocktail.” The FDA documents describe riboflavin as a water-soluble vitamin used in multivitamin preparations and generally recognized as safe at standard doses.[14] In COXPD24, clinicians sometimes prescribe higher doses off-label, with monitoring for limited side effects such as bright yellow urine.[14]

6. Coenzyme Q10 (ubiquinone)
Coenzyme Q10 is an electron carrier in the respiratory chain and a lipid-soluble antioxidant. It is not FDA-approved specifically for mitochondrial disease, but there is an orphan drug designation for primary CoQ10 deficiency, and many clinicians use it as part of a mitochondrial supplement regimen.[15] It may improve exercise tolerance or reduce fatigue in some patients, although trial results are mixed. Side effects are usually mild, such as stomach upset. CoQ10 is typically given in divided daily doses with food to enhance absorption.[15]

7. Arginine or citrulline
Arginine and citrulline are amino acids used in some mitochondrial disorders, especially MELAS, to support nitric oxide production and improve blood vessel function. Although not specific to COXPD24, some specialists include them in the cocktail when there are stroke-like episodes or severe lactic acidosis. These supplements are available as prescription or medical-grade products, and dosing is individualized; main side effects are gastrointestinal discomfort and high potassium risk in kidney disease.[8]

8. Multivitamin preparations (e.g., INFUVITE, MVI-12)
Hospitalized children who need parenteral nutrition may receive intravenous multivitamin solutions that contain thiamine, riboflavin, pyridoxine, folic acid and other vitamins important for mitochondrial enzymes. Products such as INFUVITE and MVI-12 are FDA-approved for prevention of vitamin deficiencies in patients on parenteral nutrition, with specific dosing instructions by age.[16] In COXPD24, they help ensure there is no additional vitamin deficiency on top of the primary mitochondrial disorder.[16]

9. Baclofen for spasticity
When children develop spasticity and painful muscle stiffness, oral or intrathecal baclofen may be used. Baclofen acts as a GABA-B agonist in the spinal cord, reducing excitatory neurotransmission to muscles. It is not specific to mitochondrial disease but can improve comfort, ease of care and sometimes mobility. Side effects include sleepiness, weakness and constipation; dose must be increased slowly and never stopped abruptly to avoid withdrawal.[6]

10. Proton-pump inhibitors or reflux medicines
If severe reflux or feeding difficulties cause pain, vomiting or risk of aspiration, doctors may use medicines such as proton-pump inhibitors (PPIs) or H2 blockers. These drugs reduce stomach acid, protecting the oesophagus and lowering discomfort. They are standard paediatric medications and not specific to COXPD24, but good control of reflux supports nutrition and reduces hospital admissions. Side effects can include diarrhoea and, with long-term use, possible effects on mineral absorption.[6][7]

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Dietary Molecular Supplements

Dietary supplements are widely used in primary mitochondrial disorders, although strong randomized trial evidence is limited. They should always be supervised by a specialist.

1. Coenzyme Q10
CoQ10 supports electron transfer between complexes I/II and III and acts as a powerful antioxidant inside mitochondria. In observational studies and small trials, many mitochondrial patients report better energy and less exercise intolerance when using CoQ10 as part of a cocktail.[17] Typical practice is to give divided daily doses with fat-containing meals to improve absorption; side effects are usually mild digestive upset.[17]

2. Riboflavin (B2)
Riboflavin is converted to FAD and FMN, key cofactors for multiple respiratory chain enzymes. High-dose riboflavin has shown benefit in some flavoprotein-related mitochondrial defects and is commonly used in broader mitochondrial disease as a low-risk cofactor therapy.[8] It is usually well tolerated; the most visible effect is bright yellow urine. It is often combined with other vitamins in a mitochondrial cocktail.[8]

3. L-carnitine
L-carnitine helps shuttle long-chain fatty acids into mitochondria and removes toxic acyl groups. In mitochondrial disease, it may improve fatigue and help manage secondary carnitine deficiency, though data are mixed.[18] Oral doses are divided through the day; side effects include diarrhoea and fishy odour. Carnitine can also interact with some metabolic conditions, so monitoring is important.[18]

4. Alpha-lipoic acid
Alpha-lipoic acid is a mitochondrial antioxidant and cofactor for several dehydrogenase complexes. It scavenges free radicals and may help protect mitochondrial membranes from oxidative damage. Evidence comes mainly from small studies and combination therapies, but it is often included in cocktails for its theoretical benefit.[16] High doses can cause stomach upset or, rarely, hypoglycaemia; careful dosing is needed.[16]

5. Creatine
Creatine serves as an energy buffer in muscle and brain by regenerating ATP from ADP. In mitochondrial disease, creatine may help muscles cope with energy failure and reduce fatigue in some patients.[17] It is usually given as a powder mixed in liquids, with attention to adequate hydration. Side effects can include weight gain from water retention and mild digestive symptoms.[17]

6. B-complex vitamins (B1, B6, folate, B12)
Several mitochondrial enzymes need thiamine (B1), pyridoxine (B6), folate and B12 as cofactors, so high-dose B-complex is often used to ensure no additional bottleneck in energy metabolism. These vitamins are present in many prescription multivitamin preparations and are generally safe at therapeutic doses, though neuropathy can occur with very high B6.[16]

7. Vitamin C and vitamin E
Vitamin C (water-soluble) and vitamin E (fat-soluble) are antioxidants that may help neutralize excess reactive oxygen species produced by dysfunctional mitochondria. They are frequently added to mitochondrial supplement plans because of their low risk and potential to protect cell membranes and DNA.[17] High doses should be monitored, as very large amounts may affect kidney stones (vitamin C) or bleeding risk (vitamin E).[17]

8. Folinic acid
Folinic acid is an active form of folate that can cross into the central nervous system and support one-carbon metabolism. It is sometimes used in mitochondrial and neurometabolic disorders, especially when cerebrospinal fluid folate levels are low. The goal is to support myelin and neurotransmitter synthesis; side effects are usually mild gastrointestinal symptoms.[16]

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Immune-Boosting, Regenerative and Stem-Cell-Related Drugs

For COXPD24 there are no proven regenerative or stem-cell drugs approved by regulators. Research is ongoing in gene therapy and mitochondrial replacement techniques, but these are still experimental and not routine clinical care for NARS2-related disease.[6]

Clinicians may use general immune-supportive strategies such as up-to-date vaccinations, prompt antibiotic treatment of infections and sometimes immunoglobulin therapy in children with significant antibody deficiency, but these approaches treat complications rather than repairing the mitochondrial defect itself. Nutritional optimization and avoidance of severe malnutrition are also key to supporting immune function.[6][7]

Because families often hear about “stem-cell cures” on the internet, it is important to stress that, at present, stem-cell or gene-based drugs for NARS2-related COXPD24 should only be accessed in properly regulated clinical trials, not in unproven commercial clinics, to avoid serious risks and financial harm.[6]

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Possible Surgeries and Procedures

1. Cochlear implant for severe hearing loss
In children with profound sensorineural hearing loss who do not benefit from hearing aids, a cochlear implant may be offered. Surgeons place an electrode array inside the inner ear to directly stimulate the auditory nerve. This can significantly improve sound perception and speech understanding, especially when done early and combined with intensive auditory rehabilitation.[5]

2. Gastrostomy tube placement
If a child cannot safely swallow enough food or is aspirating, doctors may place a gastrostomy tube directly into the stomach. This procedure allows safe feeding, medication delivery and hydration, reducing the risk of chest infections and improving growth. It does not treat the mitochondrial defect but supports overall health and energy.[6]

3. Orthopaedic surgery for contractures or scoliosis
Progressive muscle weakness and spasticity can cause joint contractures or spinal curvature. In selected cases, tendon-release surgery or spinal fusion can relieve pain, improve sitting balance and make care easier. Decisions are individualized, weighing anaesthesia risks in mitochondrial disease against potential functional gains.[6][7]

4. Tracheostomy or long-term ventilation support (in severe cases)
In children with recurrent life-threatening breathing problems who need frequent ventilation, a tracheostomy (surgical opening in the windpipe) may be considered to allow safer long-term support. This is a major decision involving intensive family counselling and palliative care input, focusing on comfort and family goals.[6]

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Prevention Strategies (What Can Be Prevented)

Because COXPD24 is genetic, we cannot prevent the underlying gene change in an affected child, but we can lower risk of crises and prevent some complications.

1. Genetic counselling and carrier testing help families understand recurrence risk and consider prenatal or pre-implantation genetic diagnosis in future pregnancies, which can prevent new affected births.[2]

2. Avoiding prolonged fasting reduces metabolic stress, as long gaps without food can worsen lactic acidosis and decompensation. Small, frequent meals are usually advised.[6]

3. Rapid treatment of infections (fever, chest infections, urinary infections) can prevent severe metabolic crises and hospitalization, because illness increases energy demand.[6]

4. Up-to-date vaccinations (including influenza and pneumococcal vaccines) reduce the chance of serious infections in a vulnerable child.[6]

5. Avoiding mitochondrial-toxic medicines such as valproic acid, certain aminoglycoside antibiotics and high-dose propofol when possible can lower risk of liver failure or worsening myopathy; specialists use consensus lists for safer antiseizure options.[12]

6. Good nutrition and hydration help prevent pressure sores, fractures and poor wound healing, which are more common in undernourished, immobile children.[6]

7. Physical therapy and proper positioning can prevent severe contractures and scoliosis, making daily care easier and less painful.[7]

8. Regular cardiac and respiratory monitoring can detect early problems so they can be treated before they become emergencies (for example, starting nocturnal ventilation early).[6]

9. Seizure action plans help families know exactly what to do during a seizure, which can prevent prolonged episodes and emergency complications.[12]

10. Early hearing and vision interventions may prevent additional developmental delay by giving the child better access to language and learning from the start.[5]

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When to See a Doctor Urgently

Parents or caregivers should seek urgent medical care if the child has prolonged or repeated seizures, severe breathing difficulty, persistent vomiting, signs of dehydration, sudden loss of skills, unusual sleepiness or unresponsiveness, or any new worrying symptom. These may be signs of a metabolic crisis, brain involvement or serious infection that needs hospital treatment. Because COXPD24 is complex, having a written emergency plan from the metabolic or neurology team can guide local doctors on fluids, investigations and which drugs to avoid.[6][12]

Regular planned visits with neurology, genetics, metabolic specialists, cardiology, audiology and ophthalmology are also important even when the child seems stable. These visits allow adjustment of medications, supplements and therapies, and early detection of new problems so they can be managed promptly.[6]

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Diet: What to Eat and What to Avoid (General Principles)

For COXPD24 there is no single “magic” diet, but some simple rules are often used in mitochondrial disease care.

Children are usually encouraged to eat a balanced diet with enough calories and protein, including fruits, vegetables, whole grains, lean meats, fish, eggs and dairy or alternatives. The goal is to prevent under-nutrition, support muscle mass and supply vitamins and minerals needed for mitochondrial enzymes.[6][17]

Long periods without food are generally avoided, so small, frequent meals and snacks are often recommended, especially during illness, to reduce metabolic stress and risk of hypoglycaemia.[6]

Some centres may use specialized formulas or, in selected children with difficult epilepsy, a ketogenic or modified Atkins diet under strict expert supervision. These high-fat, low-carbohydrate diets can help seizure control in some mitochondrial epilepsies but can also stress metabolism, so they must never be started without close monitoring by a metabolic team.[12]

Families are usually advised to avoid crash dieting, extreme fasting, high-dose alcohol exposure in older patients, and unregulated herbal products, because these can worsen mitochondrial stress or interact with medications. Any major diet change should be discussed with the metabolic dietitian or physician.[6][17]

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Frequently Asked Questions

1. Is COXPD24 curable?
No. At the moment there is no cure that can fix the NARS2 gene or fully restore mitochondrial function in COXPD24. Treatment is supportive: controlling seizures, optimizing nutrition, using supplements, and preventing complications. Research in gene therapy and mitochondrial medicine is active, but these approaches are still experimental in this disease.[6]

2. Do all children with COXPD24 have the same severity?
No. COXPD24 shows wide variability. Some babies are very severely affected and may die early, while others live longer with a combination of developmental delay, seizures and hearing loss. Even siblings with the same variants may differ. This variability is described in several NARS2 case series.[4]

3. Why is hearing loss so common in this disease?
The inner ear (cochlea) and auditory nerve need a lot of energy. NARS2 defects affect mitochondrial protein synthesis in these cells, so they are especially vulnerable, leading to sensorineural hearing loss. Some families show only deafness without other mitochondrial symptoms, also linked to NARS2 variants.[5]

4. Will my child’s seizures ever be fully controlled?
Seizures in COXPD24 can be very difficult to manage, but some children respond well to combinations of safer antiseizure drugs such as levetiracetam and clobazam, plus rescue medicines and, occasionally, dietary therapies. Perfect seizure freedom is not always possible, but careful management can reduce frequency and severity.[12]

5. Are mitochondrial supplements like CoQ10 and carnitine proven to work?
Many patients and doctors report improvements in fatigue or exercise tolerance with supplements such as CoQ10, riboflavin and L-carnitine, but randomized trial data are limited and mixed. They are generally low-risk when monitored, so many centres use them as part of standard care.[17]

6. Can COXPD24 affect the heart?
NARS2-related disease mainly affects brain, muscles and hearing, but mitochondrial disorders in general can involve the heart, causing cardiomyopathy or rhythm problems. Regular cardiology checks (ECG, echocardiogram) are usually recommended to detect any early heart involvement.[6]

7. Will my other children also have COXPD24?
If both parents are carriers of a NARS2 variant, each pregnancy has a 25% chance of being affected, a 50% chance of being a healthy carrier and a 25% chance of inheriting no faulty copies. Genetic counselling and, if desired, prenatal or pre-implantation genetic testing can refine these risks for your family.[2]

8. Is school possible for a child with COXPD24?
Many children with COXPD24 can attend school or special education programs with high support, including classroom aides, hearing and vision adaptations, and flexible goals. The focus is on participation and communication rather than standard academic performance.[6]

9. Are there clinical trials for COXPD24?
Because COXPD24 is very rare, most clinical trials recruit broader groups of patients with mitochondrial disease rather than this specific subtype. These may study new antioxidants, gene-targeted therapies or supportive interventions. Your mitochondrial centre can help you search registries and decide if a trial is appropriate.[6]

10. What is the long-term outlook (prognosis)?
Prognosis varies widely and depends on severity of brain involvement, seizure control, respiratory function and complications such as infections or organ failure. Some children have a rapidly progressive course, while others survive into later childhood or beyond with significant disabilities but good family support. Honest, ongoing discussions with your care team can help with planning and decision-making.[4]

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.