Combined Oxidative Phosphorylation Deficiency 40 (COXPD40)

Combined oxidative phosphorylation deficiency 40 (short name: COXPD40) is a very rare genetic disease that affects the mitochondria, the tiny “power stations” inside almost every cell. In this disease, the mitochondria cannot make enough energy using the normal oxidative phosphorylation system (the main way cells turn food into usable energy). The word “combined” means that more than one part (complex) of the oxidative phosphorylation chain in the mitochondria is not working properly. In COXPD40, the activity of complexes I, III, IV and V can all be reduced in patient tissues. This serious energy problem mainly harms organs that need a lot of energy, such as the heart, brain, liver, ears, and muscles.

Combined oxidative phosphorylation deficiency 40 (COXPD40) is a very rare, severe genetic mitochondrial disease. In this condition, the tiny “power stations” of the cell (mitochondria) cannot make enough energy, because several enzyme complexes (I, III, IV and V) in the oxidative phosphorylation chain are not working properly. This leads to energy failure in many organs that need a lot of energy, especially the heart, liver, brain and ears. [1][2]

COXPD40 is caused by harmful (pathogenic) changes in both copies of a gene called QRSL1 on chromosome 6. This gene helps correctly build a special transfer RNA (tRNA) used in mitochondrial protein production. When QRSL1 does not work, mitochondria cannot build some proteins needed for energy production, so oxidative phosphorylation becomes defective in many complexes at the same time. [3][4]

Symptoms usually start before birth or soon after birth. Babies may show hydrops fetalis (generalized fluid swelling), severe hypertrophic cardiomyopathy (very thick heart muscle), poor growth, lactic acidosis, liver problems, muscle weakness, low blood sugar, and sensorineural hearing loss. Sadly, published cases often have a very poor outcome, with death in early infancy despite supportive care. [1][2][5]

COXPD40 usually starts before birth or soon after birth. Babies may have very weak heart muscle (severe hypertrophic cardiomyopathy), poor growth, low energy, and high lactic acid in the blood (lactic acidosis). Sadly, in the cases reported so far, most babies do not survive beyond early infancy, because the heart and other organs become too weak.

COXPD40 is caused by harmful changes (mutations) in a nuclear gene called QRSL1. This gene makes part of an enzyme complex needed for correct building of some mitochondrial proteins. When QRSL1 does not work, many mitochondrial proteins are not made correctly, so oxidative phosphorylation is impaired, and cells cannot make enough energy.

Another names

Doctors and researchers use several other names for combined oxidative phosphorylation deficiency 40. These names all describe the same disease, or very closely related disease, linked to the QRSL1 gene.

Commonly used other names include:

• COXPD40 (short, code-like name for the disease).

• QRSL1-related COXPD (shows that the disease is due to the QRSL1 gene).

• QRSL1-related combined oxidative phosphorylation defect (long form saying the same thing).

• Glutaminyl-tRNA amidotransferase subunit-related combined oxidative phosphorylation defect (describes the affected enzyme complex in mitochondria).

These names may look different, but they all point to the same very rare mitochondrial disease caused by disease-causing changes in QRSL1 on chromosome 6q21.

Types

There are no strict official “types” of COXPD40 like type 1, type 2, etc. However, doctors sometimes describe different patterns of the same disease depending on age of onset and which organs are most affected. The patterns below are descriptive, not formal separate diseases.

• Prenatal (before birth) severe form – Some babies show problems already in the womb, such as fetal hydrops (widespread swelling), enlarged heart, and abnormal fluid in body spaces on ultrasound. This shows that the disease can start before birth and can be very severe.

• Early neonatal cardiomyopathy-dominant form – Other babies look fairly normal at birth but soon develop severe hypertrophic cardiomyopathy (thick heart muscle), feeding problems, and poor growth in the first weeks of life. Heart failure signs are often the main early feature.

• Multisystem form with liver and adrenal involvement – In some reported patients, in addition to the heart and growth problems, there is liver dysfunction and possible primary adrenal insufficiency (weak adrenal glands leading to low cortisol and low blood pressure). This pattern shows that endocrine organs can also be affected in some cases.

• Neurologic-predominant form – All reported patients have severe systemic disease, but some may show more obvious neurologic signs such as poor alertness, seizures, or brain MRI changes in deep gray matter, together with heart and metabolic features.

All these patterns share the same core problem: a QRSL1 gene defect causing failure of several mitochondrial respiratory complexes and severe energy shortage in many tissues.

Causes

In COXPD40, every known cause is related to genetic changes in the QRSL1 gene. There is no evidence that infections, diet, or lifestyle alone can cause this disease. It is an autosomal recessive disorder, which means a child is usually affected only if they receive one faulty copy of the gene from each parent.

1. Homozygous QRSL1 mutation
   In many families, the baby has the same disease-causing QRSL1 variant on both copies of chromosome 6 (one from each parent). This is called a homozygous mutation. Both copies of the QRSL1 gene are damaged, so the enzyme it makes cannot work properly in mitochondria.

2. Compound heterozygous QRSL1 mutations
   Some babies inherit two different harmful QRSL1 variants, one from each parent. This is called compound heterozygosity. Even though the two variants are different, together they stop QRSL1 from working well, leading to the same disease.

3. Missense variants changing key amino acids
   A missense variant swaps one amino acid in the QRSL1 protein for another. If this change is in a critical part of the enzyme, the protein cannot bind its partners or substrates properly. In COXPD40, missense variants can greatly reduce the enzyme’s activity in mitochondrial protein translation.

4. Nonsense variants causing early stop codons
   A nonsense variant introduces a “stop” signal too early in the QRSL1 gene. This makes a short, incomplete protein that is quickly destroyed by the cell. Without full-length QRSL1, the glutaminyl-tRNA amidotransferase complex in mitochondria cannot function, contributing to COXPD40.

5. Splice-site variants
   Some QRSL1 mutations occur at the borders of exons and introns (splice sites). These can disturb normal processing of the RNA message, leading to missing exons or extra intron sequence in the final mRNA. The resulting protein can be unstable or non-functional, again causing oxidative phosphorylation failure.

6. Frameshift insertions or deletions
   Tiny insertions or deletions in the QRSL1 coding sequence can shift the reading frame. After the change, many amino acids are wrong, and usually a premature stop codon appears. The abnormal protein cannot support mitochondrial translation, so respiratory chain complexes are not built correctly.

7. Variants affecting the mitochondrial targeting sequence
   The QRSL1 protein must be imported into mitochondria to work. Some variants may disrupt the beginning part of the protein that acts as a “mitochondrial address label.” If this signal is damaged, less QRSL1 reaches the mitochondria, leading to poor function of oxidative phosphorylation.

8. Variants in functional domains of QRSL1
   QRSL1 is part of the glutamyl-tRNA(Gln) amidotransferase complex, which converts mis-charged tRNA into the correct form. Mutations in key functional domains can block this reaction. As a result, mitochondrial ribosomes cannot build certain proteins, damaging several respiratory chain complexes at once.

9. Loss of enzyme stability
   Some QRSL1 mutations make the protein fold poorly. Misfolded proteins are often broken down quickly by the cell’s quality-control systems. Reduced QRSL1 levels in mitochondria lead to less efficient mitochondrial translation and combined oxidative phosphorylation deficiency.

10. Parental carrier status (autosomal recessive inheritance)
    The underlying cause at the family level is that both parents are healthy carriers of a QRSL1 variant. They usually have one normal and one mutated copy, so they have enough enzyme activity and no symptoms. When a child inherits both mutated copies, COXPD40 appears.

11. Random new (de novo) QRSL1 mutation in a parent’s egg or sperm
    In some families, a QRSL1 mutation may arise for the first time in an egg or sperm cell. That new variant can then be passed to children and act like any other recessive mutation. If both parents carry compatible variants (one inherited, one de novo), their child may develop COXPD40.

12. Consanguinity (closely related parents)
    When parents are closely related (for example, cousins), they are more likely to carry the same rare QRSL1 mutation. This raises the chance that a child will inherit two copies of the same harmful variant, leading to homozygous COXPD40.

13. Pathogenic QRSL1 variants in specific families or populations
    Some pathogenic variants may be more common in particular families or populations because of a founder effect. Even if the disease is still extremely rare worldwide, this local increase in a specific QRSL1 mutation can cause recurrent cases in related families.

14. Impaired mitochondrial tRNA processing
    QRSL1 helps correct mis-charged tRNAGln in mitochondria. When QRSL1 is defective, this step in tRNA processing fails. As a result, mitochondrial protein synthesis is decreased or produces faulty proteins, contributing directly to oxidative phosphorylation deficiency.

15. Secondary disruption of respiratory chain complexes I, III, IV, and V
    Because some mitochondrial proteins are not made properly, several respiratory chain complexes show reduced activity in patient cells. This “combined” deficiency is a direct downstream cause of low ATP production and high lactic acid in COXPD40.

16. Energy failure in high-demand organs
    The combined complex defects cause severe energy shortage in tissue with high energy needs, such as heart, brain, liver, kidney, and endocrine organs. This mismatch between energy supply and demand is a key cause of organ damage in COXPD40.

17. Increased lactic acid production
    When mitochondria cannot produce enough ATP, cells switch more to anaerobic metabolism, which produces lactic acid. High lactic acid in the blood (lactic acidosis) is not the root genetic cause, but it is an important biochemical consequence that worsens symptoms.

18. Oxidative stress and cell injury
    Defective oxidative phosphorylation can lead to higher levels of reactive oxygen species and oxidative stress in cells. Over time, this damages cell structures and may add to organ failure. This is a general mechanism in many mitochondrial diseases, including COXPD40.

19. Endocrine organ vulnerability (for example, adrenal glands)
    Endocrine organs, such as adrenal glands, depend heavily on mitochondrial function for hormone production. Reports of adrenal insufficiency in COXPD40 suggest that QRSL1 defects can also disturb hormone-producing tissues, becoming an additional “cause” of specific symptoms like low blood pressure and hypoglycemia.

20. Overall genetic and mitochondrial disease mechanism
    Putting all of this together, the fundamental cause of COXPD40 is a primary mitochondrial disease due to QRSL1 mutations, leading to defective mitochondrial translation, combined oxidative phosphorylation deficiency, and multi-organ energy failure.

Symptoms

Because COXPD40 is a severe mitochondrial disease that begins before or soon after birth, most symptoms appear in the fetus, newborn, or young infant and affect many organs at the same time.

1. Fetal hydrops (swelling before birth)
   Some babies develop generalized swelling, fluid around the lungs or heart, and thickened skin while still in the womb. This is called fetal hydrops and reflects severe heart and metabolic stress before birth. It is a warning sign of a very serious underlying problem like COXPD40.

2. Severe hypertrophic cardiomyopathy
   The heart muscle becomes abnormally thick and stiff, especially the left ventricle. This is called hypertrophic cardiomyopathy. The heart has to work harder to pump blood, and over time it may fail, causing fast breathing, poor feeding, and swelling in the baby.

3. Heart failure signs (breathing and circulation problems)
   Because the heart cannot pump well, babies may breathe rapidly, have trouble feeding, sweat with feeds, and show poor circulation (cool hands and feet, weak pulses). These are signs of heart failure from the cardiomyopathy seen in COXPD40.

4. Poor growth and failure to thrive
   Many infants with COXPD40 do not gain weight or grow as expected, even when they are fed. This “failure to thrive” happens because their bodies are under heavy stress, energy supply is low, and feeding may be difficult due to weakness or breathlessness.

5. Lactic acidosis and metabolic crisis
   High blood lactic acid is a key sign of mitochondrial energy failure. Babies may appear very ill with vomiting, fast breathing, and drowsiness when lactic acidosis is severe. In COXPD40, lactic acidosis often appears soon after birth and can be life-threatening.

6. Sensorineural hearing loss (inner ear deafness)
   Several reported patients have sensorineural hearing loss, which means damage to the inner ear or auditory nerve. Mitochondria are very important in hearing cells, so mitochondrial diseases like COXPD40 can cause early deafness.

7. Global developmental delay
   Babies may be very slow to reach milestones such as smiling, holding up the head, or rolling over. This global developmental delay is due to poor brain energy supply and overall severe illness from the mitochondrial problem.

8. Low muscle tone and weakness (hypotonia)
   Many infants with mitochondrial disease have “floppy” muscles and feel limp when held. This low tone (hypotonia) and muscle weakness come from both muscle involvement and brain involvement, because both tissues depend heavily on normal mitochondria.

9. Encephalopathy and poor alertness
   Encephalopathy means a sick brain. Babies may be unusually sleepy, difficult to wake, or show poor eye contact. Brain MRI in some mitochondrial diseases, including COXPD40-like disorders, can show damage in deep gray matter or other areas, matching the clinical encephalopathy.

10. Seizures (in some patients)
    Because the brain is very sensitive to energy failure, some mitochondrial disorders cause seizures. In COXPD40, seizures are not described in every patient, but are possible as part of severe encephalopathy and should be considered if there are abnormal movements or episodes of unresponsiveness.

11. Liver dysfunction
    Some infants show signs of liver involvement, such as high liver enzymes in blood tests, low albumin, or problems with blood clotting. The liver also has very high energy needs, so mitochondrial failure in COXPD40 can contribute to liver dysfunction.

12. Primary adrenal insufficiency (in some cases)
    A reported patient with COXPD40 had primary adrenal insufficiency, meaning the adrenal glands could not make enough cortisol. This can cause low blood pressure, low blood sugar, weakness, and salt balance problems. It suggests that, in some children, QRSL1 deficiency can also harm adrenal function.

13. Kidney problems and blood pressure issues
    Some reported cases of COXPD40 and related mitochondrial diseases show kidney impairment and high blood pressure. The kidneys and blood vessel system also rely on mitochondrial energy, so they may be affected in this disease.

14. Anemia and other blood changes
    In combined oxidative phosphorylation deficiencies, anemia and other blood abnormalities have been described. Reduced energy supply in bone marrow and ongoing illness can contribute to low red blood cell counts and fatigue.

15. Early death in infancy
    Sadly, COXPD40 is usually lethal in infancy in the cases described so far. Severe heart disease, lactic acidosis, and multi-organ failure together make long-term survival very difficult, even with intensive medical care.

Diagnostic tests

Doctors use many tests together to diagnose COXPD40. They look at the baby, do bedside (manual) checks, send blood and tissue tests to the lab, record electrical signals from the heart and ears, and take pictures of the heart and brain. Most of these tests are standard for suspected mitochondrial disease and severe infant cardiomyopathy.

Physical exam tests

1. General physical examination
   The doctor looks carefully at the baby’s overall condition: alertness, breathing pattern, skin color, muscle tone, and any swelling. They check for signs of fetal hydrops, poor growth, and distress. This first step helps the doctor see that the baby is very sick and that a serious systemic disease like a mitochondrial disorder is possible.

2. Cardiac examination (heart exam)
   The doctor listens to the heart with a stethoscope, feels the chest, and checks pulses. They look for fast heart rate, enlarged heart, abnormal sounds, and signs of heart failure such as enlarged liver or leg and belly swelling. These findings suggest a serious cardiomyopathy, which is a key clue in COXPD40.

3. Neurologic examination
   The doctor tests muscle tone, reflexes, head control, eye movements, and responses to sound and touch. Low tone, poor head control, and weak reflexes suggest brain and muscle involvement, as seen in many mitochondrial diseases including COXPD40.

4. Growth and nutrition assessment
   Weight, length, and head size are plotted on infant growth charts. Failure to thrive and small size for age are often present in COXPD40. This simple measurement supports the idea of a chronic energy problem, not just an acute infection.

Manual bedside tests

5. Developmental assessment
   The doctor or therapist checks whether the baby can fix and follow with the eyes, smile, roll, or hold up the head, using simple age-based tasks. Marked delay in several areas suggests global developmental delay, which is common in severe mitochondrial disease.

6. Manual muscle tone and strength testing
   The examiner gently moves the baby’s arms and legs and lifts the baby under the arms to feel for “floppiness” or stiffness. In COXPD40, low tone and weakness are frequent due to muscle and brain involvement, and this is clear on manual exam.

7. Bedside hearing checks
   Simple tests like making a sound with a rattle or speaking softly near each ear help see whether the baby reacts. Lack of reaction may suggest hearing loss, which can then be studied further with formal hearing tests. This is important because sensorineural hearing loss is a known feature of COXPD40 and related mitochondrial diseases.

8. Manual blood pressure and circulation check
   Nurses and doctors measure blood pressure with a small cuff and look at capillary refill (how quickly color returns to the skin after gentle pressure). Low blood pressure and poor refill can be signs of heart failure or possible adrenal insufficiency in a baby with mitochondrial disease.

Laboratory and pathological tests

9. Blood lactate and pyruvate levels
   A small blood sample is taken to measure lactic acid and pyruvate. High lactate, especially with a high lactate-to-pyruvate ratio, is a classic biochemical marker of mitochondrial oxidative phosphorylation failure and is very common in COXPD40.

10. Arterial or capillary blood gas analysis
    This test measures oxygen, carbon dioxide, pH (acidity), and bicarbonate in the blood. It helps confirm metabolic acidosis due to lactic acid buildup and shows how well the lungs and heart are working. It is crucial during acute metabolic crises in mitochondrial disease.

11. Comprehensive metabolic panel (liver, kidney, glucose, electrolytes)
    Blood chemistry tests check liver enzymes, kidney function, blood sugar, and salts. Abnormal results can show liver involvement, kidney stress, or low glucose, which are all possible in severe COXPD40. These tests help guide urgent treatment and monitor organ damage.

12. Serum and urine metabolic screening
    Doctors often send special tests for amino acids, organic acids, and acylcarnitines in blood and urine. Although results may be non-specific, they help rule out other metabolic diseases and may show patterns suggesting mitochondrial dysfunction.

13. Complete blood count (CBC)
    A CBC measures red cells, white cells, and platelets. Anemia or other blood changes can appear in mitochondrial diseases and combined oxidative phosphorylation defects. This test is simple but helps show the overall severity of illness and can suggest multi-system involvement.

14. Endocrine testing for adrenal function
    In some babies with COXPD40, doctors may measure morning cortisol, ACTH, and sometimes do stimulation tests to check adrenal gland function. Abnormal results confirm primary adrenal insufficiency, which has been reported in at least one patient with QRSL1-related COXPD40 and is described in mitochondrial endocrine reviews.

15. Muscle biopsy with histology and respiratory chain enzyme analysis
    A small piece of skeletal muscle is removed under anesthesia and examined under a microscope and with special stains and enzyme tests. In mitochondrial disease, the biopsy may show abnormal mitochondria or reduced activity of several respiratory chain complexes. This is a classic, though invasive, method for diagnosing combined oxidative phosphorylation deficiencies.

16. Genetic testing of QRSL1 and other mitochondrial genes
    Today, the key confirmatory test is genetic sequencing. Doctors may order targeted QRSL1 testing, a mitochondrial gene panel, or whole-exome/genome sequencing. Finding biallelic (two-copy) pathogenic QRSL1 variants together with the clinical picture confirms the diagnosis of COXPD40.

Electrodiagnostic tests

17. Electrocardiogram (ECG)
    An ECG records the heart’s electrical signals using small stickers on the chest and limbs. It can show fast heart rate, thickened heart muscle patterns, conduction problems, or arrhythmias. In COXPD40, the ECG helps assess how the cardiomyopathy is affecting heart rhythm and is essential in managing risk of sudden cardiac events.

18. Auditory brainstem response (ABR) or otoacoustic emissions (OAE)
    These tests measure how the inner ear and auditory nerve respond to sound, using small earphones and scalp electrodes or an ear probe. They do not require the baby to cooperate. Abnormal ABR or OAE results confirm sensorineural hearing loss, which is part of the phenotype in COXPD40 and other mitochondrial diseases.

Imaging tests

19. Echocardiography (heart ultrasound)
    An echocardiogram uses sound waves to create moving pictures of the heart. It is painless and shows how thick the heart walls are, how well the heart pumps, and whether there is fluid around the heart. In COXPD40, echocardiography usually shows severe hypertrophic cardiomyopathy and helps track how the disease is progressing and how the baby responds to treatment.

20. Brain MRI (sometimes with MR spectroscopy)
    MRI uses strong magnets and radio waves to take detailed pictures of the brain. In mitochondrial disease, MRI may show changes in white matter, basal ganglia, or other deep structures, and MR spectroscopy can detect high lactate in the brain. These findings support a diagnosis of mitochondrial encephalopathy, which fits with COXPD40 when combined with the heart and metabolic problems.

Non-pharmacological treatments (Therapies and other supports)

Each of these is supportive; most are based on general mitochondrial disease care rather than COXPD40-specific trials.

1. Structured metabolic emergency plan
   Families receive a written “sick-day” plan explaining what to do if the child has fever, vomiting, breathing problems or poor feeding. The plan usually includes rapid assessment in hospital, IV glucose, fluids and treatment of any infection, to prevent severe lactic acidosis and organ failure. This fast response can reduce the impact of metabolic crises in mitochondrial disorders. 6

2. Avoidance of fasting and regular feeds
   Babies with mitochondrial disease cannot tolerate long gaps between feeds because they quickly run out of energy and can develop low blood sugar and lactic acidosis. Frequent feeds, night feeds and sometimes continuous tube feeding are used to give a steady glucose supply and reduce stress on the mitochondria. [7][8]

3. Specialized nutrition support (dietitian-guided)
   A dietitian experienced in mitochondrial disease calculates energy, protein and micronutrient needs. The goal is to prevent malnutrition and weight loss, while avoiding excess fat or protein that may worsen metabolic load. In severe cases, high-energy formulas or parenteral nutrition may be required to maintain growth and organ function. [7][8]

4. Feeding tube (NG or gastrostomy) support
   When swallowing is weak or the baby tires easily, a nasogastric or gastrostomy tube can safely deliver nutrition and medicines. This reduces the energy cost of feeding, decreases aspiration risk, and allows continuous feeds during illness, helping to stabilize blood sugar and energy supply. [7][8]

5. Cardiac monitoring and non-drug heart support
   Regular echocardiograms, ECGs and careful fluid management are essential because hypertrophic cardiomyopathy is common. Non-drug support includes strict infection control, oxygen when needed, and careful avoidance of dehydration or sudden volume overload, which can destabilize fragile heart function. 15

6. Respiratory physiotherapy and airway clearance
   Weak muscles and heart failure can cause lung congestion and infections. Respiratory physiotherapists teach gentle chest physiotherapy, positioning and suction techniques to clear secretions, improve ventilation, and reduce pneumonia risk. Non-invasive ventilation may be considered in selected patients with respiratory failure. [6][8]

7. Seizure first-aid and safety education
   If the child develops epilepsy, families are taught simple seizure first-aid: placing the child on their side, protecting the head, timing seizures, and knowing when to call emergency services. Education reduces fear and improves rapid response during seizure clusters or status epilepticus in mitochondrial disease. [9][15]

8. Audiology and early hearing rehabilitation
   Sensorineural hearing loss is frequent in mitochondrial disease. Early hearing tests, hearing aids or cochlear implants (in selected cases) help support communication and development. Good hearing support also improves family interaction and quality of life, even when the underlying disease is severe. 17

9. Physiotherapy and gentle activity
   Carefully supervised, very gentle movement and physiotherapy can preserve joint mobility and comfort. In milder mitochondrial diseases, structured aerobic exercise can improve mitochondrial function, but in COXPD40 any activity plan must be extremely individualized to avoid over-exertion or cardiac stress. [7][14]

10. Occupational therapy and positioning aids
    Occupational therapists help with adaptive seating, cushions, and devices to prevent contractures and pressure sores. Good positioning can improve breathing, feeding, and comfort, especially in children with severe weakness and cardiomyopathy who cannot move independently. 6

11. Developmental and communication support
    Speech and language therapists can support early communication using sounds, gestures or alternative communication devices, even in very young infants. This helps families interact and make the most of the child’s abilities, improving emotional bonding and quality of life. [7][8]

12. Infection-prevention strategies
    Because any infection can trigger a metabolic crisis, families are advised on careful hand-washing, vaccination schedules, rapid assessment of fever and early treatment of respiratory or urinary infections. Reducing infection burden lowers hospitalizations and stress on fragile organs. 6[8]

13. Temperature and stress control
    High fever and prolonged crying can increase metabolic demand and worsen lactic acidosis. Using antipyretics as advised by doctors, cooling measures, and minimizing unnecessary stress (pain, loud noise, sleep deprivation) can help keep energy demand as low as possible. 6

14. Genetic counselling for the family
    Geneticists explain inheritance, recurrence risk in future pregnancies, and options such as prenatal diagnosis or preimplantation genetic testing. This information helps parents make informed reproductive decisions and connects them with support groups for rare mitochondrial diseases. 3

15. Psychological and social support
    Living with a lethal infant condition is extremely stressful. Psychological support, bereavement counselling, social-work support and contact with patient organizations can help families cope emotionally and practically with frequent hospitalizations and decision-making. [5][8]

16. Palliative-care involvement from early stage
    Early palliative-care involvement focuses on comfort, symptom control (pain, breathlessness, distress), and aligning treatment intensity with family values. This does not remove active treatment but adds an extra layer of support for complex decisions in COXPD40. 5

17. Emergency identification letter or card
    Patients with mitochondrial disease often carry a letter explaining their condition, typical complications and emergency instructions (e.g., avoid prolonged fasting, use dextrose fluids). This helps emergency teams respond quickly and consistently across different hospitals. 6

18. Careful medication review (avoid mitochondrial toxins)
    Some drugs (for example, valproate in certain mitochondrial DNA variants, or some aminoglycosides) may worsen mitochondrial function or organ toxicity. A specialist regularly reviews the child’s medication list to avoid or minimize potentially harmful agents. [9][14]

19. Organ-specific surveillance (liver, endocrine, kidneys)
    Regular blood tests check liver enzymes, blood sugar, kidney function and endocrine status. Early detection of dysfunction allows prompt management, such as treating adrenal insufficiency or adjusting drugs that can harm kidneys or liver. 1[10]

20. Participation in registries and research (when possible)
    Enrollment in mitochondrial disease registries and natural-history studies can give families access to the newest knowledge and potential future trials. It also helps researchers better understand ultra-rare conditions like COXPD40. [7][8]

Drug treatments

Again, no drug is approved specifically for COXPD40. The drugs below are used to treat complications such as seizures or heart failure, based on their U.S. Food and Drug Administration-approved indications (for epilepsy, cardiomyopathy, edema, etc.) and then applied off-label in mitochondrial patients by specialists. [6][9][10]

Doses are always individualized; here we only describe general label-based adult/pediatric patterns in simple words, not exact prescriptions.

1. Levetiracetam (Keppra®) – antiseizure drug
   Levetiracetam is a broad-spectrum antiepileptic approved for focal and generalized seizures. Labels describe weight-based dosing, usually given twice daily, with gradual dose increases and adjustments for kidney function. In mitochondrial epilepsies, neurologists often choose levetiracetam because it has relatively few mitochondrial-toxic effects; side effects can include sleepiness, dizziness or mood changes. [10]

2. Furosemide (Lasix® and related products) – loop diuretic
   Furosemide is a strong diuretic approved for edema in heart failure, liver disease and kidney disease. Label information describes IV or oral dosing titrated to urine output, with warnings about dehydration and electrolyte loss. In COXPD40, it may be used in intensive care to relieve fluid overload from severe cardiomyopathy, while carefully monitoring blood pressure, kidney function and electrolytes. [11]

3. Enalapril (Vasotec®, Epaned®) – ACE inhibitor
   Enalapril is approved for hypertension and symptomatic heart failure. The FDA label explains that it relaxes blood vessels by blocking angiotensin-converting enzyme, and uses daily oral dosing, adjusted for kidney function and blood pressure. In pediatric cardiomyopathy, specialists may use enalapril off-label to reduce afterload and support heart function; possible side effects include low blood pressure, kidney issues and high potassium. [12]

4. Carvedilol (Coreg®) – beta-blocker
   Carvedilol is a beta-blocker approved for heart failure, left ventricular dysfunction and hypertension. The label advises starting with low oral doses and slowly increasing while monitoring blood pressure and heart rate. It reduces heart work and may improve survival in heart failure. In mitochondrial cardiomyopathy, carvedilol is sometimes used under close supervision; side effects include dizziness, low blood pressure and fatigue. [13]

5. Spironolactone – mineralocorticoid receptor antagonist
   Spironolactone is approved for heart failure and certain forms of edema and hypertension. It blocks aldosterone, helping the body get rid of extra salt and water while sparing potassium. In combination with ACE inhibitors and loop diuretics, it may improve outcomes in heart failure; risks include high potassium and kidney problems, so labs are monitored closely. [13][14]

6. Thiazide diuretics (e.g., hydrochlorothiazide)
   Thiazides are approved for high blood pressure and mild edema. They increase urine output by acting on the kidney’s distal tubules. In mitochondrial cardiomyopathy, a specialist may use low-dose thiazides for additional fluid control, always watching for low blood sodium or potassium and dehydration, especially in fragile infants. [11][14]

7. Dobutamine – inotropic support (ICU use)
   Dobutamine is approved for short-term treatment of heart failure and cardiogenic shock. It is given as a hospital IV infusion and increases heart contractility and cardiac output. In COXPD40, it may be used during acute decompensation to stabilize circulation; risks include arrhythmias and blood pressure changes, so continuous monitoring is essential. [14]

8. Milrinone – phosphodiesterase-3 inhibitor
   Milrinone is an IV inotrope and vasodilator approved in some settings for short-term management of severe heart failure. It reduces the heart’s workload and improves pump function. Pediatric cardiologists may use it in intensive care to support infants with decompensated cardiomyopathy, monitoring for low blood pressure and arrhythmias. [14]

9. Antipyretic agents (paracetamol/acetaminophen)
   Acetaminophen is FDA-approved for fever and mild pain. Standard labels describe weight-based doses and liver safety warnings. In COXPD40, controlling fever is important to reduce metabolic stress. Doctors choose doses that protect the liver and avoid overuse, particularly if there is existing liver involvement. 6

10. Broad-spectrum antibiotics (e.g., ceftriaxone)
    Ceftriaxone and similar agents are approved for serious bacterial infections. In mitochondrial disease, infections often trigger metabolic crises. When sepsis is suspected, doctors may start IV antibiotics quickly, following label-based dosing, local resistance patterns and kidney function. Rapid infection control may prevent escalation of lactic acidosis and organ failure. 6[8]

11. Antiviral therapy (e.g., oseltamivir for influenza)
    Oseltamivir is approved for treatment and prevention of influenza. Mitochondrial disease guidelines stress quick treatment of flu-like illnesses. In COXPD40, early antiviral therapy during confirmed influenza infection may help shorten illness and reduce metabolic stress, but must be balanced against kidney function and potential side effects like GI upset. 6

12. Antiemetics (e.g., ondansetron)
    Ondansetron is widely used for nausea and vomiting. In mitochondrial crises, vomiting causes dehydration and poor intake, worsening lactic acidosis. Short-term ondansetron, using label-based IV or oral dosing, can allow continued feeding or IV glucose administration, but clinicians monitor heart rhythm and liver function. 6

13. Intravenous glucose and electrolyte solutions
    Dextrose-containing IV fluids are not “drugs” in the usual sense but are essential in emergency care. They provide rapid glucose, supporting ATP production when oral intake stops. Solutions are carefully chosen to correct acidosis, sodium, potassium and bicarbonate levels according to guidelines for mitochondrial crises and lactic acidosis. 6[14]

14. Bicarbonate (for severe metabolic acidosis)
    In some severe crises with life-threatening acidosis, IV sodium bicarbonate may be used. It raises blood pH temporarily, buying time while underlying causes (infection, low oxygen, poor perfusion) are corrected. This is done with great caution, as too much bicarbonate can worsen CO₂ retention and fluid balance. [14]

15. Thiamine (vitamin B1) as cofactor therapy
    Thiamine is used in several metabolic disorders to support mitochondrial enzymes that need it as a cofactor. While not specific to COXPD40, clinicians sometimes try high-dose thiamine to support residual energy pathways. It is usually well tolerated; side effects are rare and mainly involve GI upset or rare allergic reactions. [7][14]

16. Riboflavin (vitamin B2)
    Riboflavin is a precursor of FAD, an important cofactor in mitochondrial enzymes. In some mitochondrial disorders, riboflavin supplementation has improved complex I or II function. Doses used clinically are higher than standard vitamin doses but are supervised; typical side effects are harmless yellow urine and occasional GI discomfort. [7][14]

17. L-arginine
    L-arginine is approved for some metabolic conditions and is used off-label in mitochondrial stroke-like episodes associated with certain mtDNA variants. It supports nitric-oxide–mediated blood-flow regulation. While not studied in COXPD40, some clinicians consider it during acute crises if stroke-like phenomena occur, using IV or oral doses under close monitoring. [9][14]

18. Coenzyme Q10 (ubiquinone)
    CoQ10 is often used as a dietary supplement rather than a prescription drug in many countries. It acts in the electron transport chain and as an antioxidant. Small studies in mitochondrial disease suggest symptom improvement in some patients, though strong evidence is limited. Dosing and formulation vary; GI upset is the most common side effect. [7][8]

19. Carnitine (L-carnitine)
    Carnitine helps transport fatty acids into mitochondria and removes toxic acyl-groups. It is sometimes prescribed in mitochondrial disorders with low carnitine levels. Dosing is weight-based; side effects may include fishy body odor and GI discomfort. In COXPD-type diseases, carnitine is used cautiously if there is evidence of deficiency. 7

20. Proton-pump inhibitors (e.g., omeprazole)
    PPIs are approved for gastro-esophageal reflux and ulcer disease. Children with severe illness, tube feeds and many drugs often have reflux or gastritis; short-term PPI therapy can protect the GI tract and improve comfort. Long-term use requires caution because of infection and mineral-absorption risks. 6

Dietary molecular supplements

1. Coenzyme Q10 (CoQ10)
   CoQ10 works in the electron transport chain and as an antioxidant, helping mitochondria make ATP and reducing oxidative stress. In mitochondrial disorders, clinicians often use relatively high daily doses divided into 2–3 doses with fat-containing meals to improve absorption. Evidence is mixed but some patients show gains in strength or stamina; common side effects are mild GI discomfort. [7][8]

2. L-carnitine
   Carnitine shuttles long-chain fatty acids into mitochondria and helps remove toxic acyl compounds. In patients with low plasma carnitine or high acyl-carnitine levels, supplementation may support energy production and reduce accumulation of harmful metabolites. It is usually given in divided oral doses; diarrhea and characteristic body odor are the main side effects. 7

3. Riboflavin (vitamin B2)
   Riboflavin forms FAD and FMN, essential cofactors for many mitochondrial enzymes. Supplementation aims to optimize residual function of complexes I and II. Doses used in mitochondrial practice are higher than in standard multivitamins but remain generally safe; urine becomes bright yellow, and occasional GI upset can occur. [7][14]

4. Thiamine (vitamin B1)
   Thiamine supports pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key steps linking glycolysis to the Krebs cycle. In mitochondrial disorders with lactic acidosis, extra thiamine may improve use of glucose for energy. It is usually well tolerated, with rare allergy reactions at high injectable doses. [7][14]

5. Alpha-lipoic acid
   Alpha-lipoic acid is a cofactor for mitochondrial dehydrogenases and has antioxidant properties. Some small studies suggest possible benefit in mitochondrial disease by reducing oxidative stress. It is typically given orally with meals; potential side effects include nausea and, rarely, hypoglycemia or skin reactions. 7

6. Creatine monohydrate
   Creatine helps store and transfer high-energy phosphate groups in muscle and brain. In some mitochondrial myopathies, supplementation has improved exercise capacity. Doses are adjusted for age and kidney function; side effects can include weight gain from water retention and GI discomfort. 7

7. Arginine / citrulline
   These amino acids support nitric oxide production and vascular function. In some mitochondrial diseases with stroke-like episodes, arginine or citrulline may reduce frequency or severity; the evidence is still emerging. Doses are individualized, and side effects can include GI upset or changes in potassium levels. [9][14]

8. Folinic acid or folate
   Folinic acid supports one-carbon metabolism and mitochondrial folate pathways. In specific syndromes with secondary folate deficiency, supplementation has improved neurological symptoms, including seizures and cognition. Routine use in COXPD40 is not established but may be considered if deficiency is documented. [9]

9. Antioxidant vitamins (C, E)
   Vitamins C and E help neutralize free radicals and may protect mitochondrial membranes from oxidative damage. They are often included as part of a combined “mito cocktail”. At high doses, GI upset or interference with other nutrients can occur, so specialist supervision is needed. [7][14]

10. Standard multivitamin and trace elements
    A balanced multivitamin ensures adequate intake of essential vitamins and minerals that support many mitochondrial enzymes (e.g., iron, copper, selenium). This helps prevent additional nutritional deficiencies on top of the primary mitochondrial problem. Dosing usually follows age-appropriate recommendations. [7][8]

Immunity-booster, regenerative and stem-cell–related drugs

There are no proven regenerative or stem-cell drugs specifically approved for COXPD40. The items below are conceptual or research-related and are not routine care. [14]

1. Immunoglobulin (IVIG)
   IVIG is approved for several immune deficiencies and autoimmune diseases. In mitochondrial patients with documented immune problems or specific indications (e.g., severe infections, immune cytopenias), IVIG may help normalize immune function. It is given as intermittent IV infusions under close monitoring for reactions such as headache, fever or, rarely, thrombosis. [14]

2. Granulocyte-colony stimulating factor (G-CSF)
   G-CSF is used in neutropenia to increase white blood cell counts. In mitochondrial disease with bone-marrow suppression from other causes (for example, after certain drugs), it can reduce infection risk. Side effects may include bone pain and rare splenic problems. It is not specific for COXPD40 but may be considered if severe neutropenia occurs. [14]

3. Experimental mitochondria-targeted peptides (e.g., elamipretide)
   Agents like elamipretide are being studied to stabilize mitochondrial membranes and improve energy production in some mitochondrial disorders. Clinical trials are ongoing, and they are not yet approved for COXPD40. Use is limited to research settings, with dosing and safety monitored under strict protocols. [14]

4. Experimental gene-therapy approaches
   Because COXPD40 is caused by QRSL1 mutations, future gene-replacement or gene-editing therapies are theoretically possible. At present, these methods are experimental and carried out only in research laboratories or highly controlled clinical trials, not in routine clinical practice. [3][14]

5. Stem-cell or bone-marrow transplantation (research context)
   Hematopoietic stem-cell transplantation has been tried mainly in other metabolic and mitochondrial-related conditions, with mixed results and significant risk. For COXPD40, there is no evidence that stem-cell transplant corrects the underlying mitochondrial defect; any use would be strictly experimental. [14]

6. Future small-molecule modulators of mitochondrial function
   Research is exploring drugs that boost mitochondrial biogenesis, improve mitophagy, or modulate signaling pathways. These are not yet available as standard therapy. Families should be informed that participation in properly regulated clinical trials may become an option in future, depending on eligibility and location. [14]

Surgeries and procedures

1. Central venous line placement
   Some infants need long-term IV access for fluids, parenteral nutrition or medications. A central line insertion is a surgical procedure that places a catheter into a large vein. It reduces repeated needle sticks but carries risks like infection and thrombosis, so care teams decide carefully based on frequency of hospitalizations. 6

2. Gastrostomy tube placement
   A gastrostomy (G-tube) is a surgical opening in the stomach wall to insert a feeding tube. It is considered when long-term tube feeding is expected. It makes feeding easier and safer than a nasal tube, but involves anesthesia and surgical risks, which must be weighed carefully in children with cardiomyopathy. [7][8]

3. Cochlear implantation (selected cases)
   In mitochondrial sensorineural deafness, some children with enough life expectancy and stable status may benefit from cochlear implants to improve hearing. Surgery involves placing an electrode in the inner ear and an external processor. It demands anesthesia, careful cardiac assessment and intensive post-operative rehabilitation. 17

4. Implantable cardioverter-defibrillator (ICD) or pacemaker
   In older or milder mitochondrial cardiomyopathy, devices may be used to treat dangerous arrhythmias or conduction block. For COXPD40, survival is usually too short and infants too small, but in hypothetically longer-living cases these devices can reduce sudden-death risk. Surgery requires general anesthesia and lifelong follow-up. 1[14]

5. Palliative surgical or procedural interventions
   Sometimes minor procedures like draining pleural effusions or ascites are done to relieve breathlessness or discomfort. These are not curative but part of symptom-directed palliative care. Decisions are based on expected comfort gain versus procedural risk. 5

Prevention and risk reduction

Because COXPD40 is genetic, it cannot be fully prevented in an affected child, but some risks and complications can be reduced. 3

1. Genetic counselling before future pregnancies. 3

2. Prenatal or preimplantation genetic testing when QRSL1 variants are known in the family. 3

3. Strict avoidance of prolonged fasting, especially during illness. 6

4. Fast treatment of infections with appropriate antibiotics or antivirals. 6[8]

5. Up-to-date vaccinations (including influenza and pneumonia, if recommended). 6

6. Avoidance of known mitochondrial-toxic medicines whenever possible. [9][14]

7. Careful heart monitoring to detect and treat cardiomyopathy early. 1

8. Good nutrition and hydration plans tailored by a dietitian. [7][8]

9. Emergency “sick-day” protocol carried by the family. 6

10. Early palliative-care discussions to prevent overly aggressive, non-beneficial interventions at the end of life. 5

When to see doctors or go to emergency

Parents and caregivers should stay in close contact with a metabolic/mitochondrial specialist and paediatric cardiologist. Any new symptom in a child with COXPD40 can signal a serious crisis because the body has very limited energy reserve. 6[8]

Urgent medical review or emergency care is usually needed if:

• The baby feeds poorly, refuses feeds, or vomits repeatedly. 6

• There is fever, cough, difficulty breathing, fast breathing, or blue lips/skin. 6

• There are seizures, unusual eye movements, stiffening or loss of consciousness. [9][15]

• The baby is unusually sleepy, floppy, or hard to wake. 6

• Swelling of legs, tummy, or sudden weight gain suggests heart failure worsening. 15

• There are signs of shock (cold hands/feet, fast pulse, mottled skin) or any other worrying change. 6

What to eat and what to avoid

Diet is always individualized, especially in such severe disease, but general mitochondrial nutrition principles apply. [7][8]

1. Prefer frequent, small feeds rather than big gaps between meals, to avoid low blood sugar and energy dips. 7

2. Use energy-dense formulas or breast milk fortification if recommended, to support growth without huge feed volumes. [7][8]

3. Include adequate protein (per dietitian advice) to support muscle and organ repair. 7

4. Avoid long periods with only water; babies usually need carbohydrate (milk, formula) to keep glucose stable. 7

5. Avoid extreme high-fat or fad diets unless part of a supervised medical plan; they may increase metabolic load in fragile infants. [7][14]

6. Limit excessive simple sugars (like sweet juices) that can cause rapid swings in blood sugar; use balanced feeds instead. 7

7. Ensure enough fluids to avoid dehydration, especially during hot weather, vomiting or diarrhea. [7][8]

8. Use prescribed supplements (CoQ10, carnitine, vitamins) exactly as the specialist recommends; more is not always better. [7][8]

9. Avoid herbal or “energy” products without specialist approval, as some can harm the liver, heart or kidneys. [7][14]

10. Review the diet regularly with a mitochondrial-experienced dietitian, because needs change with growth and disease course. [7][8]

Frequently asked questions

1. Is there any cure for Combined oxidative phosphorylation deficiency 40?
   Right now there is no cure or disease-specific medicine for COXPD40. Care focuses on supporting the heart, controlling seizures and infections, and keeping nutrition and comfort as good as possible. Research into gene therapy, mitochondrial-targeted drugs and better supportive treatments is ongoing, but nothing is yet proven for this specific subtype. 1[14]

2. How is COXPD40 different from other combined oxidative phosphorylation deficiencies?
   COXPD40 is specifically linked to QRSL1 gene variants and often shows very early onset with severe cardiomyopathy, lactic acidosis and hearing loss. Other COXPD types are caused by different genes and may have different age of onset, organs affected and severity. Genetic testing is needed to distinguish these subtypes. 14

3. Why is the heart so badly affected in this disease?
   The heart muscle needs a constant large supply of ATP to beat continuously. When mitochondrial oxidative phosphorylation fails, the heart cannot generate enough energy, leading to hypertrophic cardiomyopathy and heart failure. This pattern is common in severe mitochondrial disorders affecting multiple complexes. 1[14]

4. Can supplements like CoQ10 or carnitine reverse the disease?
   Supplements may support remaining mitochondrial function or reduce oxidative stress, and some patients with other mitochondrial diseases report modest improvements. However, in COXPD40 there is no evidence that supplements can reverse the underlying genetic defect or dramatically change prognosis; they are supportive, not curative. [7][8]

5. Are there special antiseizure drugs for mitochondrial disease?
   There are no mitochondrial-specific antiseizure drugs, but some medicines (like levetiracetam, lamotrigine) are often preferred because they are considered less harmful to mitochondria, while others (like valproate) may be avoided in certain mitochondrial DNA defects. Choice is individualized by a neurologist familiar with mitochondrial epilepsy. [9][15]

6. Why do doctors worry so much about infections in COXPD40?
   Infection increases metabolic demand, fever and inflammation, which can tip already stressed mitochondria into crisis, causing worsening lactic acidosis, heart failure and multi-organ dysfunction. That is why early antibiotics or antivirals, antipyretics and hospital monitoring are used aggressively in mitochondrial patients. 6[8]

7. Can children with COXPD40 be vaccinated?
   In most mitochondrial diseases, standard inactivated vaccines are recommended because preventing infections is vital. Live vaccines and timing can be discussed with the care team, but in general the benefits of vaccination outweigh the risks, especially for influenza and pneumococcal disease. 6

8. What is the usual life expectancy in COXPD40?
   Published cases suggest COXPD40 is often lethal in early infancy despite intensive care. However, exact life expectancy varies between individuals, and new cases may expand our understanding. Doctors discuss realistic goals of care with each family, based on the child’s actual course, not only statistics. 15

9. Can a mother or father with a QRSL1 variant be healthy?
   Yes. COXPD40 is autosomal recessive, so parents usually each carry one non-working copy and one working copy of QRSL1, and they are typically healthy carriers. The affected child inherits the non-working copy from both parents, leading to disease. 3

10. Will all future pregnancies have COXPD40?
    If both parents are carriers, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier child, and 25% chance of a child with two working copies. Genetic counselling and early testing options can help parents plan future pregnancies. 3

11. Is heart transplant an option?
    In theory, heart transplant could treat severe cardiomyopathy, but in COXPD40 the disease affects many organs, including brain and liver, and overall prognosis is extremely poor. Therefore, most centres consider heart transplant inappropriate, focusing instead on supportive and palliative care. 16

12. Can lifestyle changes help, even in such a severe condition?
    Gentle positioning, good nutrition, careful infection prevention, stress reduction and loving family care can still improve comfort and daily quality of life. While they cannot change the underlying defect, they help ensure the child’s short life is as comfortable and connected as possible. [7][8]

13. Are there clinical trials for COXPD40 specifically?
    Because the condition is ultra-rare, most trials enroll broader mitochondrial disease groups rather than COXPD40 alone. Families can ask their metabolic centre or mitochondrial registries about ongoing studies, but eligibility may be limited by age, organ function and geography. [7][8][14]

14. What support is available for families?
    International mitochondrial disease foundations, national rare disease groups, and hospital-based palliative-care teams can provide emotional, financial and practical support. Many families value contact with others facing similar rare conditions, even if the exact gene is different. [5][8]

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 25, 2025.