Glutaminyl-Transfer Ribonucleic Acid Amidotransferase Subunit-Related Combined Oxidative Phosphorylation Defect

Glutaminyl-transfer ribonucleic acid amidotransferase subunit-related combined oxidative phosphorylation defect is a very rare, serious genetic disease that affects the mitochondria, which are the “power stations” inside our cells. In this condition, changes (mutations) in genes for special proteins called glutamyl-tRNA(Gln) amidotransferase subunits stop mitochondria from making energy in the normal way. Because of this, many energy-making steps together, called “oxidative phosphorylation,” do not work well, so doctors call it a “combined oxidative phosphorylation deficiency.”

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

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 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. 15

The disease usually starts before birth or in early baby life and often causes weak heart muscle (cardiomyopathy), poor growth, very low energy, and problems in many organs at the same time. It is inherited in an autosomal recessive way, which means a baby gets one faulty gene from each parent, even though the parents are usually healthy themselves. The Genetic and Rare Diseases program of the National Institutes of Health lists this condition as an ultra-rare mitochondrial disease with very few known families in the world.

Other names

Doctors and medical websites use several names for this condition. All of them are talking about the same or very closely related problems in the same group of genes:

• “Combined oxidative phosphorylation deficiency 40 (COXPD40)”

• “QRSL1-related COXPD”

• “QRSL1-related combined oxidative phosphorylation defect”

• “Glutaminyl-transfer ribonucleic acid amidotransferase subunit-related combined oxidative phosphorylation defect”

Experts sometimes also talk about a group of closely related diseases where different subunits of the same enzyme complex are affected. These subunits are called QRSL1, GATB, and GATC, and together they form the mitochondrial GatCAB complex. So in very simple words, you can think about “types” in this broader sense:

• Type by main gene involved:

  • QRSL1-related disease (often named COXPD40)

  • GATB-related disease

  • GATC-related disease

Even though the names are different, the core idea is the same: a problem in a subunit of the glutamyl-tRNA(Gln) amidotransferase enzyme that damages mitochondrial energy production and leads to a serious multi-organ disease.

How the problem happens in the body

Inside mitochondria, our cells must make many proteins that are used to generate energy from food and oxygen. To build these proteins, the cell uses “tools” called transfer RNAs (tRNAs) and enzymes that load amino acids onto these tRNAs correctly. The QRSL1, GATB, and GATC genes code for different parts (subunits) of one enzyme complex called GatCAB, which helps attach the amino acid glutamine correctly to a special tRNA (mt-tRNAGln^\text{Gln}Gln).

When these genes are damaged by mutations, the GatCAB complex cannot work properly. This means the mitochondria cannot make some key proteins that are needed for the oxidative phosphorylation system, which includes several enzyme complexes (I, III, IV, V) in the respiratory chain. Because of that, cells cannot produce enough ATP, the main energy “currency,” and they switch to less efficient backup ways of making energy, which leads to high levels of lactic acid and other chemical changes in the blood.

Organs that need a lot of energy, like the heart, brain, muscles, and liver, are hit the hardest. Babies and young children with this condition often show heart muscle thickening (hypertrophic cardiomyopathy), low muscle tone, weakness, and failure to thrive because their cells are constantly short of energy.

Causes

In strict medical terms, the main and direct cause of this disease is a genetic mutation in one of the genes that encode a subunit of the glutamyl-tRNA(Gln) amidotransferase complex, most often QRSL1. However, for learning and understanding, we can describe about twenty related “cause-type” factors and situations that help explain how and why the disease appears:

1. Homozygous QRSL1 mutation – The child gets the same faulty QRSL1 gene copy from both parents, which removes or strongly reduces the function of the QRSL1 protein and causes COXPD40.

2. Compound heterozygous QRSL1 mutation – The child gets two different harmful changes in QRSL1 (one from each parent), but together they still damage QRSL1 function and lead to the disease.

3. Loss-of-function variants in QRSL1 – Some mutations stop the protein being made at all or cut it short (nonsense or frameshift variants), and this loss of QRSL1 activity blocks proper mitochondrial translation.

4. Missense variants in QRSL1 – Other mutations change just one amino acid in the protein, but this is enough to disturb the structure or activity of the enzyme and can still produce the disease.

5. Mutations in GATB – Some families have mutations in the GATB gene, which codes for another subunit of the same GatCAB complex, leading to a very similar lethal mitochondrial cardiomyopathy.

6. Mutations in GATC – Changes in the GATC gene can also disrupt the GatCAB complex, again giving a similar pattern of heart disease and lactic acidosis.

7. Autosomal recessive inheritance in both parents – When both parents carry one harmful copy of the same gene (QRSL1, GATB, or GATC), there is a 25% chance in each pregnancy that their child will have the disease.

8. Consanguinity (parents related by blood) – In some reported families, the parents are related (such as cousins), which increases the chance that both carry the same rare harmful gene change.

9. Defective mitochondrial translation – The gene changes cause poor building of mitochondrial proteins, so the whole energy production line becomes weak and unstable, which is a central “cause” of the symptoms.

10. Respiratory chain complex deficiency – Several complexes of the respiratory chain (I, III, IV, and sometimes V) can have reduced activity, and this combined failure is the basis for the term “combined oxidative phosphorylation deficiency.”

11. High energy demand in heart muscle – The heart uses a lot of energy; when mitochondrial energy is low, heart muscle cells cannot work well, which promotes early and severe cardiomyopathy.

12. High energy demand in brain and muscles – Brain and skeletal muscles also require continuous energy, so they are affected, leading to poor tone, weakness, and possible seizures.

13. Metabolic stress during infections – When a baby with this defect gets a fever or infection, the body needs more energy, which can uncover or worsen symptoms like lactic acidosis or heart failure.

14. Limited ability to clear lactic acid – Because oxidative phosphorylation is weak, cells make more lactate, and the body struggles to remove it, causing lactic acidosis, which itself makes organs work less well.

15. Fetal hydrops and prenatal stress – In some cases, the disease is so severe that babies show swelling before birth (hydrops fetalis), which shows that the heart and circulation are already failing in the womb.

16. Imbalance in amino acid handling (glutamine) – Because the enzyme complex handles glutamine-related tRNA charging, changes in how cells process glutamine can influence how strong the mitochondrial problem becomes.

17. Modifier genes in mitochondrial pathways – Other genetic differences in mitochondrial function or stress response may change how severe the disease is from one child to another, even with similar main mutations.

18. Environmental stressors (like fasting) – Long periods without food or other stress conditions that increase energy demand may make the disease show earlier or more strongly, because the already weak mitochondria are over-challenged.

19. Delayed diagnosis and management – Because the disease is rare and hard to recognize, diagnosis can be delayed, which may allow heart and metabolic problems to worsen, although this does not cause the disease itself.

20. Lack of effective curative therapy – At present there is no cure that fixes the gene defect, so the natural course of the disease is often severe, and this underlying lack of correction helps explain why the condition can be life-threatening.

Main symptoms and signs

Because this disease affects many organs, symptoms can be different from one child to another, but several patterns are seen again and again in reported families. Here are fifteen important symptoms explained in simple words:

1. Poor growth and “failure to thrive” – Babies may not gain weight or grow in height as expected, even when they are fed carefully, because their bodies are using much of the energy just to keep basic functions going.

2. Low muscle tone (hypotonia) – The baby may feel “floppy” when held, with soft muscles and weak head control, because muscle cells cannot produce enough energy to stay firm and strong.

3. Muscle weakness – Older infants may have trouble lifting their head, rolling, sitting, or later standing and walking, as muscle weakness makes active movement difficult.

4. Breathing problems – Some babies have rapid breathing or trouble breathing, especially when their heart is weak or when lactic acid is high, because their body is struggling to get enough oxygen to low-energy tissues.

5. Hypertrophic cardiomyopathy – The heart muscle can become thick and stiff, so it cannot pump blood well; this may show as heart failure, poor feeding, fast breathing, or swelling.

6. Heart failure signs (such as swelling, enlarged liver) – When the heart cannot pump strongly, fluid may build up in the lungs or body, and the liver can enlarge, which doctors can feel during an exam.

7. Lactic acidosis symptoms – High lactic acid can cause vomiting, fast breathing, sleepiness, or confusion; in babies, these signs can be subtle but are serious.

8. Feeding difficulties – Babies may tire easily when feeding, take a long time to finish a bottle, or not show interest in feeding, because both heart and muscle fatigue make the effort hard.

9. Vomiting and poor appetite – Digestive symptoms can appear as the body tries to cope with metabolic stress and high acid levels, which can further worsen growth.

10. Developmental delay – Because the brain and muscles are affected, children may reach milestones late, such as sitting, crawling, walking, or speaking, compared to other children their age.

11. Seizures (in some patients) – In some reported cases, seizures occur, likely due to energy shortages and metabolic stress in the brain.

12. Extreme tiredness and low energy – Even simple activities may make the child very tired; sometimes they sleep more than usual or seem listless.

13. Abnormal muscle reflexes – On examination, doctors may find that reflexes are decreased or sometimes abnormal, depending on how the nervous system and muscles are affected.

14. Abnormal lab tests (high lactate, abnormal liver tests) – Though not a “feeling,” these lab changes are signs that cells and organs are under heavy metabolic stress.

15. Prenatal problems such as fetal hydrops – In very severe cases, problems begin before birth, with swelling, fluid collection, or poor fetal growth seen on pregnancy scans.

Diagnostic tests

Physical and manual bedside checks

Doctors start by examining the baby or child carefully to look for patterns that could suggest a mitochondrial disease like this one.

General physical examination 
The doctor looks at the child’s overall appearance, weight, length, head size, breathing pattern, skin color, and level of alertness. They check for signs such as poor growth, unusual swelling, or jaundice. This broad check helps the doctor see that more than one organ system may be involved, which is a clue toward a multi-system disease like a combined oxidative phosphorylation defect.

Detailed heart examination 
Using a stethoscope, the doctor listens to the heart for abnormal sounds (murmurs, gallops) and checks heart rate, rhythm, and signs of heart failure such as enlarged liver or fluid in the lungs. In this disease, heart muscle thickening and weakness can cause special sounds and signs that guide the doctor to think about cardiomyopathy.

Breathing and lung examination 
The doctor watches how fast and how hard the child is breathing, listens to the lungs, and looks for chest retractions or noisy breathing. In mitochondrial heart disease, the lungs may sound wet from extra fluid, or breathing may be rapid due to both heart failure and lactic acidosis.

Growth and nutrition assessment 
Height, weight, and head size are plotted on growth charts, and feeding history is taken. Poor growth and difficulty feeding, especially in a baby with heart problems, increase the suspicion of a serious inherited metabolic disease.

Neurologic exam with tone and reflex testing 
The doctor gently moves the child’s arms and legs, checks head control, and taps tendons to see reflex responses. Low muscle tone and weak or abnormal reflexes suggest that both muscles and possibly the nervous system are affected, which fits a mitochondrial translation defect.

Developmental milestone assessment 
By asking the parents what the child can do (roll, sit, crawl, walk, speak), the doctor measures development against standard age norms. A pattern of delay across several areas, combined with other findings, supports suspicion of a genetic metabolic or mitochondrial disease rather than an isolated muscle or heart problem.

Laboratory and pathological investigations

After the bedside exam, doctors order blood and other tests to study metabolism and organ function and to look for mitochondrial disease markers.

Blood lactate and pyruvate levels 
A blood sample is checked for lactic acid and pyruvate; in combined oxidative phosphorylation defects, these are often raised because cells switch to less efficient energy-making routes. A high lactate level that stays high or rises with mild stress is a strong clue that mitochondria are not working properly.

Blood gas and acid–base balance 
Arterial or capillary blood gases measure pH, carbon dioxide, and bicarbonate. Lactic acidosis shows up as low pH and low bicarbonate, telling doctors that the body is in metabolic acidosis, which is common in severe mitochondrial defects. This helps judge how sick the child is and guides urgent treatment.

Basic metabolic panel
Glucose, electrolytes, kidney function markers, and other routine blood tests are checked to look for low blood sugar, salt imbalance, or kidney stress. While these may not be specific for this disease, they show how the whole body is coping with the energy shortage and can guide supportive care.

Liver function tests
Enzymes such as AST and ALT and levels of bilirubin and albumin are measured. In serious mitochondrial disease, the liver may be stressed or enlarged, and these tests help show the level of damage and rule out other liver-only diseases.

Creatine kinase and muscle enzyme tests 
Blood tests for creatine kinase (CK) and other muscle enzymes can reveal muscle injury or stress. Elevated or sometimes normal values, combined with other tests, can support a picture of systemic muscle involvement due to poor mitochondrial energy supply.

Plasma amino acid and acylcarnitine profiles 
Special metabolic labs can measure detailed amino acid patterns and acylcarnitines, which may show subtle changes hinting at mitochondrial or other metabolic diseases. In some reported patients with GatCAB defects, these profiles helped show that the metabolic problem was broad and not limited to one enzyme.

Urine organic acid analysis 
By studying organic acids in urine, doctors can detect characteristic patterns of lactic acid and other metabolites that occur when oxidative phosphorylation is impaired. This test supports the diagnosis of a mitochondrial disorder and helps rule out other inborn errors of metabolism.

Genetic testing: mitochondrial disease panels and QRSL1/GATB/GATC sequencing (lab / molecular test)
Modern genetic tests can sequence many genes at once, including QRSL1, GATB, and GATC, or can use whole-exome or whole-genome sequencing. Finding homozygous or compound heterozygous pathogenic variants in these genes confirms the diagnosis of a glutamyl-tRNA(Gln) amidotransferase subunit-related combined oxidative phosphorylation defect.

Muscle or heart biopsy with respiratory chain enzyme analysis 
In some cases, doctors may take a tiny piece of muscle or heart tissue to examine under the microscope and to measure the activity of respiratory chain complexes. Reduced activity across several complexes supports the diagnosis of “combined” oxidative phosphorylation deficiency and can be linked with the genetic findings.

Electrodiagnostic and imaging studies

Because heart problems are central in this disease, electrodiagnostic and imaging tests of the heart and other organs are very important.

Echocardiogram 
An echocardiogram is an ultrasound scan of the heart. It shows how thick the heart walls are, how well they pump, and whether there is fluid around the heart. In this disease, echocardiography often reveals hypertrophic cardiomyopathy and poor pumping function, which are key signs of the condition.

Electrocardiogram (ECG/EKG) 
An ECG records the electrical activity of the heart through small stickers on the chest. It can show abnormal rhythms, strain patterns, or conduction delays that occur when the heart muscle is thick, enlarged, or stressed, as seen in mitochondrial cardiomyopathy.

Holter monitoring or continuous ECG 
A Holter monitor records ECG signals continuously over 24 hours or more while the child moves and sleeps. This test helps detect heart rhythm problems that come and go, which may not show on a single ECG tracing but can be present in severe cardiomyopathy.

Brain MRI 
Magnetic resonance imaging of the brain can look for structural changes, delayed myelination, or areas affected by repeated metabolic crises. In some mitochondrial diseases, brain MRI changes help support the diagnosis and rule out other neurological conditions.

Abdominal ultrasound 
An ultrasound of the abdomen allows doctors to check for an enlarged liver, abnormal blood flow, or other organ changes due to heart failure or metabolic stress. In mitochondrial cardiomyopathy, liver enlargement and congestion are common and give more evidence that the heart and metabolism are both involved.

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

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

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

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

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

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

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. 68

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

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

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. 110

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

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. 610

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

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

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. 68

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. 614

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

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

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

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

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

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

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

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

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

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

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

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

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. 114

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. 68

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

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

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

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

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. 68

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

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

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

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

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

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

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. 114

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. 114

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

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. 68

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

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. 714

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

15. What should families remember most?
    Families should remember that COXPD40 is nobody’s fault; it results from random genetic changes. Focusing on comfort, connection and informed decisions with a trusted multidisciplinary team can help them navigate this very hard journey with as much support and dignity as possible. 58

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.