Combined Oxidative Phosphorylation Deficiency Caused by Mutation in SLC25A26

Basic mechanism (SLC25A26 mutation)
Other names
Types
Causes
Symptoms
Diagnostic tests
Non-pharmacological (non-drug) treatments
Drug treatments –
Dietary molecular supplements
Immune-boosting, regenerative and stem-cell–related drugs
Surgical and procedural options
Prevention strategies
When to see a doctor
Diet – simple eat and avoid tips
Frequently asked questions (FAQs)

Combined oxidative phosphorylation deficiency caused by mutation in SLC25A26 is a very rare inherited mitochondrial disease. In this disease, both copies of a gene called SLC25A26 are changed (mutated). This gene makes a transport protein that sits in the inner membrane of mitochondria, the “power plants” of our cells. The protein normally brings a small molecule called S-adenosylmethionine (SAM) into mitochondria and carries S-adenosylhomocysteine (SAH) out again. [1]

Combined oxidative phosphorylation deficiency caused by mutation in SLC25A26 is a very rare inherited mitochondrial disease. In simple words, mitochondria are the “power plants” of the cell, and oxidative phosphorylation is the main process they use to turn food into usable energy (ATP). In this condition, a faulty SLC25A26 gene stops mitochondria from working properly, so many organs in the body do not get enough energy, especially the brain, heart, liver and muscles.[1]

The SLC25A26 gene makes a transport protein called the mitochondrial S-adenosylmethionine carrier (SAMC). This carrier moves a molecule called S-adenosylmethionine (SAM) into mitochondria. SAM is used to add “methyl groups” to DNA, RNA, proteins, coenzyme Q10 and lipoic acid. When SLC25A26 is mutated, SAM does not enter mitochondria properly, so many mitochondrial molecules are not correctly methylated. This leads to poor function of several respiratory chain complexes and causes “combined oxidative phosphorylation deficiency.”[1]

Basic mechanism (SLC25A26 mutation)

SAM is needed inside mitochondria to add “methyl” groups to DNA, RNA, proteins, fats, and special helper molecules such as coenzyme Q and lipoic acid. When SLC25A26 does not work, these methylation steps cannot happen normally. As a result, several parts of the mitochondrial energy chain (oxidative phosphorylation complexes I, III, and IV) may work poorly, so the cell cannot make enough ATP, the cell’s main energy fuel. [2][3]

Because energy production is reduced in many tissues at the same time, doctors call this a combined oxidative phosphorylation deficiency. When it is caused specifically by SLC25A26 mutation, it is sometimes numbered as type 28 (COXPD28). Symptoms can start before birth, in newborns, in infancy, or rarely in later life, and can affect muscles, heart, lungs, brain, and other organs. [1][4]

This condition follows an autosomal recessive pattern. This means a child is affected when they inherit one faulty SLC25A26 gene from each parent. Parents are usually healthy carriers and do not show symptoms themselves. The disease is extremely rare in the general population and has been described only in small numbers of families worldwide. [1][5]

Other names

Doctors and researchers use several other names for this same condition. Having many names can be confusing, but they all point to the same core problem: SLC25A26-related mitochondrial methylation and energy failure. Commonly used names include:

This condition is often called “combined oxidative phosphorylation deficiency 28 (COXPD28)”, using a numbering system for different genetic causes of combined mitochondrial respiratory chain defects. [1]

It may also be called “combined oxidative phosphorylation deficiency caused by mutation in SLC25A26” or “SLC25A26-related S-adenosylmethionine carrier deficiency”, which clearly link the disease to the underlying gene and transport problem. [1][6]

Some descriptions, especially in neonatal cases, use names such as “neonatal severe cardiopulmonary failure due to mitochondrial methylation defect”, to highlight that the main early signs can be severe heart and lung failure linked to disrupted mitochondrial methylation. [1][3]

Other synonyms you may see in specialist databases are “combined oxidative phosphorylation defect type 28”, “SLC25A26 combined oxidative phosphorylation deficiency”, or simply “COXPD28, SLC25A26-related”. All of these terms refer to the same group of patients with SLC25A26 mutations and a combined respiratory chain deficiency. [1][4]

Types

Doctors do not yet have a strict, universally agreed “type” system for SLC25A26-related combined oxidative phosphorylation deficiency, because only a small number of patients have been reported. However, based on case reports and reviews, they often think in terms of clinical patterns that differ mainly by age of onset and severity. [1][4][5]

One type is a severe neonatal form. In this pattern, the baby may show problems before birth (such as hydrops or poor growth), and soon after delivery develops weak muscle tone, slow heart rate, breathing failure, and very high lactic acid levels. Many of these infants die in the newborn period despite intensive care. [1][4]

A second pattern is an infantile episodic crisis form. Here, the baby may seem well at first, but in the first months of life develops sudden episodes of heart and lung failure, often during infections, together with lactic acidosis and metabolic decompensation. Between crises, the child may have poor weight gain, weak muscles, or developmental delay. [1][3]

A third pattern is a childhood-onset muscle and multi-organ form. Children may have delayed motor milestones, low muscle tone, easy fatigue, and sometimes heart or lung problems. They can experience repeated metabolic crises, but some survive longer with supportive care. [3][5]

A fourth pattern is a late-onset or adult mitochondrial myopathy form. In a few reported adults with SLC25A26 variants, main problems were exercise intolerance, episodes of severe abdominal pain with lactic acidosis, and muscle weakness. Muscle biopsy in these patients showed respiratory chain defects, similar to those seen in early-onset cases, but overall survival was better. [4][5]

Finally, there are asymptomatic carriers. People who carry one mutated SLC25A26 gene and one normal copy usually have no symptoms. They are important for family planning and genetic counseling, but they are not considered a disease “type” themselves. [1][5]

Causes

Below, “cause” means either the basic gene problem or a factor that strongly contributes to how the disease appears or worsens. The core cause is always a change in both copies of the SLC25A26 gene; other points describe how and why this leads to disease or crises.

Homozygous pathogenic SLC25A26 variants
In many families, both copies of the SLC25A26 gene have exactly the same harmful change (homozygous variant). This stops or reduces the normal transport of SAM and SAH across the inner mitochondrial membrane and leads to broad methylation and respiratory chain problems. [2][3][4]
Compound heterozygous SLC25A26 variants
Some patients have two different harmful changes, one on each copy of the gene (compound heterozygous). Even though each mutation is different, together they greatly reduce the function of the SAM carrier, causing a similar disease picture. [5][6]
Missense mutations in key functional domains
A missense mutation changes a single amino acid in the protein. When this happens in important regions that bind SAM or help move it through the membrane, the carrier may be present but work poorly. Even partial loss of transport can seriously disturb mitochondrial methylation in sensitive tissues. [2][3][6]
Truncating (nonsense or frameshift) variants
Some mutations introduce a premature stop signal or shift the reading frame, creating a shortened protein. These truncated proteins are often unstable or non-functional and may be destroyed by the cell’s quality-control systems, so almost no working SAM carrier reaches the mitochondrial membrane. [3][6]
Defective import of SAM into mitochondria
Because SLC25A26 is the main human mitochondrial SAM carrier, loss of its function means SAM cannot enter the mitochondrial matrix efficiently. Mitochondria then lack enough SAM for methylation reactions, even if SAM in the cytosol is normal. This mismatch is a central cause of disease. [2][3][7]
Impaired export of SAH from mitochondria
The carrier also exchanges SAM for SAH. When this exchange is disrupted, SAH may build up inside mitochondria. SAH is a strong inhibitor of methylation reactions, so its accumulation further blocks methylation and makes the energy problem worse. [2][3]
Defective methylation of mitochondrial DNA and RNA
Mitochondrial DNA and RNA need methyl groups to maintain their stability and to support proper protein production. In SLC25A26 deficiency, methylation of these nucleic acids is impaired. This can reduce mitochondrial protein synthesis and disturb the assembly of respiratory chain complexes. [3][4]
Defective methylation of mitochondrial proteins and lipids
SAM-dependent methylation modifies certain proteins and lipids, including components of coenzyme Q and lipoic acid. When these modifications are reduced, coenzyme Q and lipoic acid levels or structure may be abnormal, contributing to combined defects in oxidative phosphorylation and energy production. [3][4]
Secondary combined respiratory chain deficiency (complex I, III, IV)
Because methylation defects disturb several parts of the respiratory chain at once, enzymes in complexes I, III, and IV may show reduced activity on testing. This combined enzyme deficiency is a direct result of the SLC25A26-related methylation problem and is a key biochemical cause of symptoms. [1][3]
Autosomal recessive inheritance in carrier parents
When both parents are healthy carriers, each pregnancy has a one-in-four chance of producing a child with two faulty copies of SLC25A26. This inheritance pattern is a basic cause of new cases in families and explains why siblings may be affected in more than one generation. [1][5]
Consanguinity (parents related by blood)
In some reported families, parents are related (for example, cousins). When relatives have children together, they are more likely to share the same rare gene variant, which increases the chance that a child will inherit two copies of a harmful SLC25A26 mutation. [5][6]
Additional variants in other mitochondrial genes (possible modifiers)
Genetic studies suggest that variants in other mitochondrial or metabolic genes may modify the severity of SLC25A26-related disease. They may not cause the condition alone, but they can make the energy failure better or worse in a given person. This is an area of ongoing research. [3][5]
Metabolic stress from infections
In babies and children with SLC25A26 mutations, infections (such as a common cold or pneumonia) can sharply raise energy needs. Because their mitochondria cannot produce enough ATP, these stresses may trigger metabolic crises with lactic acidosis and organ failure. In this sense, infections are immediate causes of acute decompensation. [1][3]
Fasting or poor feeding
Long periods without food reduce glucose supply and push the body to use stored fats and proteins for energy. In a child with combined oxidative phosphorylation deficiency, this switch can overwhelm already weak mitochondria, causing acidosis and worsening heart, muscle, or breathing problems. [1][3]
High fever or overheating
Fever increases metabolic rate and oxygen demand. In SLC25A26 deficiency, the mitochondria cannot match this increased demand, which may lead to fast breathing, lactic acidosis, and rapid decline, especially in infants. [3]
Certain drugs or anesthetic stress (possible triggers)
Some anesthetic agents and other drugs can stress mitochondria or lower blood pressure and breathing. In a patient with SLC25A26-related disease, these effects can unmask or worsen energy failure during surgery or procedures, although specific drug lists are not yet well defined. [3][8]
Poor nutritional status (cofactor deficiency)
Even though SLC25A26 deficiency is genetic, lack of vitamins and cofactors that support mitochondrial function (such as B vitamins) may make the energy problem more severe. Supportive treatment sometimes includes vitamin “cocktails” in an attempt to improve remaining mitochondrial activity. [3]
Pregnancy in an affected adult woman
In rare adult female patients, pregnancy places extra demands on the heart, lungs, and metabolism. For a woman with limited mitochondrial reserve due to SLC25A26 variants, this can trigger worsening symptoms or new complications. This is based on broader experience in mitochondrial disease in general. [3]
Progressive mitochondrial damage over time
Over years, ongoing energy shortage and oxidative stress can gradually damage mitochondria and cells. This slow accumulation of damage is a cause of progression from mild muscle symptoms to more serious weakness or organ involvement in some longer-surviving patients. [3][4]
Random (stochastic) cellular differences
Even in the same person, different tissues may show different levels of mitochondrial damage. Small random differences in how cells handle stress can therefore cause some organs (for example the heart or lungs) to be affected more strongly than others, contributing to the variable picture of the disease. [3][4]

Symptoms

Low muscle tone (hypotonia)
Many babies with this condition feel “floppy” when held. Their muscles do not provide normal resistance to movement, because the cells do not have enough energy to maintain constant tone. Hypotonia often appears soon after birth and may be one of the first signs noticed by parents or doctors. [1][3][9]
Muscle weakness and delayed motor milestones
Older infants and children may struggle to lift their head, roll, sit, or walk at the expected ages. Weakness often affects the trunk and limbs. In milder or later-onset forms, children or adults may still walk but tire quickly, especially when climbing stairs or walking long distances. [3][4][9]
Breathing problems and respiratory failure
Because breathing muscles and control centers in the brain need a lot of energy, they can be strongly affected. Babies may breathe rapidly, have pauses in breathing, or fail to maintain normal oxygen levels. In severe forms, they may need ventilator support, especially during infections or metabolic crises. [1][3][9]
Heart problems (cardiomyopathy and heart failure)
The heart is a very energy-hungry organ. Some patients develop thick or weak heart muscle (cardiomyopathy), leading to poor pumping and heart failure. Symptoms can include poor feeding, sweating with feeds, fast breathing, swelling, or low blood pressure. These problems can be life-threatening in infants. [1][3][9]
Episodes of metabolic decompensation
Many children experience sudden episodes where they become very ill, often during an infection or fasting. They may show vomiting, fast breathing, confusion or lethargy, and laboratory tests show high lactic acid and metabolic acidosis. These crises reflect a sudden mismatch between energy demand and impaired mitochondrial supply. [1][2][3]
Lactic acidosis
Because mitochondria cannot fully use fuel to make ATP, cells switch to less efficient pathways that produce lactic acid. This acid builds up in the blood, causing lactic acidosis. Signs include fast breathing, nausea, vomiting, and in severe cases, drowsiness and shock. Lactic acidosis is a key biochemical feature of this disease. [1][3][9]
Developmental delay and learning difficulties
The brain is highly dependent on constant energy supply. Some children show delays in speech, cognition, and movement. They may need extra support for learning, therapy for speech and motor skills, and careful monitoring of development. Severity varies widely, from mild delay to profound impairment. [1][2][4]
Failure to thrive and poor weight gain
Even when feeding seems adequate, babies may not gain weight normally. The body spends extra energy just to keep basic functions going, leaving less energy available for growth. Vomiting during metabolic crises and frequent illnesses can also limit calorie intake. [1][3]
Seizures or abnormal movements (in some patients)
In some reported cases, children developed seizures, abnormal eye movements, or other movement disorders. These signs suggest that mitochondrial dysfunction is affecting brain circuits that control electrical activity and movement. Seizure risk seems to vary between families and mutations. [1][3][4]
Abdominal pain and gastrointestinal symptoms
Adult patients with SLC25A26 variants have been described with recurrent severe abdominal pain, sometimes with lactic acidosis during episodes. Nausea, vomiting, and feeding intolerance can also occur in infants and children, especially during metabolic stress. [4][5]
Shortness of breath and low exercise tolerance
Older children and adults may report that they become short of breath and exhausted with modest physical activity. This reflects reduced muscle energy production and sometimes heart or lung involvement. They may avoid sports or have to stop frequently when walking or climbing stairs. [3][4]
Pulmonary hypertension (high pressure in lung vessels)
Some patients develop high blood pressure in the arteries of the lungs, known as pulmonary hypertension. This worsens shortness of breath and heart failure and can be difficult to treat. It likely reflects combined effects of heart disease, low oxygen levels, and endothelial mitochondrial dysfunction. [1][9]
Liver involvement (hepatopathy)
The liver also contains many mitochondria and can be affected. Some patients show enlarged liver, raised liver enzymes, or more severe liver failure. Liver dysfunction can aggravate metabolic instability because the liver is key for handling lactate and other metabolites. [3][9]
Vision problems (in some cases)
In the broader group of combined oxidative phosphorylation deficiencies, some patients show vision impairment and optic nerve problems. For SLC25A26-related disease, data are limited, but mitochondrial dysfunction can, in theory, disturb the eye’s energy-intense tissues, leading to visual symptoms in some individuals. [1][2]
Early death in severe neonatal or infantile forms
Sadly, in the most severe forms, babies may die in the neonatal period or early infancy due to heart failure, respiratory failure, or overwhelming metabolic acidosis. Early diagnosis, careful supportive care, and avoidance of triggers are important but cannot fully prevent this outcome in all cases. [1][3][4]

Diagnostic tests

In practice, doctors do not rely on a single test. They combine clinical examination, basic laboratory tests, specialized metabolic and genetic tests, electrodiagnostic studies, and imaging to confirm SLC25A26-related combined oxidative phosphorylation deficiency. Many tests are general for mitochondrial disease but are still useful here.

Physical examination tests

General physical and neurologic examination
The doctor checks growth, muscle tone, strength, reflexes, and overall responsiveness. They look for signs such as hypotonia, delayed milestones, and abnormal reflexes. This examination guides which further tests are needed and helps distinguish mitochondrial disease from other neurologic and muscle disorders. [1][3]
Cardiovascular examination
The doctor listens to heart sounds, checks heart rate and rhythm, and looks for signs of heart failure such as swelling, liver enlargement, or cool extremities. Because cardiomyopathy and heart failure are common in severe forms, careful heart examination is essential. [1][3][9]
Respiratory examination
Breathing rate, depth, use of accessory muscles, and oxygen saturation are assessed. Rapid breathing, grunting, or low oxygen levels may suggest lactic acidosis or heart and lung involvement. These findings often prompt urgent blood gas and lactate testing. [1][3]
Developmental and functional assessment
Clinicians assess motor skills, speech, and learning level compared with age norms. They may use simple developmental scales or ask parents about milestones. Delays in several areas raise suspicion of a multi-system disorder such as a mitochondrial disease. [1][2]
Eye and vision examination
An eye specialist may check visual acuity, eye movements, and the back of the eye (fundus). Although not specific, findings such as optic nerve changes or retinal abnormalities can support the idea of a systemic mitochondrial problem and guide further testing. [1][2]

Manual / bedside functional tests

Manual muscle strength testing
Using simple bedside techniques, the clinician asks the patient to push or pull against resistance. Grading of muscle strength in different groups helps document the distribution and severity of weakness over time. This pattern can point toward a primary muscle and mitochondrial disorder. [3][4]
Gowers’ maneuver observation and standing from the floor
In children who can walk, the doctor may ask them to rise from the floor. Use of hands to “climb up” the legs (Gowers’ sign) suggests proximal muscle weakness, which fits with mitochondrial myopathy in some patients with SLC25A26 variants. [3][4]
Simple exercise or walk tests (in older patients)
For older children or adults, short standardized walk tests or stair climbing can be used. Excessive fatigue, shortness of breath, or muscle pain with mild exertion supports a diagnosis of mitochondrial myopathy and helps monitor disease progression. [3][4]
Bedside coordination and balance tests
Tests such as heel-to-shin, finger-to-nose, and simple balance checks can reveal subtle cerebellar or proprioceptive problems. While not specific, abnormalities suggest broader nervous system involvement, which is common in combined oxidative phosphorylation deficiencies. [1][2][3]

Laboratory and pathological tests

Blood lactate and pyruvate levels
Measurement of lactate is one of the most important screening tests. Persistent or episodic high lactate, especially with elevated lactate-to-pyruvate ratio, suggests impaired mitochondrial oxidative phosphorylation. It strongly supports a mitochondrial disease but is not specific to SLC25A26 mutations. [1][3][9]
Blood gas analysis
Arterial or capillary blood gas tests show pH and bicarbonate levels. In metabolic crises, patients often have metabolic acidosis with low pH and low bicarbonate due to lactic acid buildup. These results guide urgent treatment and give objective evidence of metabolic decompensation. [1][3]
Plasma amino acids, acylcarnitine profile, and urine organic acids
These metabolic panels help rule out other inborn errors of metabolism that can mimic mitochondrial disease. In SLC25A26 deficiency, they may be normal or show non-specific changes, but they are still important to exclude other treatable disorders. [3]
Liver function tests and coagulation profile
Blood tests for liver enzymes, bilirubin, albumin, and clotting factors help detect hepatic involvement. Abnormalities can indicate liver stress or failure, which is a serious complication in some mitochondrial disorders and affects management decisions. [3][9]
Creatine kinase (CK) and other muscle enzymes
CK may be normal or mildly elevated in mitochondrial disease. A raised CK supports muscle involvement but is usually not as high as in primary muscular dystrophies. CK can be used to follow muscle damage over time. [3][4]
Genetic testing of SLC25A26
Definitive diagnosis usually requires DNA testing. This can be done by sequencing the SLC25A26 gene directly, by using a targeted mitochondrial disease panel, or by whole-exome or whole-genome sequencing. Finding biallelic pathogenic variants in SLC25A26 confirms the genetic cause of combined oxidative phosphorylation deficiency in a patient with a fitting clinical picture. [1][5][6][7]
Muscle biopsy with histology and respiratory chain enzyme analysis
In some patients, doctors take a small piece of muscle. Under the microscope, they may see signs of mitochondrial myopathy, such as abnormal mitochondria. Biochemical assays often show reduced activity of complexes I, III, and IV, confirming a combined oxidative phosphorylation defect. In SLC25A26 deficiency, these findings match the expected consequences of impaired mitochondrial methylation. [1][3][4][9]

Electrodiagnostic tests

Electrocardiogram (ECG)
An ECG records the heart’s electrical activity. It can show rhythm problems (such as bradycardia or other arrhythmias) and patterns suggesting cardiomyopathy. This is important because heart involvement is a major cause of illness and death in severe cases. [1][3]
Electromyography (EMG) and nerve conduction studies
EMG measures electrical activity in muscles, and nerve conduction studies assess how fast nerves conduct signals. In mitochondrial myopathy, EMG may show myopathic patterns. These tests help distinguish muscle disease from nerve disease and support the diagnosis of a primary muscle energy problem. [3][4]
Holter monitoring or extended rhythm recording
Sometimes, doctors use 24-hour ECG monitoring (Holter) to catch intermittent rhythm problems that a single ECG might miss. This can reveal episodes of slow heart rate or other arrhythmias that contribute to fainting, fatigue, or heart failure symptoms. [3]

Imaging tests

Echocardiography (heart ultrasound) and brain MRI
Echocardiography uses sound waves to show heart size, wall thickness, and pumping function, and to detect cardiomyopathy and pulmonary hypertension. Brain MRI may show structural changes, delayed myelination, or other features seen in mitochondrial encephalopathies. While not specific to SLC25A26, these imaging findings help confirm multi-organ mitochondrial involvement. [1][2][3][9]

Non-pharmacological (non-drug) treatments

These are supportive therapies used in primary mitochondrial disease and may be adapted for SLC25A26-related combined oxidative phosphorylation deficiency by a specialist team. Evidence is limited and mostly based on expert consensus and case series.[1]

1. Multidisciplinary specialist care
Care is usually led by a mitochondrial or metabolic specialist and coordinated with cardiology, neurology, hepatology, nutrition, physiotherapy, respiratory and palliative care. Having one central team reduces conflicting advice, allows regular monitoring and ensures fast action during crises. This team also creates written care plans, educates families and liaises with local hospitals and schools so that everyone understands the child’s condition and emergency needs.[1]

2. Energy conservation and pacing
Because cells cannot make energy efficiently, even small tasks can be very tiring. Pacing means balancing activity and rest across the day: planning rest breaks, avoiding long walks or climbing many stairs, and using mobility aids when needed. This helps prevent sudden exhaustion, muscle pain and metabolic crisis. Families are taught to recognize early fatigue signs (slower speech, heavier breathing, irritability) and to stop and rest before the child is completely worn out.[1]

3. Avoidance of prolonged fasting
Fasting forces the body to burn stored fat and protein, which is harder for damaged mitochondria and can increase lactic acid. Children with mitochondrial disease are often fed more frequently than usual, especially during illness. Overnight feeds, snacks before bed, or tube feeds may be used. In hospital, intravenous glucose may be given early to prevent low blood sugar and metabolic decompensation.[1]

4. Prompt treatment of infections
Infections are a common trigger for metabolic crises. Families receive a written “sick day plan” explaining when to seek care, when to give extra fluids or carbohydrates and when to go to the emergency department. Doctors are advised to treat fever, vomiting, dehydration and low oxygen quickly and to monitor lactate and blood gases during serious illnesses.[1]

5. Physiotherapy and safe exercise
Gentle, individualized physiotherapy helps maintain joint flexibility, prevent contractures and support posture. When tolerated, low-to-moderate endurance exercise (for example, short walks or cycling with rest breaks) can improve mitochondrial function and fitness. Exercise programs must be tailored, started slowly and adjusted if symptoms worsen.[1]

6. Occupational therapy and adaptive equipment
Occupational therapists help the child manage daily activities like dressing, writing, playing and moving around school. They may suggest wheelchairs, walking aids, special seating, bathroom equipment, and energy-saving techniques. This makes life safer and less tiring and supports independence and participation at home and school.[1]

7. Speech, feeding and swallow therapy
Some children have weak mouth and throat muscles, leading to speech delay, choking or aspiration. Speech and language therapists assess swallowing, recommend safe food textures and teach techniques to reduce aspiration risk. They also support speech and communication, sometimes using communication boards or devices if speech is very delayed.[1]

8. Respiratory support and airway care
Weak respiratory muscles can cause shallow breathing, sleep-disordered breathing and repeated infections. Non-invasive ventilation (such as CPAP or BiPAP), airway clearance techniques and chest physiotherapy may be used. Vaccinations against influenza and pneumonia are encouraged, and respiratory therapists teach families how to recognize early breathing problems.[1]

9. Cardiac monitoring and lifestyle adjustments
Because cardiomyopathy and rhythm problems can occur, regular heart checks (ECG and echocardiogram) are recommended. Families are advised to avoid extreme exertion, dehydration and overheating, which can strain the heart. If heart function worsens, activity levels may need to be reduced, and parents are taught warning signs such as breathlessness, swelling and fainting.[1]

10. Nutritional counseling and tailored feeding
Dietitians calculate energy and protein needs and suggest meal plans that provide steady carbohydrates, adequate protein and healthy fats. They may recommend frequent small meals, fortified foods or tube feeding if oral intake is poor. The goal is to prevent under-nutrition and weight loss while avoiding very high protein or fat loads that stress mitochondria.[1]

11. Gastrostomy (feeding tube) support and care
If a feeding tube is placed (gastrostomy), families receive training on tube care, feeding schedules, and infection prevention. This non-pharmacological support ensures that the child receives reliable nutrition and fluids, reducing the risk of metabolic crises triggered by poor intake or vomiting.[1]

12. Developmental and educational support
Many children with mitochondrial disease have developmental delays or learning difficulties. Early intervention programs, special education services, individualized education plans (IEPs) and classroom accommodations (rest breaks, extra time, elevator access) help the child reach their potential and reduce fatigue at school.[1]

13. Psychological and family support
Living with a chronic, sometimes life-threatening disease is stressful. Psychologists and social workers can help families manage anxiety, depression, grief and uncertainty. Support groups and patient organizations allow families to share experiences, learn coping skills and understand new research developments.[1]

14. Genetic counseling and reproductive planning
Because SLC25A26-related disease is autosomal recessive, parents and older siblings may want to know their carrier status and recurrence risks. Genetic counselors explain inheritance in simple language and discuss options such as prenatal diagnosis, preimplantation genetic testing and family testing for at-risk relatives.[1]

15. Temperature and environmental control
Heat, cold, dehydration and high altitude can stress mitochondria and worsen symptoms. Families are advised to keep the child in a comfortable temperature range, avoid saunas and very hot environments, prevent dehydration and be cautious with long air travel without medical planning.[1]

16. Avoidance of mitochondrial toxins
Certain medicines such as valproic acid (for seizures) and some aminoglycoside antibiotics can worsen mitochondrial function in some genetic backgrounds. Doctors try to avoid or carefully justify such drugs when possible and choose safer alternatives. An updated medication list and “alert card” help emergency teams avoid harmful drug choices.[1]

17. Sleep hygiene and routine
Good sleep reduces stress on mitochondria. Families are encouraged to keep regular bedtimes, limit caffeine in older children, create a quiet bedtime routine and treat sleep apnea or restless sleep if present. Better sleep can improve daytime energy, mood and cognition.[1]

18. Written emergency plan
A clear one-page document summarizing the diagnosis, baseline status, usual medications and emergency instructions is very helpful. It explains to other doctors that the child has a mitochondrial disease, should avoid fasting and may need early glucose, fluids and monitoring of lactate and electrolytes in any serious illness.[1]

19. Palliative care and symptom relief planning
Palliative care does not mean “giving up.” It focuses on comfort, quality of life and symptom control alongside active treatment. Teams help manage pain, breathlessness, anxiety and feeding problems, and guide difficult decisions about intensive care, ventilation and resuscitation based on the family’s values.[1]

20. Participation in registries and research
Enrollment in mitochondrial disease registries and natural-history studies helps doctors better understand rare conditions such as SLC25A26 deficiency. Families may be offered clinical trials in the future, but any research participation should be carefully explained and ethically approved.[1]

Drug treatments –

Important safety note: No drug has been specifically proven to cure SLC25A26-related combined oxidative phosphorylation deficiency. Most medicines below are used off-label to support mitochondrial function or treat complications, based on expert opinion, case reports and general mitochondrial disease guidelines. Doses must always be individualized by a specialist; do not start or change medicines without your doctor.[1]

Levocarnitine (Carnitor®) – a carrier for fatty acids into mitochondria; often used when carnitine is low. Typical dosing for metabolic disorders in FDA labeling is weight-based and given several times daily; dosing is set by specialists.[1] It may improve energy and reduce muscle weakness but can cause diarrhea or fishy body odor and must be used carefully in cardiac disease.[1]
Thiamine (vitamin B1) – a cofactor for several enzymes in energy pathways. High-dose thiamine has helped some patients with mitochondrial encephalopathy and Leigh disease, so clinicians often include it in mitochondrial “cocktails.” Side effects are usually mild (upset stomach or rare allergy), but dosing is decided by the treating team.[1]
Riboflavin (vitamin B2) – supports complex I and II of the respiratory chain and is sometimes dramatically effective in riboflavin-responsive disorders. In general mitochondrial disease, it is used empirically at moderate-to-high doses, divided during the day. Urine may turn bright yellow; nausea or headaches are possible but usually mild.[1]
Coenzyme Q10 (ubiquinone/ubiquinol) – an essential electron carrier in the respiratory chain and a strong antioxidant. It is one of the most commonly used agents in mitochondrial medicine, with typical divided daily dosing adjusted to age and weight. Some patients report improved stamina and reduced lactic acid; side effects are usually minor gastrointestinal symptoms.[1]
Alpha-lipoic acid – an antioxidant and cofactor in mitochondrial dehydrogenase complexes. It may help reduce oxidative stress and improve nerve function, though evidence in mitochondrial disease is limited. It is usually given by mouth, and higher doses can cause nausea or tingling; it is avoided in children unless guided by specialists.[1]
Vitamin C – a water-soluble antioxidant sometimes added to mitochondrial cocktails. It may help reduce oxidative damage but has not been proven to change long-term outcomes. High doses can cause stomach upset or kidney stones in susceptible people, so dosing is kept within safe ranges.[1]
Vitamin E – a fat-soluble antioxidant that protects cell membranes from damage. In mitochondrial disease, it is used in cautious doses to avoid toxicity. Excess vitamin E can increase bleeding risk, especially when combined with anticoagulants, so monitoring is needed.[1]
Folic acid / folinic acid – support one-carbon metabolism and may improve mitochondrial enzyme function in specific genetic backgrounds. They are sometimes used together with B12 and B6. Excessive dosing can mask B12 deficiency, so clinicians monitor blood counts and B12 levels.[1]
Cyanocobalamin or hydroxocobalamin (vitamin B12) – used to correct B12 deficiency and support methylation pathways. In some mitochondrial and metabolic conditions, high-dose injections improve neurologic symptoms. Side effects are rare but can include itching or local injection reactions.[1]
Biotin (vitamin B7) – essential for certain carboxylase enzymes. High-dose biotin is life-saving in biotinidase or holocarboxylase deficiency and is sometimes added empirically in unclear mitochondrial pictures. It is usually well tolerated, though very high doses can interfere with some lab tests.[1]
L-arginine (intravenous/oral) – commonly used in MELAS stroke-like episodes to support nitric oxide production and blood flow in the brain. In mitochondrial disease, it may reduce severity or frequency of such episodes. Side effects can include low blood pressure or high potassium, so monitoring in hospital is required.[1]
Levetiracetam – a modern anti-seizure medicine often preferred in mitochondrial epilepsy because it has fewer mitochondrial side effects than some older drugs. Dosing is weight-based and carefully increased. Possible side effects include mood changes, irritability and drowsiness.[1]
Topiramate or other second-line antiepileptics – may be used when seizures are difficult to control. Some anti-seizure medicines (especially valproate) can be harmful in certain mitochondrial DNA polymerase disorders, so drug choice is individualized. Topiramate can cause weight loss, kidney stones or cognitive slowing; monitoring is essential.[1]
Ondansetron – an anti-nausea drug widely used to treat vomiting during illness or after surgery. It can help prevent dehydration and metabolic crises triggered by poor intake. Rarely, it can affect heart rhythm, so ECG monitoring may be needed in high-risk patients.[1]
Proton pump inhibitors (for example, omeprazole) – reduce stomach acid and help manage reflux or gastritis, which are common in chronically ill children. They are generally safe but, with long-term use, may affect mineral absorption and infection risk, so the lowest effective dose is used.[1]
ACE inhibitors (for example, enalapril) – used for cardiomyopathy and heart failure by reducing blood pressure and cardiac workload. These drugs can slow progression of heart dysfunction in some mitochondrial cardiomyopathies but require monitoring of blood pressure, kidney function and potassium.[1]
Beta-blockers (for example, carvedilol or metoprolol) – improve heart function and control abnormal rhythms. They slow heart rate and reduce oxygen demand. Common side effects include tiredness, cold hands and low blood pressure. Dosing must be started at low levels and slowly increased.[1]
Loop diuretics (for example, furosemide) – used if heart failure or liver disease leads to fluid overload. They help remove extra fluid but can disturb electrolytes and kidney function, so blood tests and careful dosing are required.[1]
Insulin and glucose infusions during crises – in severe metabolic decompensation, insulin and glucose may be used in hospital to control blood sugar and manage lactic acidosis. This is an intensive-care treatment guided by specialists and is not used at home.[1]
Broad-spectrum antibiotics when infection is suspected – infections can quickly trigger severe decompensation. Early, appropriate antibiotic therapy in hospital can be lifesaving. Doctors try to balance rapid treatment with careful choice to avoid mitochondrial-toxic agents where possible.[1]

Dietary molecular supplements

These supplements are often discussed for primary mitochondrial disorders, but evidence is usually from small studies or case reports. They should only be used under medical supervision because quality and dosing vary.[1]

Coenzyme Q10 – often considered the core supplement in mitochondrial “cocktails.” It helps move electrons along the respiratory chain and acts as an antioxidant. Typical doses are divided through the day with fatty food to aid absorption. Some patients report better endurance; side effects are usually mild stomach upset.[1]
L-carnitine (oral) – can be used as a supplement (in addition to or instead of prescription forms) to support fatty-acid transport into mitochondria. It may reduce muscle pain and fatigue but can cause gastrointestinal symptoms or a distinctive body odor. Dosage is individualized based on blood carnitine levels.[1]
Alpha-lipoic acid – used as an antioxidant and mitochondrial cofactor. In some neurological and metabolic conditions, it may improve nerve function and reduce oxidative stress, but data in SLC25A26 disease are lacking. Over-the-counter doses should not be used without checking for drug interactions and safety in children.[1]
B-vitamin complexes (B1, B2, B6, B12, folate) – many mitochondrial cocktails include a “B-50” complex because B-vitamins are central to energy metabolism. Supplements can correct mild deficiencies and support enzyme function. High doses must be supervised, as some vitamins (for example, B6, folate) have toxicity at very high levels.[1]
Vitamin D – important for bone health, muscle function and immune support. Many chronically ill children are vitamin D deficient, so supplementation guided by blood levels is common. Too much vitamin D can cause high calcium and kidney problems, so dosing must follow lab results.[1]
Omega-3 fatty acids (fish oil) – may help reduce inflammation and support heart and brain health. Evidence in mitochondrial disease is limited, but some clinicians use omega-3 as part of a healthy diet plan. Side effects can include fishy after-taste and increased bleeding tendency at high doses.[1]
Magnesium – supports muscle and nerve function and may help with cramps or arrhythmias if deficiency is present. It must be dosed carefully to avoid diarrhea or, at very high levels, heart rhythm problems, especially in kidney disease.[1]
Creatine – stores high-energy phosphate in muscles and may partly compensate for reduced mitochondrial ATP output. Small studies in mitochondrial myopathies show mixed results. High doses can affect kidney function, so it should only be used under medical supervision with lab monitoring.[1]
NADH or niacin (vitamin B3 forms) – support redox balance and mitochondrial electron transfer. Some supplements combine NADH with CoQ10 and B-vitamins; evidence remains limited, and side effects include flushing or stomach upset.[1]
S-adenosylmethionine (SAMe) – particularly interesting in SLC25A26 disease because this carrier moves SAM into mitochondria. Experimental studies in other conditions show that SAMe can improve mitochondrial function and reduce oxidative stress, but clinical data in this exact disorder are lacking. Any use should be in research or specialist settings, not as routine self-supplementation.[1]

Immune-boosting, regenerative and stem-cell–related drugs

These are advanced or experimental therapies sometimes discussed for severe mitochondrial or metabolic diseases. They are not standard treatment for SLC25A26 deficiency and should only be considered in specialist centers or research settings.[1]

Intravenous immunoglobulin (IVIG) – pooled antibodies from donors, used to treat immune deficiency or autoimmune disease. It may be considered if a patient with mitochondrial disease has recurrent infections or proven immune defects. It is given by slow infusion in hospital and can cause headaches, fever or rare allergic reactions.[1]
Granulocyte colony-stimulating factor (filgrastim) – stimulates bone marrow to make neutrophils. If a patient has severe neutropenia and repeated infections, filgrastim may reduce infection risk. It is given by injection and can cause bone pain or spleen enlargement, so close monitoring is needed.[1]
Erythropoiesis-stimulating agents (for example, erythropoietin) – increase red blood cell production and may be used if chronic anemia causes fatigue and breathlessness. They are injected under the skin and require monitoring of hemoglobin and blood pressure to avoid clotting complications.[1]
Allogeneic hematopoietic stem cell transplantation (HSCT) – replacing the patient’s bone marrow with donor stem cells has helped some inborn errors of metabolism and specific mitochondrial disorders like MNGIE. HSCT carries high risks (infection, graft-versus-host disease, organ damage) and is only considered in carefully selected cases in expert centers.[1]
Mitochondrial augmentation of autologous stem cells – early clinical work shows that adding healthy mitochondria to a patient’s own stem cells and reinfusing them may improve mitochondrial function in some settings. This is highly experimental and available only in research protocols.[1]
Mesenchymal stem cell–based therapies – laboratory and animal studies suggest that mesenchymal stem cells can transfer healthy mitochondria to damaged cells and reduce inflammation. Clinical trials for mitochondrial encephalomyopathies are still in early stages, and risks and benefits are not fully understood.[1]

Surgical and procedural options

Again, there is no disease-specific curative surgery for SLC25A26 deficiency; procedures are used to manage complications.[1]

Gastrostomy tube placement – a small tube is surgically placed into the stomach to allow safe, reliable feeding and medication delivery. It is done when oral intake is insufficient or unsafe. It reduces the risk of malnutrition, dehydration and aspiration and makes “sick day” high-carbohydrate feeding easier.[1]
Fundoplication (anti-reflux surgery) – sometimes performed if severe reflux causes repeated aspiration and lung disease despite medicines. The top of the stomach is wrapped around the lower esophagus to reduce acid reflux. This may improve comfort and decrease infections but can cause gas bloating or swallowing changes.[1]
Pacemaker or implantable cardioverter-defibrillator (ICD) – used when dangerous heart rhythm problems or heart block occur. A small device is placed under the skin with leads into the heart to maintain safe rhythms or treat life-threatening arrhythmias. These procedures carry anesthesia risks that must be carefully managed in mitochondrial disease.[1]
Spinal surgery for severe scoliosis – in children with significant muscle weakness, scoliosis can worsen breathing and sitting balance. Spinal fusion surgery may improve posture and respiratory mechanics but is a major operation. Pre-operative planning with the mitochondrial team and anesthesiologists is essential.[1]
Liver transplantation (very selected cases) – if liver failure becomes life-threatening and disease appears to be mainly liver-limited, transplant may be considered. However, many mitochondrial diseases affect multiple organs, so replacing only the liver may not fully solve the problem. Risks and benefits must be weighed very carefully.[1]

Prevention strategies

Because this is a genetic disease, full prevention is not always possible, but some steps can reduce risk or severity.[1]

Genetic counseling for affected families – helps parents understand recurrence risks and options for future pregnancies.[1]
Carrier testing for at-risk relatives – allows informed family planning choices.[1]
Prenatal or preimplantation genetic testing – can identify affected embryos or fetuses in families with known SLC25A26 mutations.[1]
Avoiding consanguineous (close-relative) marriages where possible – may lower the chance of recessive conditions appearing.[1]
Prompt vaccination and infection prevention – reduces metabolic crises triggered by infections.[1]
Careful anesthesia planning – sharing mitochondrial diagnosis with anesthetic teams so they avoid prolonged fasting, hypothermia and certain drugs.[1]
Avoidance of clearly mitochondrial-toxic medicines when alternatives exist – for example, valproate in some genetic backgrounds.[1]
Early treatment of any serious illness – to prevent decompensation and organ damage.[1]
Healthy lifestyle in the wider family – balanced diet, no smoking around the child, good sleep and stress management help overall resilience.[1]
Participation in registries and research – supports development of future preventive and disease-modifying therapies.[1]

When to see a doctor

Families should seek urgent medical attention if the child has fast breathing, severe sleepiness, seizures, sudden weakness, chest pain, persistent vomiting, very poor feeding, high fever, strong abdominal pain, fainting, or any rapid change in behavior or consciousness. These may be signs of a metabolic crisis, heart problem or serious infection. For milder symptoms such as slow growth, new feeding difficulties or school decline, a routine but prompt review with the metabolic or mitochondrial clinic is important.[1]

Diet – simple eat and avoid tips

Diet plans must always be tailored, but general principles for primary mitochondrial disease are:[1]

Eat: frequent small meals with complex carbohydrates (whole grains, fruits, vegetables) to provide steady energy and avoid fasting.[1]
Eat: adequate high-quality protein (fish, poultry, eggs, dairy or plant proteins) to support growth and muscle repair.[1]
Eat: healthy fats (olive oil, nuts, seeds, avocado) rather than deep-fried foods.[1]
Eat: foods rich in natural antioxidants and vitamins (colorful fruits, vegetables, whole grains).[1]
Eat: enough fluids, especially during hot weather or illness, to prevent dehydration.[1]
Avoid: long periods without food, crash diets or ketogenic diets unless prescribed by the specialist team.[1]
Avoid: very high sugar drinks and large sugary snacks that cause rapid swings in blood sugar.[1]
Avoid: heavily processed fast food high in trans-fats and salt.[1]
Avoid: alcohol, smoking and vaping in older patients, as these further damage mitochondria and organs.[1]
Avoid: untested “miracle” herbal products or mega-dose supplements bought online; always check with the metabolic team first.[1]

Frequently asked questions (FAQs)

Is SLC25A26-related combined oxidative phosphorylation deficiency curable?
No cure is known at present. Treatment focuses on preventing crises, treating complications and supporting development and quality of life. Research into gene-based and mitochondrial-targeted therapies is ongoing.[1]
How is the diagnosis confirmed?
Doctors usually combine clinical features, blood and urine tests (including lactate), brain and heart imaging, muscle or liver biopsy in some cases, and, most importantly, genetic testing showing biallelic pathogenic variants in SLC25A26.[1]
Does every SLC25A26 mutation cause the same severity?
No. Different variants can cause different levels of mitochondrial dysfunction. Some babies have very severe early-onset disease, while others have milder, later-onset phenotypes. Factors like other genes and environment also influence severity.[1]
Can adults have this condition?
Yes, although many reported cases are in infants or children, some individuals with milder variants may reach adolescence or adulthood with chronic but less severe symptoms. Adult diagnoses are increasingly recognized as genetic testing becomes more widely available.[1]
Is it safe to give routine vaccinations?
In general, expert groups support routine vaccinations because infections are a major trigger for metabolic crises. Live vaccines may need special consideration in some situations, so schedules should be discussed with the metabolic and immunology teams.[1]
What is the life expectancy?
Life expectancy varies widely. Some infants with very severe disease die early despite intensive care, while others live many years with chronic disability but stable health. Early diagnosis, careful supportive care and rapid treatment of crises can improve outcomes, but exact prediction for one child is not possible.[1]
Can school attendance be possible?
Many children attend school with adaptations such as shortened days, rest breaks, wheelchair access and extra learning support. Close communication between the school, family and medical team helps balance education with health and energy needs.[1]
Are “mitochondrial cocktails” scientifically proven?
Supplements like coenzyme Q10, carnitine and B-vitamins are widely used and many patients report benefits, but high-quality randomized trials are limited. Experts often offer a monitored trial of a cocktail, adjusting ingredients based on response and any side effects.[1]
Can diet alone treat the disease?
No diet can correct the genetic mutation, but a well-planned diet helps maintain energy balance, reduce illness-related stress and support growth. Diet should be seen as one part of a broader care plan, not as a stand-alone cure.[1]
Is exercise good or bad?
Carefully supervised, moderate exercise can improve mitochondrial function and physical capacity, but over-exertion can trigger exhaustion or crises. Exercise prescriptions must be individualized and adjusted if the child feels worse afterward.[1]
Are stem-cell or gene therapies available now?
Stem-cell and mitochondrial augmentation approaches are being studied in some mitochondrial and metabolic diseases, but they are still experimental and not standard care for SLC25A26-related disease. Gene therapy research is ongoing in mitochondrial medicine, but clinical use is still limited.[1]
Can siblings be tested?
Yes. Once the family’s SLC25A26 variants are known, siblings can be tested to see if they are affected or carriers. Testing is usually done with informed consent and counseling to explain the meaning of the results.[1]
Does this condition affect pregnancy in the mother?
If the mother is just a carrier (one mutated copy), her own risk is usually low. However, if she has any symptoms of mitochondrial disease, pregnancy places extra stress on the heart and metabolism and needs high-risk obstetric care. Genetic counseling is important before pregnancy.[1]
What can families do day-to-day to help?
Following the care plan, avoiding fasting, seeking early treatment for illness, keeping appointments, providing balanced nutrition, protecting against infections and maintaining emotional support and routines all make a real difference. Keeping written notes of symptoms, triggers and helpful strategies can guide the team.[1]
Where can families find reliable information and support?
International mitochondrial disease foundations, rare-disease networks and hospital-based mitochondrial clinics provide educational materials, support groups and updates on research. Families should rely on reputable medical organizations and peer-reviewed information rather than unverified online sources or social media claims.[1]

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 24, 2025.

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