FARS2 Combined Oxidative Phosphorylation Deficiency

FARS2 combined oxidative phosphorylation deficiency is a very rare mitochondrial disease. It happens when a gene called FARS2 does not work properly, so the tiny “power plants” of the cell (mitochondria) cannot make energy in the normal way. Doctors and researchers use several different names for the same condition, which can be confusing, but they all point to this FARS2-related mitochondrial energy problem. [1]

FARS2 combined oxidative phosphorylation deficiency (also called COXPD14 or FARS2 deficiency) is a genetic disease where the FARS2 gene does not work properly.[5][6] This gene makes a protein that helps the mitochondria build other proteins needed for energy. When it is faulty, mitochondrial energy production is weak and many organs cannot get enough energy to work normally.[7]

Doctors describe two main forms. The infantile form usually starts in the first months of life with hard-to-control seizures, weak muscles, feeding problems, and high lactic acid in blood, and it often has a poor outcome.[8][9] The later-onset form may appear in childhood or later with stiff legs and spastic paraplegia, sometimes with milder learning or movement problems and longer survival.[3][6]

Because mitochondria are in almost every cell, this disorder can affect the brain, muscles, liver, heart, blood cells, and growth. Symptoms can include developmental delay, microcephaly, failure to thrive, anemia, and thrombocytopenia, but the exact picture differs between people.[9][10]

Common other names include: [2]

• Combined oxidative phosphorylation deficiency 14 (COXPD14) – this is the official “numbered” name used in genetic databases. [3]

• Combined oxidative phosphorylation defect type 14 – very similar wording, also used in rare-disease catalogues. [4]

• FARS2 combined oxidative phosphorylation deficiency – clearly links the disease to the FARS2 gene. [5]

• FARS2 deficiency or FARS2 phenylalanyl-tRNA synthetase 2 deficiency – shorter terms that focus on the faulty enzyme. [6]

• Alpers-like encephalopathy due to FARS2 – used when the brain involvement looks like Alpers syndrome, with early severe seizures and brain damage. [7]

All these names describe the same main idea: a recessive genetic disease where both copies of the FARS2 gene are changed, leading to poor mitochondrial energy production in many organs, especially the brain and muscles. [8]

Types of FARS2 combined oxidative phosphorylation deficiency

Doctors usually talk about two main clinical types (phenotypes) of FARS2 deficiency. These types describe how old the patient is when symptoms start and which problems are most obvious. [9]

• Infantile-onset epileptic encephalopathy type
  In this type, symptoms start in the newborn period or early infancy. Babies develop frequent, hard-to-control seizures, very poor muscle tone, and severe delay in development. Blood tests often show high lactic acid, which means mitochondria are under stress and not making energy normally. This early type is usually severe and can sadly lead to serious disability or early death. [10]

• Later-onset spastic paraplegia type
  In this type, children may develop more slowly than usual but often sit, stand, and walk at some point. Over time, they develop stiff, tight muscles in the legs (spasticity) and weakness, so walking becomes difficult. Seizures may be mild or absent, and lactic acid levels may be less high. This form is usually milder, and people can live into later childhood or adulthood, but walking problems can be strong. [11]

• Intermediate / mixed type
  Some patients do not fit perfectly into either group. They may have seizures and also spastic paraplegia, or their symptoms may start in late infancy or childhood in between the two main types. Researchers are still learning about these mixed patterns as more patients are reported in medical journals. [12]

Even though there are these “types,” they are all part of one FARS2-related mitochondrial disease spectrum, and the exact symptoms depend on which FARS2 variants a person has and how strongly they affect the enzyme. [13]

Causes of FARS2 combined oxidative phosphorylation deficiency

Important note: The only proven root cause of this disease is having harmful changes (pathogenic variants) in both copies of the FARS2 gene. The “causes” listed below explain different genetic patterns and body stresses that either create or worsen this same mitochondrial problem. [14]

1. Biallelic pathogenic variants in FARS2
   The main cause is having disease-causing variants in both copies of the FARS2 gene (one from each parent). This stops the FARS2 enzyme from working properly in mitochondria, so cells cannot make proteins for the respiratory chain and cannot make enough energy. [15] [1]

2. Missense variants that change a single amino acid
   Many patients have missense variants, where one “letter” in the DNA code is changed. This swaps one amino acid in the FARS2 protein, which can bend the protein into the wrong shape and reduce its activity, leading to energy failure in mitochondria. [16] [2]

3. Truncating variants (nonsense or frameshift)
   Some variants create a “stop” signal too early or shift the reading frame of the gene. This makes a very short, incomplete FARS2 protein that cannot work at all, so the mitochondria lose much of their ability to carry out oxidative phosphorylation. [17] [3]

4. Splice-site variants
   Variants at splice sites can disturb how the FARS2 gene is cut and joined into mRNA. Abnormal splicing can remove or add important parts of the protein, lowering enzyme function and disturbing mitochondrial protein building. [18] [4]

5. Compound heterozygous state
   Many affected children inherit two different harmful variants (one from each parent). This “compound heterozygous” pattern still leads to severe loss of FARS2 function because both copies are damaged in different ways. [19] [5]

6. Homozygous variants in consanguineous families
   In some families where parents are related, the child inherits the same FARS2 variant from both parents, making them homozygous. This raises the chance of getting a very severe form of the disease because there is no normal copy of the gene. [20] [6]

7. Variants affecting the catalytic site of FARS2
   Some variants hit key amino acids in the active site of the enzyme, where phenylalanine and tRNA bind. When this site is damaged, the enzyme cannot “charge” tRNA with phenylalanine, blocking mitochondrial protein translation and harming oxidative phosphorylation. [21] [7]

8. Variants affecting the tRNA-binding region
   Other variants affect regions that hold the tRNA molecule in place. If binding is weak, aminoacylation is slow or incomplete, causing partial loss of function and a milder but still serious disease, often with spastic paraplegia. [22] [8]

9. Mitochondrial stress during rapid growth
   Early life is a time of fast brain and muscle growth. When FARS2 is already weak, this high energy demand can unmask the disease, leading to seizures and developmental delay. The underlying cause is still FARS2 variants, but rapid growth makes the deficit more visible. [23] [9]

10. Fever and infections as metabolic triggers
    Illnesses with fever can increase energy needs and push already fragile mitochondria into crisis. During infections, children may have more seizures, lactic acidosis, or regression. The infection does not cause the disease but triggers worsening because of the FARS2 defect. [24] [10]

11. Prolonged fasting or poor feeding
    Long gaps without food or feeding problems can force the body to use emergency energy pathways. In children with FARS2 deficiency, this can worsen lactic acidosis and weakness because mitochondria cannot handle the extra stress. [25] [11]

12. Co-existing mitochondrial DNA variants
    Some patients may also carry variants in mitochondrial DNA. While the main issue is in FARS2 (a nuclear gene), extra mitochondrial DNA changes may further damage oxidative phosphorylation and make the phenotype more severe. [26] [12]

13. Oxidative stress and reactive oxygen species
    When mitochondria fail, they can produce more harmful reactive oxygen species. Over time this oxidative stress damages brain cells and muscles further, deepening the clinical picture, although the start of the problem is still the FARS2 mutation. [27] [13]

14. Possible nutritional deficiencies
    Poor nutrition or lack of some vitamins and cofactors may not cause FARS2 deficiency by themselves, but they can lower the reserve capacity of mitochondria, making symptoms appear earlier or more strongly in a child who already has FARS2 variants. [28] [14]

15. Co-existing liver disease
    The liver is rich in mitochondria. If a child with FARS2 deficiency also has liver stress from other causes, lactic acidosis and energy problems can become more obvious, adding to the impact of the genetic defect. [29] [15]

16. Co-existing anemia or low platelets
    Some children with this condition also show anemia and thrombocytopenia. When red cells are low, oxygen delivery to tissues falls, which stresses mitochondria and makes symptoms such as fatigue and poor growth worse. [30] [16]

17. Environmental toxins that affect mitochondria
    Exposure to certain toxins or drugs that damage mitochondria could worsen energy failure in someone with FARS2 deficiency. They are not primary causes but act as “second hits” on an already weak system. [31] [17]

18. Pregnancy-related stress in the fetus
    Problems during pregnancy that limit oxygen or nutrients may put extra pressure on fetal mitochondria. In a baby with FARS2 variants, this may contribute to an earlier or more severe presentation after birth. [32] [18]

19. Delayed diagnosis and lack of supportive care
    If FARS2 deficiency is not recognized, seizures and lactic acidosis may not be optimized early. Ongoing uncontrolled crises can cause more permanent brain injury, making the disease course appear worse, even though the genetic cause is the same. [33] [19]

20. Random variation between individuals (genetic modifiers)
    Other genes in the person’s genome, called modifier genes, may change how serious FARS2 deficiency becomes. Some may offer small protection, and others may make the disease more severe, which is why even siblings with the same variants can look different. [34] [20]

Symptoms of FARS2 combined oxidative phosphorylation deficiency

Symptoms can vary from person to person, but many follow a similar pattern that reflects energy failure in the brain, muscles, and other organs. [35]

1. Global developmental delay
   Children are slow to reach developmental steps such as smiling, sitting, crawling, or talking. They may never achieve some milestones. This happens because the brain does not get enough stable energy to build and keep normal nerve connections. [36] [1]

2. Refractory (hard-to-control) seizures
   Many babies develop seizures that keep coming back even with medicine. Seizures happen because energy-starved brain cells fire in an uncontrolled way. In FARS2 deficiency, seizures can be frequent and resistant, making this a major problem. [37] [2]

3. Lactic acidosis
   Blood tests often show high lactic acid. This means the body is switching from efficient oxygen-based energy production to emergency “backup” pathways because the mitochondria are not working. Lactic acidosis can cause vomiting, fast breathing, and tiredness. [38] [3]

4. Hypotonia (low muscle tone)
   Babies may feel “floppy” when held, with poor head control and weak muscles. Low tone occurs because muscle cells cannot generate enough energy for normal contraction and because the brain signals to the muscles are weak. [39] [4]

5. Spasticity and spastic paraplegia
   In later-onset cases, legs may become stiff and tight. Joints resist movement, and walking becomes awkward, with toe-walking or scissoring of the legs. This reflects damage to long motor pathways in the brain and spinal cord that control movement. [40] [5]

6. Microcephaly (small head size)
   Some children develop a head size that is smaller than expected for age. This suggests poor brain growth or loss of brain tissue over time due to ongoing energy shortage and seizures. [41] [6]

7. Failure to thrive and poor weight gain
   Feeding difficulties, vomiting, or poor appetite are common. Because the body needs more energy just to survive, weight gain may be very slow, and children may fall off the growth chart. [42] [7]

8. Feeding and swallowing problems
   Weak muscles in the mouth and throat can make it hard to suck, chew, or swallow. Some children need feeding tubes to get enough nutrition. This problem adds extra stress to an already energy-poor body. [43] [8]

9. Abnormal movements (tremor, dystonia, ataxia)
   Some individuals have shakiness, twisting movements, or poor balance. These signs show involvement of brain areas that coordinate movement, such as the cerebellum and basal ganglia, which are very sensitive to mitochondrial problems. [44] [9]

10. Regression of skills
    Children who had learned skills such as sitting or saying words may lose them over time. This regression often follows periods of illness or increased seizures and reflects new damage to brain tissue. [45] [10]

11. Abnormal muscle reflexes
    On examination, doctors may find very brisk reflexes, ankle clonus, or abnormal responses to stimulation. These signs help show that the problem is in the motor pathways of the brain and spinal cord, not only in the muscles. [46] [11]

12. Vision problems
    Some patients develop optic nerve damage or other eye movement problems. Vision may become blurred or reduced because the cells in the visual pathways use a lot of energy and are easily harmed by mitochondrial failure. [47] [12]

13. Hearing loss
    Hearing problems can also appear, especially in mitochondrial diseases. The tiny cells in the inner ear need stable energy to convert sound into nerve signals, so they are vulnerable when oxidative phosphorylation is weak. [48] [13]

14. Breathing difficulties
    Some children have weak breathing muscles or central breathing control problems. They may breathe fast during lactic acidosis or have shallow breathing during seizures or in sleep, and may need respiratory support. [49] [14]

15. Multi-organ involvement (liver, blood, heart)
    Because mitochondria are everywhere, other organs can be involved. Some children have enlarged or damaged liver, anemia, low platelets, or heart problems. These features show how systemic the underlying energy defect is. [50] [15]

Diagnostic tests for FARS2 combined oxidative phosphorylation deficiency

Diagnosis usually needs a combination of careful clinical examination, metabolic tests, brain studies, and finally genetic testing to confirm FARS2 variants. [51]

Physical examination tests

1. Detailed pediatric physical examination
   The doctor examines the child’s general health, growth, head size, muscle tone, and any unusual facial or body features. This helps show that many body systems may be involved, which suggests a genetic or metabolic disorder rather than a simple isolated problem. [52] [1]

2. Neurological examination
   The neurologist checks reflexes, muscle strength, eye movements, coordination, and sensation. Patterns such as low tone in infancy, followed by increased tone and brisk reflexes later, strongly suggest a brain and spinal cord problem seen in FARS2 deficiency. [53] [2]

3. Growth and nutritional assessment
   Measuring weight, height, and head circumference over time shows whether the child is thriving or failing to grow, which is common in mitochondrial disease. Poor growth together with neurological signs supports the need for metabolic and genetic testing. [54] [3]

4. Systemic examination of liver, heart, and spleen
   The doctor feels the abdomen for an enlarged liver or spleen and listens to the heart. Organ enlargement or heart murmurs can point toward a systemic mitochondrial disease like FARS2 deficiency rather than a purely brain-limited disorder. [55] [4]

Manual / bedside functional tests

5. Manual muscle strength testing
   In older infants and children, the clinician grades muscle strength by asking them to push or pull against resistance. Weakness in specific patterns, together with spasticity or low tone, helps to describe the motor involvement typical of FARS2-related disorders. [56] [5]

6. Tone assessment and passive range-of-motion testing
   By gently moving the child’s arms and legs, the examiner can feel if they are floppy or stiff. Increased resistance suggests spasticity, while very little resistance suggests hypotonia. Both findings are common at different stages of FARS2 disease. [57] [6]

7. Developmental milestone evaluation
   Using simple tasks (reaching, rolling, sitting, walking), clinicians compare the child’s abilities with age-based expectations. Large delays across several areas—motor, language, and social—raise suspicion for a global brain disorder such as mitochondrial encephalopathy. [58] [7]

8. Gait and posture observation
   For children who can walk, doctors watch how they move. A stiff, scissoring gait or toe-walking suggests spastic paraplegia, which is a key feature in the later-onset form of FARS2 deficiency. [59] [8]

Lab and pathological tests

9. Serum lactate and pyruvate levels
   High lactate, often with abnormal lactate-to-pyruvate ratio, is a hallmark of mitochondrial oxidative phosphorylation problems. Persistently high levels in a symptomatic child strongly suggest the need to search for a mitochondrial disease such as FARS2 deficiency. [60] [9]

10. Blood gas analysis
    Blood gas tests measure pH, carbon dioxide, and bicarbonate. In lactic acidosis, the blood becomes more acidic, and bicarbonate may fall. This test helps assess how severe the metabolic crisis is and guides urgent treatment in the hospital. [61] [10]

11. Comprehensive metabolic panel (liver and kidney function)
    Tests such as AST, ALT, bilirubin, and creatinine show how well the liver and kidneys are working. Abnormal liver enzymes or liver enlargement, together with lactic acidosis and neurologic signs, support the diagnosis of a systemic mitochondrial disease. [62] [11]

12. Creatine kinase (CK) level
    CK is a muscle enzyme that may be mildly elevated when muscles are stressed or damaged. In mitochondrial conditions, CK can be normal or slightly high, but it helps rule out other muscle diseases and adds information about muscle involvement. [63] [12]

13. Plasma amino acids and acylcarnitine profile
    These tests look for other metabolic disorders that can mimic mitochondrial disease. In FARS2 deficiency, they may be normal or show mild nonspecific changes, but they are important to exclude other treatable conditions. [64] [13]

14. Urine organic acids
    Analysis of organic acids in urine can show patterns consistent with mitochondrial dysfunction or other metabolic blocks. While not specific for FARS2, an abnormal pattern supports the idea of a generalized energy-production problem. [65] [14]

15. Muscle biopsy with respiratory chain enzyme analysis
    In some cases, a small piece of muscle is taken and examined. Staining and biochemical tests can show reduced activity in multiple respiratory chain complexes, which is typical of combined oxidative phosphorylation deficiency. This supports the suspicion of FARS2-related disease before genetic confirmation. [66] [15]

16. Genetic testing: FARS2 gene sequencing
    The most specific test is sequencing the FARS2 gene to look for pathogenic variants. Next-generation sequencing panels for mitochondrial disease or whole exome/genome sequencing often identify biallelic FARS2 variants and confirm the diagnosis. [67] [16]

Electrodiagnostic tests

17. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity. In FARS2 deficiency, EEG often shows abnormal background activity and frequent epileptic discharges, matching the severe seizure pattern. In some reports, specific migrating seizure patterns have been linked to FARS2 variants. [68] [17]

18. Nerve conduction studies and electromyography (EMG)
    These tests study how well nerves send signals and how muscles respond. They can help rule out peripheral nerve or primary muscle diseases. In many FARS2 patients, studies may be normal or show mild changes, supporting a mainly central (brain/spinal cord) problem. [69] [18]

Imaging tests

19. Brain MRI (magnetic resonance imaging)
    MRI often shows changes in the brain’s gray and white matter, sometimes with features similar to Alpers syndrome, such as cortical atrophy or laminar necrosis. These structural changes reflect areas where energy failure has damaged brain tissue. [70] [19]

20. Brain MR spectroscopy
    MR spectroscopy is an MRI-based technique that looks at brain chemicals. In mitochondrial disease, it may show high lactate peaks in the brain, confirming that energy failure is happening inside brain tissue itself, not just in the blood. This supports the diagnosis of a mitochondrial encephalopathy like FARS2 deficiency. [71] [20]

Non-pharmacological (non-drug) treatments

These are therapies and supports that do not rely on medicines but can greatly improve comfort and function.

1. Multidisciplinary specialist team
Children with FARS2 deficiency usually need a team: neurologist, metabolic specialist, dietitian, physiotherapist, occupational therapist, speech therapist, and sometimes cardiologist and pulmonologist.[2][11] Working together, they track growth, seizures, movement, feeding, and breathing, and adjust the care plan as the child changes over time.

2. Early physiotherapy
Physiotherapy uses stretching, positioning, and gentle exercises to reduce stiffness, prevent contractures, and support head and trunk control.[2][11] This helps children keep as much movement and comfort as possible, and may delay problems like hip dislocation or scoliosis.

3. Occupational therapy
Occupational therapists focus on day-to-day activities, like sitting, playing, holding toys, and later using assistive devices to eat or write.[11] They adapt the environment, recommend special seating and hand splints, and train caregivers to make daily life safer and easier.

4. Speech and feeding therapy
Many children have swallowing problems and are at risk of choking and aspiration.[2][9] Speech-language pathologists teach safe swallowing techniques, advise on food textures and positions, and support early communication using eye gaze, pictures, or devices if speech is limited.

5. High-calorie nutritional support
Because of feeding difficulties and high energy needs, children can lose weight easily. Dietitians design high-calorie, high-protein feeding plans, using special formulas or thickened foods as needed.[2][11] The goal is to keep weight and growth as close to normal as possible.

6. Gastrostomy (feeding tube) support without drugs
If oral feeding is unsafe or too slow, a gastrostomy tube (G-tube) can bring nutrition directly to the stomach.[2] Non-drug care includes tube care, posture during feeds, and careful schedules to avoid vomiting, reflux, and aspiration.

7. Seizure emergency plan
Families are given a written seizure plan that explains what to do during different types of seizures, when to call an ambulance, and which emergency medicines to use.[3] This reduces panic, shortens seizure duration, and can prevent injury or brain damage.

8. Respiratory physiotherapy and airway clearance
Weak muscles and poor cough increase the risk of chest infections. Respiratory therapists teach chest physiotherapy, assisted coughing, and safe suctioning. They may also suggest devices like cough-assist machines and non-invasive ventilation at night.[2][11]

9. Orthotics and supportive seating
Ankle-foot orthoses, hand splints, and custom seating systems help keep joints in good position, prevent contractures, and improve comfort and posture.[11] These aids also make it easier to use wheelchairs and to be positioned safely for feeding and play.

10. Mobility aids (strollers, wheelchairs, walkers)
As weakness or spasticity increases, children may need special strollers, standing frames, or wheelchairs. The aim is to maintain mobility, independence, and participation, rather than to force walking at all costs.[11]

11. Vision and hearing support
Some patients have vision or hearing problems due to brain involvement.[9] Regular screening, glasses, low-vision tools, and hearing aids help the child interact with people and the environment, which is vital for development and quality of life.

12. Developmental and early-intervention programs
Even when prognosis is limited, early-intervention services (play therapy, special education, developmental clinics) support communication, cognition, and social interaction.[2][11] These services are adapted to the child’s abilities and can be provided at home or in specialized centers.

13. Individualized education plans (IEP)
For children who reach school age, a personalized education plan helps teachers adjust expectations, use assistive technology, allow rest breaks, and coordinate with the medical team.[11] This respects the child’s abilities while providing stimulation.

14. Psychological and social support for family
FARS2 deficiency is emotionally and financially hard on families. Psychologists, social workers, and peer-support groups offer counseling, coping strategies, respite, and help with benefits and equipment funding.[2][11]

15. Infection prevention routines
Care teams stress hand hygiene, updated vaccinations, fast treatment of fevers, and avoiding contact with sick people when possible.[11] This lowers the risk that infections will trigger metabolic crises or worsening seizures.

16. Careful management during surgery and anesthesia
If surgery or procedures with anesthesia are needed, anesthesiologists are told about the mitochondrial disease so they can avoid certain drugs, maintain sugars, and prevent prolonged fasting.[4][12] Good planning reduces the chance of metabolic decompensation.

17. Avoiding prolonged fasting and dehydration
Long periods without food can cause hypoglycemia and lactic acidosis in mitochondrial disease.[4] Families are taught to give frequent meals, extra fluids during illnesses, and sometimes glucose-containing drinks as recommended by the metabolic team.

18. Regular monitoring and screening
Doctors monitor lactate, liver function, blood counts, heart function, and growth, because FARS2 deficiency can affect many organs.[1][9] Early detection of complications allows earlier supportive treatment.

19. Genetic counseling for parents and relatives
Because FARS2 deficiency is autosomal recessive, each pregnancy in carrier parents has a 25% chance of being affected.[1] Genetic counseling explains this risk, options for prenatal or pre-implantation testing, and helps family members decide whether they want carrier testing.

20. Connection with rare-disease and mitochondrial advocacy groups
Families can gain practical advice and emotional support from mitochondrial disease organizations and FARS2-specific communities, which also share news about research and clinical trials.[10][13]

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Drug treatments

Important: There is no FDA-approved drug specifically for FARS2 combined oxidative phosphorylation deficiency. Medicines are used to control seizures, spasticity, reflux, infections, and nutritional or metabolic issues, often off-label.[3][4] Doses must always follow the official label plus specialist advice.

Below are examples, not prescriptions.

1. Levetiracetam (Keppra)
Levetiracetam is a widely used anti-seizure medicine that calms abnormal electrical activity in the brain. It is often chosen in mitochondrial disease because it has fewer liver and mitochondrial toxicity concerns than some older drugs.[3][4] FDA labeling gives standard weight-based doses, but in FARS2 patients neurologists start low, increase slowly, and watch mood, behavior, and sleep.

2. Clobazam (Onfi, Sympazan)
Clobazam is a benzodiazepine-type anti-seizure drug used as add-on therapy for hard-to-control epilepsies.[14] It enhances the calming GABA system and can reduce seizure frequency or intensity in FARS2-related epileptic encephalopathy, though sedation, drooling, and breathing depression are important risks, especially when combined with other sedatives.

3. Topiramate (Topamax)
Topiramate is another broad-spectrum antiseizure drug used for partial and generalized seizures.[15] It blocks certain ion channels and enhances GABA, but can cause appetite loss, kidney stones, or metabolic acidosis, which are important in a child who already has feeding problems and lactic acidosis, so mitochondrial specialists use it cautiously.

4. Lamotrigine (Lamictal)
Lamotrigine helps treat focal and generalized seizures by blocking voltage-gated sodium channels and stabilizing neuronal firing.[16] It is titrated very slowly to reduce the risk of serious skin rashes. In mitochondrial disease it may be preferred to valproate when possible, but its use still requires close monitoring.

5. Phenobarbital (including Sezaby)
Phenobarbital is one of the oldest antiepileptic barbiturates and may be used in neonatal or refractory seizures.[17] It depresses brain activity and can control seizures but often causes sedation, respiratory depression, and cognitive slowing. In a fragile FARS2 infant, dosing must be conservative and carefully monitored.

6. Diazepam (Valium, diazepam injection)
Diazepam is a benzodiazepine used mainly as a rescue medicine for prolonged seizures or clusters, often given rectally, intranasally, or intravenously.[18][19] It acts quickly to stop seizures but can slow breathing and cause sleepiness; families are trained when and how to use it safely as part of the emergency plan.

7. Baclofen (oral or intrathecal)
Baclofen is a muscle-relaxant that helps reduce spasticity by activating spinal GABA-B receptors.[20] In FARS2-related spastic paraplegia, it can ease stiffness and pain and improve positioning, but sudden withdrawal can cause severe rebound spasticity and even seizures, so tapers must be slow and supervised.

8. Levocarnitine (Carnitor)
Levocarnitine is approved to treat carnitine deficiency, but is often used off-label in mitochondrial disorders to help transport fatty acids into mitochondria.[21][4] In FARS2 deficiency, some teams add it as part of a “mitochondrial cocktail” when blood carnitine levels are low or borderline, while monitoring for diarrhea and fishy body odor.

9. Acid-suppressing drugs (e.g., proton pump inhibitors)
Children with severe reflux may receive acid-suppressing medicines (like omeprazole) to reduce pain, vomiting, and risk of aspiration. Evidence comes from general pediatric reflux care, not FARS2-specific trials, but better reflux control can improve comfort and nutrition.[2][11]

10. Standard antibiotics for infections
When FARS2 patients develop pneumonia, urinary infections, or sepsis, they are treated with standard pediatric antibiotics according to local guidelines. Mitochondrial doctors try to avoid drugs with known mitochondrial toxicity when alternatives exist, and may shorten fasting during IV treatments.[4][11]

Because of the risk of liver failure in some mitochondrial diseases, valproic acid is used very cautiously or avoided unless there is no other option, and then with strict monitoring.[4][12]

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Dietary molecular supplements

These are vitamins and cofactors often used as part of a “mitochondrial cocktail”. Evidence in FARS2 is limited and mostly comes from broader mitochondrial disease studies.

1. Coenzyme Q10 (CoQ10)
CoQ10 is a natural molecule in the mitochondrial electron transport chain. Supplementation may support ATP production and reduce oxidative stress in mitochondrial cytopathies, and has shown benefit in some trials.[22][23] Doses and forms (oil-based capsules, ubiquinol) are chosen by specialists, and it is generally well tolerated but can cause mild stomach upset.

2. Riboflavin (vitamin B₂)
Riboflavin is a cofactor for multiple mitochondrial enzymes and is a standard part of mitochondrial cocktails, especially for complex I and II defects.[24][25] High-dose riboflavin has improved symptoms in some mitochondrial and neurometabolic conditions. In FARS2 disease, it is used empirically to support residual oxidative phosphorylation.

3. L-carnitine (oral)
Oral L-carnitine adds to or replaces endogenous carnitine, helping to move fatty acids into mitochondria and remove toxic acyl groups.[21] It is especially considered if blood carnitine is low or if the child is on valproate. Doctors adjust the dose based on weight and blood levels, watching for diarrhea.

4. Thiamine (vitamin B₁)
Thiamine is needed for pyruvate dehydrogenase and other enzymes linking glycolysis to the Krebs cycle.[26] In mitochondrial disease, it is sometimes added to support carbohydrate processing and limit lactic acidosis, although direct FARS2 data are lacking.

5. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant cofactor of mitochondrial dehydrogenase complexes and may reduce oxidative stress and improve energy metabolism in some mitochondrial disorders.[27] It is used carefully, as data in children and in FARS2 specifically are limited, and doses must be supervised.

6. L-arginine or L-citrulline
L-arginine has been used in MELAS to support nitric-oxide production and reduce stroke-like episodes.[28][29] In FARS2, there is no specific evidence, but some clinicians consider arginine or citrulline to support vascular function and possibly brain perfusion, especially if similar stroke-like symptoms appear.

7. Vitamin D and calcium
These nutrients are important for bone health, especially in non-ambulant children on antiepileptic drugs that affect bone density.[3][11] Supplementation follows standard pediatric bone-health guidelines, not FARS2-specific trials.

8. Multivitamin with B-complex
A balanced multivitamin, including B-complex vitamins, supports many metabolic pathways, and may help if intake is limited by feeding problems.[25] The goal is to avoid secondary vitamin deficiencies that could worsen energy production.

9. Antioxidant vitamins (C and E)
Vitamins C and E are used empirically to limit oxidative damage in mitochondrial disease, with mixed but generally safe experience.[22][27] They should not replace proven medical treatments but can be part of a carefully designed supplement plan.

10. L-phenylalanine (very experimental and rare)
A small N-of-1 trial reported that oral L-phenylalanine supplementation improved motor function in one child with FARS2 deficiency, likely by helping the defective enzyme’s substrate supply.[30] This is very experimental and must only be done inside a specialist research protocol, as too much phenylalanine can be harmful.

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Regenerative, immunity-booster, and stem-cell-related approaches

At present, there are no approved stem-cell or gene therapies for FARS2 deficiency. Research in mitochondrial disease more broadly is active but still early.[31][27]

Examples of directions researchers are exploring (mostly not available in routine care):

1. Mitochondria-targeted drugs (e.g., elamipretide)
Elamipretide is approved for Barth syndrome, another mitochondrial disease, by stabilizing mitochondrial membranes and improving respiratory chain function.[27] It has not been studied in FARS2 deficiency, but shows how targeted mitochondrial therapies may eventually be adapted to other disorders.

2. Orphan-designated small molecules (e.g., zagociguat)
Some investigational drugs have FDA orphan designation for “mitochondrial diseases” in general, such as zagociguat.[32] Whether these will help FARS2 patients is unknown; future trials may include specific genetic subgroups.

3. Gene-based and RNA-based therapies
Gene therapy and RNA-based approaches are being developed for some nuclear-encoded mitochondrial disorders.[31] For FARS2, researchers still need to understand which mutations are most common and which tissues must be targeted before trials become realistic.

4. Hematopoietic stem cell or organ transplantation (very rare, case-by-case)
For some mitochondrial or metabolic disorders, bone marrow or liver transplants can help, but these are not standard for FARS2 and carry huge risks.[4] Such options would only be considered in exceptional cases within expert centers and research protocols.

Surgeries and procedures (supportive, not curative)

1. Gastrostomy tube placement
If feeding by mouth is unsafe or inadequate, surgeons can place a G-tube through the abdominal wall into the stomach.[2] This improves nutrition, reduces aspiration risk, and makes it easier to give medicines and supplements.

2. Nissen fundoplication (anti-reflux surgery)
For severe reflux that does not respond to medicines, surgeons can wrap the top of the stomach around the lower esophagus to reduce vomiting and aspiration.[2][11] This may protect lungs and improve comfort, but carries standard surgical risks.

3. Orthopedic surgery for contractures or hip dislocation
Tendon lengthening, hip reconstruction, or spinal fusion may be needed if spasticity leads to fixed deformities, pain, or difficulty sitting.[11] These procedures aim to improve positioning and care, not to restore normal walking.

4. Neurosurgical procedures for epilepsy (very selective)
In extremely drug-resistant focal epilepsy, options like vagus nerve stimulation or palliative disconnection surgery may be discussed.[3] Because FARS2 epilepsy is often diffuse and metabolic, only a few highly selected patients would be candidates.

5. Respiratory procedures (tracheostomy, long-term ventilation)
If chronic respiratory failure develops, some children may need tracheostomy and long-term ventilation support.[2][11] This is a major decision involving ethical, quality-of-life, and family-preference discussions.

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Key prevention and risk-reduction strategies

These do not prevent the genetic disease, but they may reduce complications and crises.

1. Avoid prolonged fasting by giving frequent meals and extra calories during illnesses.[4]

2. Treat infections early and seek medical care quickly for fever, vomiting, or breathing problems.[11]

3. Keep all routine vaccines up to date to reduce pneumonia, flu, and other preventable infections.[11]

4. Share a “mitochondrial disease letter” with emergency departments so they know how to avoid harmful drugs and manage fluids and glucose.[4]

5. Avoid drugs with known mitochondrial toxicity when alternatives exist (for example, cautious or no use of valproate unless absolutely necessary).[4][12]

6. Plan procedures and surgeries carefully with anesthesia teams familiar with metabolic disorders.[4]

7. Maintain good nutrition and hydration, with dietitian support, to avoid secondary malnutrition.[2]

8. Use proper positioning and physiotherapy every day to prevent contractures, scoliosis, and pressure sores.[11]

9. Regularly check vision, hearing, and heart function so problems can be treated early.[1][9]

10. Offer genetic counseling to parents and adult relatives to prevent unexpected recurrence in future pregnancies.[1]

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When to see a doctor urgently

With FARS2 combined oxidative phosphorylation deficiency, you should seek urgent medical review (often emergency care) if there is:

• A new or prolonged seizure, especially lasting more than a few minutes or clusters that do not stop with rescue medicine.[3]

• Sudden change in consciousness (very sleepy, not waking, or unusually irritable or confused).

• Breathing problems, fast breathing, pauses, or bluish lips or skin.

• Persistent vomiting, inability to keep fluids down, or no urine for many hours, suggesting dehydration or metabolic crisis.

• Fever with lethargy or signs of infection (cough, breathing difficulty, rash, or severe pain).[11]

• Rapid loss of skills (for example, losing the ability to sit, stand, talk, or feed that they recently had).

For day-to-day management, regular follow-up with neurology, metabolic medicine, dietetics, physiotherapy, and primary care should be scheduled according to the child’s condition.[2][11]

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Diet: what to eat and what to avoid

Diet in FARS2 deficiency should always be designed by a metabolic dietitian. General principles from mitochondrial disease care include:

• Prefer balanced meals with complex carbohydrates, adequate protein, and healthy fats to provide steady energy and avoid long gaps between feeds.[4][15]

• Use high-calorie formulas or fortification (adding oils, modular powders) if weight gain is poor or feeding volumes are small.[2]

• Avoid extreme low-carbohydrate or fasting-type diets unless prescribed for epilepsy by a specialist, because they may worsen lactic acidosis in some mitochondrial patients.[4]

• Ensure enough fluids to prevent dehydration, especially during hot weather or illness.

• Watch for and report feeding intolerance, reflux, or constipation, which may need diet changes or medical treatment.[2][11]

Because needs are very individual, never change diet or supplements without the metabolic team’s guidance.

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FAQs

1. Is there a cure for FARS2 combined oxidative phosphorylation deficiency?
No. Right now there is no cure. All treatments are aimed at supporting organs, controlling symptoms, improving comfort and quality of life, and avoiding complications.[2][11]

2. Is this disease always fatal in infancy?
The infantile epileptic form often has a poor prognosis, but some children live longer with intensive support. There is also a later-onset spastic paraplegia form, which can have longer survival and milder symptoms.[3][6]

3. Can adults have FARS2 combined oxidative phosphorylation deficiency?
Yes. Recent reports describe adolescent and adult-onset cases with spastic paraplegia or mixed neurologic symptoms, though they are rare.[33]

4. Is FARS2 deficiency inherited?
Yes. It is usually autosomal recessive: both parents carry one non-working copy of the gene, and a child who inherits both non-working copies is affected.[1]

5. Can anything prevent the disease in a future baby?
The gene change itself cannot be removed, but carrier testing, prenatal diagnosis, or pre-implantation genetic testing may help parents avoid having another affected child if they wish.[1]

6. Are all seizures in FARS2 the same?
No. Seizures may be focal, generalized, myoclonic, or infantile spasms, and they are often hard to control.[3][34] EEG patterns and brain MRI findings can vary, so treatment is always individualized.

7. Why do so many treatments focus on energy and mitochondria?
FARS2 deficiency damages mitochondrial oxidative phosphorylation, which is how cells make ATP (energy). Supporting the respiratory chain with vitamins, cofactors, and careful nutrition may help cells work better, even if it does not fix the gene.[7][24]

8. Do supplements like CoQ10 and riboflavin really help?
Evidence is mixed and mostly from small studies in various mitochondrial diseases, not specifically FARS2, but they are commonly used and often well tolerated.[22][24] Families should see them as supportive, not magic cures.

9. Can regular exercise help or harm?
Gentle, tailored physiotherapy and movement often help maintain flexibility and comfort, but over-exertion can worsen fatigue and lactic acidosis.[11][21] The physiotherapist guides how much activity is safe.

10. Are experimental drugs or gene therapies available now?
Some mitochondrial diseases now have first targeted drugs, and more are in trials, but none are specific for FARS2 yet.[27][31] Families can ask their specialists about research registries and trials.

11. Does every FARS2 variant cause the same severity?
No. Different mutations in FARS2 can produce a spectrum from very early, severe epileptic encephalopathy to later-onset spastic paraplegia.[3][6] Genetic reports and clinical features together guide prognosis.

12. Why do doctors worry about valproate in mitochondrial disease?
Valproic acid can trigger serious liver failure in some mitochondrial conditions and is contraindicated in disorders with POLG mutations.[12] In FARS2, some patients have taken it without obvious harm, but evidence is limited, so specialists are careful.[3][12]

13. Can “immune-boosting” over-the-counter products help?
Most commercial “immune boosters” have no proven benefit in FARS2 and could interact with medicines or cause side effects. Always ask the metabolic or neurology team before adding anything new.[4][22]

14. What is the role of palliative care in FARS2 deficiency?
Palliative care is not only for end of life. It focuses on comfort, symptom control, communication, and support for decisions throughout the illness, and can be involved from the time of diagnosis.[2][11]

15. Where can families find reliable information?
Trusted sources include GeneReviews, Orphanet, national mitochondrial foundations, and specialist hospital factsheets, which provide up-to-date, peer-reviewed information on FARS2 and related disorders.[1][2][10]

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 19, 2025.