Combined Oxidative Phosphorylation Deficiency Caused by Mutation in FARS2

Combined oxidative phosphorylation deficiency caused by mutation in FARS2 is a very rare genetic disease that affects how the “power plants” of the cell, called mitochondria, make energy. [1] In this condition, harmful changes (variants) in the FARS2 gene stop the cell from making some important mitochondrial proteins properly. These proteins are needed for oxidative phosphorylation, which is the main process that makes cellular energy (ATP). When this process does not work well, many organs that use a lot of energy – especially the brain, liver, and muscles – start to fail. [1][2]

This disease is usually called combined oxidative phosphorylation deficiency 14 (COXPD14). “Combined” means that more than one mitochondrial respiratory chain complex is affected at the same time. “Deficiency” means those complexes are weak or missing. The problem is autosomal recessive, which means a child becomes ill when they receive one faulty copy of the FARS2 gene from each parent. [2][3]

Combined oxidative phosphorylation deficiency caused by mutation in the FARS2 gene is a very rare inherited mitochondrial disease. In this condition, the FARS2 gene (which makes mitochondrial phenylalanyl-tRNA synthetase) does not work properly, so mitochondria cannot make some proteins needed to produce energy through oxidative phosphorylation. This mainly affects the brain and nerves, and can cause early-onset seizures, low muscle tone, developmental delay, spastic (stiff) legs, and high lactate levels in blood or cerebrospinal fluid.

Doctors also call this FARS2 deficiency or combined oxidative phosphorylation deficiency 14 (COXPD14). It usually appears in babies, but some people present later with spastic paraplegia (stiff, weak legs). Because mitochondria are involved in energy production in almost every cell, many organs can be involved, including brain, muscles, liver, and sometimes heart. There is no single approved curative drug. Treatment is supportive and often includes seizure control, physical and speech therapy, and a “mitochondrial cocktail” of vitamins and cofactors.

COXPD14 most often starts in the newborn period or early infancy. Babies may show severe developmental delay, seizures that are hard to control, and high lactic acid levels in the blood, which is a sign that cells are not making energy in a normal way. [3] Some people, however, present later in childhood or even adulthood with milder but still serious symptoms, such as stiff, weak legs or repeated seizures. [4]

Other Names

This disorder appears in the medical literature under several different names. All these names describe the same basic problem – energy failure due to FARS2-related mitochondrial dysfunction. [4]

Common other names include: [4][5]

• Combined oxidative phosphorylation deficiency 14 (COXPD14)

• Combined oxidative phosphorylation defect type 14

• FARS2 combined oxidative phosphorylation deficiency

• Combined oxidative phosphorylation deficiency caused by mutation in FARS2

• FARS2 deficiency

• Mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) deficiency

Some older reports may also call the severe early form “Alpers-like encephalopathy due to FARS2,” because the brain changes can resemble Alpers syndrome. [5] These different labels can be confusing, but they all point back to the same underlying gene, FARS2, and the same main problem: poor mitochondrial energy production. [5][6]

Types

Doctors now understand that FARS2-related combined oxidative phosphorylation deficiency is not just one single pattern, but a spectrum of disease. The severity and age at which symptoms begin can be very different from person to person, even within the same family. [6]

The main clinical types (phenotypes) described are:

1. Infantile-onset epileptic mitochondrial encephalopathy
   This is the most common and usually the most severe type. Babies start to have seizures within the first months of life. The seizures are often frequent, difficult to control, and may progress to status epilepticus (long or repeated seizures). There is usually profound developmental delay, poor head control, low muscle tone (hypotonia), and high lactic acid in blood or cerebrospinal fluid. Many children with this type have a poor survival. [1][6]

2. Later-onset spastic paraplegia (SPG77)
   In this type, children or teenagers may first look fairly well, then slowly develop stiffness and weakness in the legs, trouble walking, and exaggerated reflexes. [6][7] The main problem is in the long nerve pathways in the spinal cord, so thinking and learning can be more mildly affected. This type is often less severe and people may live to adulthood, although walking can become harder over time. [7]

3. Juvenile-onset refractory epilepsy
   Some patients develop seizures later in childhood or adolescence, instead of in early infancy. Their seizures can still be frequent and hard to control, but overall growth and development may be better than in the infantile form. Brain imaging and blood lactate may still show mitochondrial dysfunction. [8]

4. Adult-onset epileptic status phenotype
   A few reported adults had FARS2 mutations and presented mainly with episodes of status epilepticus (very long seizures) but otherwise milder symptoms and better outcome. [9] This shows that FARS2-related disease can sometimes remain hidden until later life and then appear suddenly under stress. [9]

These types overlap. Many patients show features from more than one group, and experts think of them as points on a continuous spectrum rather than completely separate diseases. [6][9]

Causes

The root cause of this disease is always a problem in the FARS2 gene, but there are many ways this can happen and many factors that can change how severe the disease becomes. [1]

1. Homozygous pathogenic FARS2 variants
   Many patients have the same harmful change (variant) in both copies of their FARS2 gene – one from each parent. This is called a homozygous variant and it strongly reduces the function of the FARS2 enzyme in mitochondria. [1][6]

2. Compound heterozygous FARS2 variants
   Some people inherit two different harmful FARS2 variants, one on each copy of the gene. This is called compound heterozygosity. The two variants together reduce FARS2 activity enough to cause disease. [2][8]

3. Missense mutations in the catalytic domain
   A missense mutation changes one amino acid in the protein. When this happens in the “catalytic” part of FARS2 – the part that does the chemical work of attaching phenylalanine to tRNA – the enzyme may work much more slowly or not at all. [6][10]

4. Missense mutations in the tRNA-binding domain
   Some mutations affect the region that binds mitochondrial tRNA(Phe). If the tRNA cannot bind properly, the enzyme cannot put phenylalanine in the right place, and mitochondrial protein synthesis fails. [3][10]

5. Splice-site variants
   Splice-site changes occur in the parts of the gene that tell the cell how to cut and join the RNA. These can lead to missing exons or frameshifts, and the cell makes an abnormal or very short FARS2 protein. [6]

6. Exon deletions or duplications
   Large deletions or duplications remove or repeat whole exons. This usually disrupts the reading frame and produces a truncated, non-functional enzyme. Patients with one such severe variant and one milder missense change can still survive but often with severe disease. [6]

7. Founder mutations (for example, p.Tyr144Cys)
   In some populations, one specific FARS2 variant is found in many unrelated families because it started from a common ancestor (founder effect). The p.Tyr144Cys change has been reported many times and is linked with a severe infantile epileptic phenotype. [6][8]

8. Mutations affecting the mitochondrial targeting sequence
   FARS2 protein must be imported into mitochondria. Variants near the start of the protein can damage the targeting signal, so less FARS2 reaches the mitochondria, and energy production suffer. [3][11]

9. Mutations that destabilize the enzyme structure
   Some amino acid changes make the protein fold incorrectly or become unstable. The cell may break down this misfolded protein quickly, leaving too little working enzyme. [10]

10. Reduced charging of mitochondrial tRNA(Phe)
    No matter where the mutation sits, the final effect is often the same: FARS2 does not attach phenylalanine efficiently to mitochondrial tRNA. This step is vital for building mitochondrial proteins, so all oxidative phosphorylation complexes can be affected. [3][11]

11. Defective mitochondrial protein synthesis
    When mitochondrial proteins cannot be made correctly, complexes I–IV of the respiratory chain become weak. This is why the disease is called “combined oxidative phosphorylation deficiency.” [1][2]

12. Autosomal recessive inheritance with carrier parents
    Parents of an affected child are usually healthy carriers. Each pregnancy has a 25% chance of being affected. The inheritance pattern itself is a key cause of how the disease appears in families. [2][6]

13. High consanguinity (parents related by blood)
    In some reports, parents were cousins or from small communities. This increases the chance that both parents carry the same rare FARS2 variant, so the child is more likely to be homozygous. [6][10]

14. Modifier genes in other mitochondrial pathways
    Other genetic changes in mitochondrial or nuclear genes can make the FARS2 defect better or worse. These “modifier genes” may partly explain why some people have milder disease than others with similar FARS2 variants. [8][9]

15. Intercurrent infections and fever as triggers
    In a child who already has FARS2 deficiency, infections and fever put extra stress on the body and can trigger metabolic crises, seizures, or rapid worsening. These are not root causes but important precipitating factors. [1]

16. Poor nutrition or prolonged fasting
    Long periods without food or poor calorie intake force the body to rely even more on mitochondrial energy pathways. In FARS2 deficiency, this can worsen lactic acidosis and symptoms. [1][12]

17. High energy demand in early brain development
    The newborn brain needs a lot of energy. Because FARS2 deficiency hits mitochondrial ATP production, this high demand period can unmask the disease very early with seizures and developmental problems. [1][7]

18. Liver vulnerability to mitochondrial defects
    The liver is a major energy-using organ. In some patients, FARS2 deficiency causes liver failure, especially during infections or metabolic stress, because the liver cannot keep up with detox and glucose control. [11][12]

19. Accumulation of lactic acid and other metabolites
    When oxidative phosphorylation is weak, cells switch to less efficient energy production, which makes lactic acid. High lactate damages tissues further and contributes to many symptoms. [1][11]

20. Unknown environmental and epigenetic factors
    Even with the same FARS2 variants, some siblings can be more or less affected. This suggests that unknown environmental factors and epigenetic changes (how genes are switched on or off) also contribute to disease severity. [8][9]

Symptoms

Because mitochondria are in almost every cell, FARS2-related oxidative phosphorylation deficiency can affect many body systems, especially brain and liver. Not everyone has every symptom, but these are common features. [1][6]

1. Global developmental delay
   Children may learn skills such as smiling, rolling, sitting, or walking much later than expected. Some may never learn to sit or walk without support. Thinking, talking, and social skills are often delayed as well. [1][11]

2. Early-onset seizures
   Many babies start to have seizures within the first months of life. The seizures can be different types, including jerking movements, stiffening, or staring spells, and they may happen many times a day. [1][6]

3. Refractory or intractable epilepsy
   Seizures in this disease are often hard to control, even with several anti-seizure medicines. Status epilepticus (very long seizures) is common and can lead to further brain injury. [4][9]

4. Early-onset encephalopathy
   Encephalopathy means global brain dysfunction. Babies can be very sleepy, unresponsive, or irritable, with poor eye contact and weak responses to sounds or touch. This reflects widespread brain energy failure. [1][8]

5. Hypotonia (low muscle tone)
   Many infants feel “floppy” when held, with poor head control and weak trunk muscles. This low tone comes from both brain involvement and, in some cases, direct muscle mitochondrial dysfunction. [1][12]

6. Spasticity and spastic paraplegia
   In later-onset cases, leg muscles may become stiff and tight. Reflexes become exaggerated, and walking becomes clumsy or impossible. This pattern is called spastic paraplegia and reflects long-tract damage in the spinal cord. [6][7]

7. Microcephaly (small head size)
   Some children develop a head size that is smaller than normal for their age. This often reflects poor brain growth due to chronic energy shortage. [1][12]

8. Poor feeding and failure to thrive
   Babies may not suck well, tire easily during feeds, or vomit frequently. Over time, they may not gain weight or grow as expected, which is called failure to thrive. [1][4]

9. Lactic acidosis
   High levels of lactic acid in blood or cerebrospinal fluid are a key sign of mitochondrial energy failure. Clinically, this may show as fast breathing, vomiting, and extreme tiredness, especially during illness. [1][11]

10. Liver dysfunction or liver failure
    Some patients develop enlarged liver, jaundice, abnormal liver enzymes, or even acute liver failure. The liver is very sensitive to defects in oxidative phosphorylation. [11]

11. Abnormal movements and tone patterns
    In addition to seizures and spasticity, there may be tremor, myoclonus (sudden jerks), or dystonia (twisting movements and postures), reflecting widespread involvement of motor control circuits in the brain. [8]

12. Ataxia and poor coordination
    Some individuals, especially in later-onset forms, have trouble with balance and coordination. They may walk with a wide-based gait or have difficulty with fine hand movements. [7]

13. Hearing and vision problems
    A few reports describe hearing loss or visual impairment, likely from damage to the nerves or pathways serving these senses. These problems can add to communication and learning difficulties. [11][12]

14. Anemia and thrombocytopenia
    Some patients develop low red blood cell counts (anemia) and low platelets (thrombocytopenia), probably because the bone marrow is also affected by mitochondrial dysfunction. This can cause tiredness, pallor, and easy bruising. [1][12]

15. Shortened life span in severe early-onset forms
    In the most severe infantile cases, repeated seizures, lactic acidosis, and liver failure can lead to death in early childhood, despite supportive care. Milder later-onset forms can have near-normal survival but with lifelong disability. [1][6]

Diagnostic Tests

Because this is a complex mitochondrial disease, diagnosis usually needs a combination of clinical examination, laboratory tests, electrodiagnostic studies, imaging, and finally genetic testing. [6]

Physical Examination Tests

1. General neurological examination
   The doctor looks at how the child responds, moves, and behaves. They check alertness, muscle tone, strength, reflexes, and coordination. In FARS2-related COXPD14, they may find low tone in infants, brisk reflexes, abnormal movements, and signs of encephalopathy. This basic exam guides which further tests are needed. [6][7]

2. Growth and nutrition assessment
   Height, weight, and head circumference are measured and compared with age-matched charts. Poor weight gain, small head size, or falling off the growth curve can suggest chronic energy failure and malnutrition related to mitochondrial disease. [1][12]

3. Musculoskeletal and posture assessment
   The examiner observes posture, spine alignment, and joint range of motion. Floppy posture in early infancy or later stiff, scissoring legs can point toward hypotonia or spastic paraplegia as part of FARS2 deficiency. [6][7]

4. Developmental milestone review
   Doctors or therapists ask detailed questions about when the child first smiled, rolled, sat, walked, and spoke. Marked delay or regression of milestones is a major clue to an early-onset mitochondrial encephalopathy such as COXPD14. [1][11]

Manual (Bedside Functional) Tests

5. Manual muscle strength testing
   In older children and adults, strength can be graded by asking them to push or pull against the examiner’s hands. Weakness in the legs with increased tone fits a spastic paraplegia pattern seen in some FARS2 patients. [6][7]

6. Gait and spasticity assessment
   When the child can walk, the clinician watches their gait and may use simple bedside maneuvers (such as stretching muscles) to feel resistance. A stiff, scissoring gait and high resistance to movement suggest spasticity related to corticospinal tract involvement. [6]

7. Coordination tests (finger-to-nose, heel-to-shin)
   These simple tasks test the cerebellum and coordination. In FARS2 deficiency with cerebellar involvement, movements may be shaky or inaccurate, pointing to mitochondrial damage in coordination centers. [7][8]

8. Cranial nerve bedside tests
   Checking eye movements, facial symmetry, hearing, swallowing, and tongue movement can reveal subtle nerve problems. Abnormal findings may signal brainstem or cranial nerve involvement in the mitochondrial disease. [11][12]

Laboratory and Pathological Tests

9. Blood lactate and pyruvate levels
   High lactate and altered lactate-to-pyruvate ratio are classic biochemical markers of mitochondrial oxidative phosphorylation defects. In COXPD14, many patients show persistently elevated lactate, especially during illness or seizures. [1][11]

10. Serum amino acids and acylcarnitine profile
    These tests screen for other inborn errors of metabolism and can show patterns suggesting mitochondrial dysfunction. While not specific for FARS2, they help rule out alternative diagnoses and may show secondary changes due to energy failure. [12]

11. Plasma or urine organic acids
    Organic acid analysis can reveal elevated metabolites related to lactic acidosis and mitochondrial dysfunction. Abnormal results support the diagnosis of a respiratory chain disorder, although they do not identify the exact gene. [12]

12. Complete blood count and liver function tests
    These tests can show anemia, thrombocytopenia, and liver enzyme abnormalities that are reported in many FARS2-related cases. Combined neurological and liver or blood findings raise suspicion for a multisystem mitochondrial disease. [1][12]

13. Respiratory chain enzyme analysis in muscle or fibroblasts
    In some patients, a biopsy of muscle or skin cells is used to measure the activity of mitochondrial respiratory chain complexes. In COXPD14, multiple complexes may show reduced activity, confirming a combined oxidative phosphorylation defect. [1][11]

14. Genetic testing of the FARS2 gene (panel, exome, or genome)
    The final and most specific test is DNA sequencing. This may be done as a targeted FARS2 test, part of a mitochondrial gene panel, or through whole-exome or whole-genome sequencing. Finding biallelic pathogenic FARS2 variants confirms the diagnosis. [2][6]

Electrodiagnostic Tests

15. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity. In infantile FARS2-related encephalopathy, EEG often shows frequent epileptic discharges, sometimes a chaotic pattern called hypsarrhythmia, and evidence of status epilepticus. This helps document the severity and type of epilepsy. [4][5]

16. Nerve conduction studies (NCS)
    NCS measure the speed and size of signals in peripheral nerves. While not always abnormal, they can detect peripheral neuropathy in some mitochondrial diseases and help distinguish central from peripheral causes of weakness or sensory symptoms. [6]

17. Electromyography (EMG)
    EMG looks at electrical activity in muscles. In mitochondrial myopathies, EMG can show non-specific myopathic changes. This can support the idea that both brain and muscle are affected by the underlying FARS2 defect. [6][11]

Imaging Tests

18. Brain MRI
    MRI is a key tool. In FARS2-related COXPD14, scans may show cortical and subcortical signal changes, basal ganglia involvement, white matter abnormalities, or cortical atrophy. In some severe cases, neuropathology reveals laminar cortical necrosis, similar to Alpers syndrome. [1][11]

19. Magnetic resonance spectroscopy (MRS)
    MRS can be added to MRI to measure chemicals in the brain. A lactate peak on MRS can support the suspicion of mitochondrial energy failure, especially in a child with elevated blood lactate and seizures. [12]

20. Liver ultrasound or MRI
    Imaging of the liver can show enlargement, abnormal texture, or signs of liver failure in patients with significant hepatic involvement. Combined liver and brain findings strengthen the case for a multisystem mitochondrial disorder like COXPD14. [11][12]

Non-pharmacological (non-drug) treatments –

1. Multidisciplinary care team
Care is safest when a team works together. This usually includes a metabolic specialist, neurologist, pediatrician, physiotherapist, occupational therapist, speech therapist, dietitian, and sometimes a genetic counselor and psychologist. The team coordinates seizure care, nutrition, movement, and learning support, and reviews changes over time. A shared care plan helps families know what to do in everyday life and in emergencies such as infections or seizures.

2. Genetic counseling and family planning
Genetic counseling explains that FARS2 deficiency is usually autosomal recessive, meaning both parents carry one non-working copy of the gene. Counselors discuss recurrence risk for future pregnancies, offer carrier testing to relatives, and can discuss options such as prenatal diagnosis or pre-implantation genetic testing if desired. They also help families understand prognosis, research options, and registries. This support can reduce anxiety and improve long-term planning.

3. Regular monitoring and follow-up
Because symptoms can change, regular clinic visits are very important. Doctors usually monitor growth, development, seizure control, muscle tone, spasticity, vision, hearing, liver function, and sometimes heart function. Blood tests may include lactate and liver enzymes, and brain MRI may be repeated when needed. Watching trends over time helps adjust therapies, detect complications early, and decide if new treatments or supportive devices are needed.

4. Physiotherapy for strength and movement
Physiotherapy aims to reduce weakness, contractures (fixed joint stiffness), and spasticity. Gentle stretching, positioning, and guided exercises can maintain joint range of motion and improve sitting, standing, or walking ability. For children with spastic paraplegia, physiotherapy supports gait training and balance. Regular therapy may also delay secondary problems such as scoliosis or hip dislocation.

5. Occupational therapy and daily-living support
Occupational therapists focus on skills such as feeding, dressing, writing, and playing. They can suggest splints, adaptive cutlery, special seats, or bathroom aids. The goal is to make daily activities easier and safer, and to support independence at whatever level the child or adult can reach. This also reduces caregiver burden and improves quality of life.

6. Speech and feeding therapy
Many children with FARS2 deficiency have delayed speech or trouble swallowing. Speech-language therapists can use exercises, picture communication boards, or augmentative and alternative communication (AAC) devices. For feeding problems, they teach safe swallowing positions and textures to reduce choking and aspiration. Early intervention supports communication, nutrition, and social development.

7. Nutritional assessment and high-energy diet
A dietitian familiar with mitochondrial disease can calculate energy and protein needs, suggest frequent small meals, and add calorie-dense foods or formulas. The aim is to prevent malnutrition and support growth while avoiding long fasting times that can trigger metabolic decompensation. In some cases, special formulas or feeding tubes are needed for adequate nutrition and medication delivery.

8. Avoidance of fasting and catabolic stress
Because mitochondria are already weak, long fasting, dehydration, and severe infections can push the body into “catabolic” mode, breaking down its own tissues for energy. Families are often given a “sick day plan” that explains when to give extra fluids or carbohydrates and when to seek hospital care for IV glucose during vomiting or high fever. This reduces risk of lactic acidosis and regression.

9. Seizure safety education and emergency plans
Caregivers learn how to recognize seizures, keep the airway safe, time seizures, and use rescue medicines prescribed by the neurologist. An emergency action plan describes when to give rescue medicine and when to call an ambulance. Older children and adults can be taught how to avoid known seizure triggers such as sleep deprivation, flashing lights, or missed doses.

10. Spasticity management with therapy and positioning
In later-onset spastic paraplegia, stiffness and tight muscles can make walking painful and unsafe. Physiotherapists and physiatrists (rehabilitation doctors) use stretching programs, standing frames, night splints, and sometimes serial casting to keep joints as flexible as possible. This can be combined with medications or injections if needed.

11. Assistive devices for mobility and posture
Depending on weakness and spasticity, people may benefit from ankle–foot orthoses, walkers, canes, wheelchairs, or custom seating systems. Good seating prevents pressure sores and helps with breathing and feeding. Mobility aids improve participation at school, home, and in the community, even if independent walking is not possible.

12. Respiratory physiotherapy and airway support
If breathing muscles are weak or seizures affect breathing, respiratory therapists may teach airway clearance techniques, such as chest physiotherapy or assisted coughing devices. Non-invasive ventilation (like BiPAP) can be used at night in some patients. The goal is to prevent infections, improve sleep quality, and maintain oxygen and carbon dioxide at safe levels.

13. Vision and hearing support
Some people with mitochondrial disease have visual or hearing problems related to optic neuropathy or central brain involvement. Early ophthalmology and audiology checks allow glasses, low-vision aids, hearing aids, or cochlear implants to be considered. Better sensory input helps development, communication, and learning.

14. Special education and individualized learning plans
Children with cognitive delay or motor disability may need individualized education plans (IEPs) or similar supports in school. Smaller class sizes, one-to-one aides, extra time for tasks, and assistive technology (like tablets or eye-gaze devices) can make learning more accessible. Early school support improves long-term skills and social inclusion.

15. Psychological and social support
Living with a rare, chronic disease is stressful for patients and families. Psychologists, social workers, and peer support groups can help with coping strategies, anxiety, depression, and grief. They also assist families in accessing financial support, respite care, and community services. Good mental health care improves overall quality of life.

16. Palliative and supportive care when disease is severe
Palliative care does not mean “giving up.” It focuses on comfort, symptom control, and family goals at any stage of illness. A palliative team can help manage pain, breathing difficulties, feeding issues, and sleep problems, and can support parents in making complex decisions. This care can be given alongside active treatments.

17. Home and environmental adaptations
Simple changes at home, such as ramps, grab bars, non-slip bathroom floors, and hospital-style beds, can greatly improve safety and independence. These changes reduce falls, make transfers easier, and decrease caregiver strain. Occupational therapists can visit the home and suggest practical modifications tailored to each family.

18. Telehealth and online therapy services
Telemedicine allows families who live far from specialist centers to access metabolic, neurology, and therapy consultations from home. Online physiotherapy, occupational therapy, or speech sessions can continue even when travel is difficult. For rare diseases like FARS2 deficiency, telehealth may connect families with highly specialized clinics in other regions.

19. Participation in registries and research
Because FARS2 deficiency is extremely rare, each patient’s information is very valuable for research. When families consent, clinical data can be entered into mitochondrial disease registries or natural history studies. This helps researchers understand how the disease changes over time and design clinical trials for new treatments.

20. Family education about drugs and anesthetic risks
Some medicines (for example, certain valproate regimens or prolonged high-dose propofol) may be risky in mitochondrial disease. Families should carry a written “mitochondrial anesthesia and medication alert” for use in emergencies and surgeries. This helps healthcare teams choose safer drugs and monitor more closely.

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Drug treatments

There is no drug currently approved specifically to cure FARS2 deficiency. Most medicines are used to control seizures or support mitochondrial function. Doses must always follow the official label and your specialist’s advice.

1. Levetiracetam (KEPPRA / SPRITAM)
Levetiracetam is a broad-spectrum anti-seizure medicine often chosen in mitochondrial diseases because it has relatively few interactions and a neutral effect on mitochondria. It is used in partial-onset, myoclonic, and generalized seizures. Typical dosing is weight-based and given twice daily, adjusted slowly by the neurologist. Common side effects include sleepiness, dizziness, and mood or behavior changes, so families are advised to watch for irritability or depression.

2. Topiramate (TOPAMAX)
Topiramate is another broad-spectrum anti-seizure drug used as monotherapy or add-on therapy in children and adults with epileptic encephalopathy. It works by blocking voltage-dependent sodium channels, enhancing GABA activity, and inhibiting certain glutamate receptors, which calms over-excitable brain cells. It is usually started at a low dose and increased slowly to limit side effects like appetite loss, weight loss, tingling in fingers or toes, and cognitive slowing, which can be problematic in children with developmental delay.

3. Valproic acid / valproate (DEPAKENE / DEPACON)
Valproate is a powerful anti-seizure drug that increases brain GABA levels and blocks sodium and calcium channels. It can control many seizure types but must be used very cautiously in mitochondrial disease because of risk of liver failure, pancreatitis, thrombocytopenia, and hyperammonemia. Some experts avoid valproate entirely in suspected mitochondrial disorders, especially in children. When used, doctors use the lowest effective dose, frequent liver tests, and careful monitoring.

4. Diazepam (VALIUM; diazepam injection or autoinjector)
Diazepam is a benzodiazepine used as a rescue medicine for prolonged seizures or seizure clusters. It enhances GABA’s inhibitory effect in the brain, rapidly reducing abnormal electrical activity. Rectal, buccal, nasal, or injectable forms may be prescribed for emergencies at home or in hospital. Side effects include sleepiness, breathing depression (especially with other sedatives), and risk of dependence with frequent use, so it is reserved for specific emergency plans.

5. Midazolam injection / autoinjector
Midazolam is a fast-acting benzodiazepine often used for status epilepticus (very long or repeated seizures). It can be given IV, IM, buccally, or intranasally. It works like diazepam, enhancing GABA, but has a shorter duration. Autoinjector devices are designed for trained caregivers. Side effects include breathing depression and low blood pressure, so monitoring in medical settings is important.

6. Levocarnitine (CARNITOR)
Levocarnitine is a natural compound that helps transport long-chain fatty acids into mitochondria for energy production. In primary carnitine deficiency it is approved as a drug, and many mitochondrial specialists also use it empirically in disorders like FARS2 deficiency to support energy metabolism or treat carnitine depletion from certain anti-seizure drugs. It is available orally and intravenously. Side effects can include diarrhea and a fishy body odor; high doses may rarely worsen heart or vascular disease, so dosing is individualized.

7. Riboflavin (Vitamin B2) – prescription formulations
Riboflavin is a key cofactor for mitochondrial enzyme complexes. High-dose riboflavin is used in several mitochondrial and metabolic disorders to support oxidative phosphorylation. Intravenous multivitamin solutions used in hospitals contain riboflavin and can correct deficiency in acutely ill patients who cannot eat. Side effects are usually mild, such as bright yellow urine. The exact dose in FARS2 deficiency is not standardized and is chosen by metabolic specialists.

8. Thiamine (Vitamin B1)
Thiamine is another vitamin cofactor used in mitochondrial “cocktails,” especially because thiamine-dependent enzymes feed into the Krebs cycle and electron transport chain. Intravenous or high-dose oral thiamine is used in some mitochondrial encephalopathies and during metabolic crises. It is generally safe, though rare allergic reactions to IV thiamine can occur, so it is given under supervision.

9. Pyridoxine (Vitamin B6)
Pyridoxine participates in many enzymatic reactions, including neurotransmitter synthesis. Certain epilepsies respond dramatically to vitamin B6 (pyridoxine-dependent epilepsy), so specialists sometimes try pyridoxine in hard-to-treat seizures. Injectable and multivitamin formulations are regulated as drugs. Very high, long-term doses can cause sensory neuropathy, so doctors limit dose and duration.

10. Coenzyme Q10 (Ubiquinone)
Coenzyme Q10 is an antioxidant and key electron carrier in the mitochondrial respiratory chain. It is widely used in primary mitochondrial disorders to support ATP production and reduce oxidative stress, though high-quality trials are limited. It is usually given orally in divided doses with fat-containing meals to improve absorption. Side effects are generally mild (stomach upset, appetite loss), but pure pharmaceutical-grade preparations are preferred when possible.

11. Creatine monohydrate
Creatine acts as an energy buffer in muscle and brain by regenerating ATP from ADP through the creatine kinase system. In mitochondrial disorders, supplemental creatine may improve exercise tolerance and muscle strength in some patients. It is available as a powder and is usually mixed with liquids. Side effects can include weight gain from water retention and, rarely, kidney strain in people with kidney disease, so kidney function is monitored.

12. L-arginine
L-arginine is used in some mitochondrial diseases (such as MELAS) to treat or prevent stroke-like episodes, likely by improving nitric oxide-mediated blood flow in small arteries. Although FARS2 deficiency is different, some clinicians extrapolate this approach for severe lactic acidosis or vascular events on a case-by-case basis. IV arginine is given in hospital; oral forms are sometimes used for prophylaxis. Side effects include nausea, low blood pressure, and electrolyte changes.

13. L-phenylalanine supplementation (emerging, experimental)
A small N-of-1 trial in a child with FARS2 deficiency reported improvement in motor skills, movement, and postural stability with oral L-phenylalanine, the amino acid that FARS2 normally attaches to tRNA in mitochondria. During a withdrawal period, skills regressed but returned after restarting. This suggests that providing extra phenylalanine might partially bypass the enzyme defect. This remains experimental and must only be tried within specialist care or clinical studies.

14. Folate (Folic acid) and related vitamins
Folate supports one-carbon metabolism and nucleotide synthesis, which are important for mitochondrial DNA repair and cell division. Many mitochondrial “cocktails” include folic acid or active folate forms, especially in patients with elevated homocysteine or nutritional risk. It is usually well tolerated; very high doses may mask vitamin B12 deficiency, so doctors monitor blood counts and B12 levels.

15. Antispasticity agents (e.g., baclofen)
For patients with later-onset FARS2-related spastic paraplegia, drugs like baclofen may help reduce muscle stiffness and spasms. Baclofen acts as a GABA-B agonist in the spinal cord, reducing excitatory transmissions. Oral baclofen can cause sleepiness and weakness; intrathecal pumps are reserved for severe cases. Botulinum toxin injections into specific muscles are another option in specialized centers.

16. Proton-pump inhibitors or H2 blockers (for reflux)
Some children with severe neurological impairment have reflux, vomiting, or feeding intolerance. Acid-suppressing drugs can protect the esophagus and improve comfort, indirectly supporting nutrition and medication adherence. These drugs do not treat the mitochondrial defect itself, but they improve overall wellbeing. Long-term use should be reviewed regularly because of possible effects on mineral absorption and infection risk.

17. Antiemetics and prokinetics
During metabolic crises or chronic feeding problems, anti-nausea medicines and drugs that improve stomach emptying may be used to keep oral nutrition and medicines down. Choices depend on age and cardiac risk. They help prevent dehydration and catabolic stress but should be used at the lowest effective dose and stopped when stable.

18. Antibiotics for infections (as needed)
Infections can rapidly worsen mitochondrial disease by increasing energy demands and reducing intake. Prompt, appropriate antibiotics for bacterial infections, guided by local guidelines, are critical supportive therapy. Doctors carefully pick drugs, avoiding those with higher mitochondrial or neuromuscular toxicity when alternatives exist. Good infection control may prevent irreversible regression after severe illnesses.

19. Intravenous fluids with dextrose during acute illness
When a patient with FARS2 deficiency cannot eat or drink because of vomiting or serious infection, hospital teams often give IV fluids containing glucose to prevent hypoglycemia and catabolism. They may add electrolytes, vitamins, and, when needed, bicarbonate to correct acidosis. This is a key supportive “drug therapy” in emergency care, planned in advance in an individualized emergency letter.

20. Standard vaccines and, when indicated, monoclonal antibodies or antivirals
Vaccines are medications that safely train the immune system. Routine childhood vaccines and additional influenza and pneumococcal vaccines help prevent serious infections that could trigger decompensation in mitochondrial disease. During respiratory virus seasons, doctors may also consider monoclonal antibody prophylaxis or early antivirals in high-risk children if available locally.

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Dietary molecular supplements

1. Coenzyme Q10
As described above, CoQ10 supports the mitochondrial electron transport chain and acts as an antioxidant. In diet-style supplementation, it is usually given as softgels or oil-based liquids. The functional goal is to improve ATP production and reduce oxidative damage. Benefits are variable, but it is widely used because of its biological role and generally mild side-effect profile.

2. L-carnitine
Dietary L-carnitine can be given as a supplement to support fatty acid transport into mitochondria. It may be especially important if blood tests show low carnitine or if the patient uses valproate, which can deplete carnitine. Mechanistically, it helps shuttle long-chain fatty acids into mitochondria and remove toxic acyl groups.

3. L-phenylalanine
In FARS2 deficiency, phenylalanine is the “cognate” amino acid for the defective enzyme. Controlled L-phenylalanine supplementation, as studied in a small trial, may increase substrate availability and partially improve mitochondrial protein synthesis. The supplement is usually given as measured capsules or powders. This is still experimental and should only be done under a metabolic specialist’s supervision.

4. Riboflavin (Vitamin B2)
Dietary riboflavin is found in dairy, meat, and fortified foods, but higher pharmacologic doses are often used as supplements in mitochondrial disease. Functionally, it forms FAD and FMN, which are required for complex I and II activity in the respiratory chain. It may slightly improve muscle strength or reduce lactic acidosis in some patients, though evidence is limited.

5. Thiamine (Vitamin B1)
Supplemental thiamine supports pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key enzymes connecting glycolysis to the Krebs cycle. In mitochondrial disorders, thiamine may help the body use glucose more efficiently and reduce lactate. It is usually well tolerated, and dietary sources include whole grains, beans, and meat, but higher doses are often given as tablets.

6. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant and cofactor for mitochondrial dehydrogenase complexes. As a supplement, it may reduce oxidative stress and support mitochondrial metabolism. Some small studies suggest benefits in neuropathy and metabolic diseases. Side effects include stomach upset and, rarely, low blood sugar, so it should be monitored, especially in children.

7. Creatine monohydrate
Creatine, as noted, acts as a phosphate reservoir to re-generate ATP quickly. Dietary creatine supplementation aims to improve short-term energy availability in muscle and possibly brain. It is usually mixed with water or juice and taken daily. Long-term kidney safety is generally good in healthy individuals, but mitochondrial patients should have kidney function checked.

8. L-arginine and/or L-citrulline
L-arginine and its precursor L-citrulline can support nitric oxide production and vascular function. In some mitochondrial diseases, they are used to manage metabolic strokes and severe lactic acidosis. As dietary supplements, they are powders or capsules, often divided into doses with meals. Blood pressure and potassium levels should be monitored.

9. N-acetylcysteine (NAC)
NAC is a precursor of glutathione, one of the body’s main antioxidants. It may help mop up reactive oxygen species in mitochondrial disease, reducing oxidative damage to lipids, proteins, and DNA. NAC is available as effervescent tablets or capsules. Side effects include nausea and, with IV forms, rare allergic-type reactions.

10. Omega-3 fatty acids (EPA/DHA)
Omega-3 fatty acids from fish oil or algae may support neuronal membrane health and have anti-inflammatory effects. In children with neurodevelopmental disorders, they are sometimes used as adjuncts for cognitive and behavioral symptoms, though evidence is mixed. They can thin the blood slightly, so high doses require medical advice, especially if combined with anticoagulants.

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

At present, there are no approved gene or stem-cell drugs specifically for FARS2 deficiency. The options below are research concepts or general approaches, not standard care.

1. Experimental gene therapy concepts
In theory, delivering a working FARS2 gene to mitochondria could correct the enzyme defect. Researchers are exploring viral vectors and mitochondrial-targeted gene delivery for related diseases, but this is still in preclinical or very early clinical stages. Families may hear about such work in research updates, but these therapies are not yet available in routine practice.

2. Hematopoietic stem cell transplantation (HSCT) – theoretical
HSCT has been used in some mitochondrial and immune diseases to replace defective blood-forming cells. For FARS2 deficiency, there is currently no evidence that HSCT changes the course, because the main problem is in neurons and other tissues, not just blood cells. HSCT carries major risks, so it is not recommended outside of carefully designed research.

3. Mesenchymal stem cell infusions – experimental
Mesenchymal stem cells (MSCs) have been studied in various neurodegenerative and metabolic diseases for their potential anti-inflammatory and trophic effects. For FARS2 deficiency, there is no strong evidence yet. Any offers of “stem cell cures” outside of regulated clinical trials should be viewed with extreme caution.

4. Immune-modulating biologics for associated autoimmune features
If a person with FARS2 deficiency also develops autoimmune problems, standard immune-modulating drugs or biologics may be considered, but they treat the autoimmune disease, not the mitochondrial defect. The choice depends on the specific condition and must be led by specialists.

5. Neurotrophic or neuroprotective agents (research stage)
Various neuroprotective molecules (for example, antioxidants, growth factors, or mitochondria-targeted peptides) are being studied across mitochondrial and neurodegenerative diseases. Their aim is to protect neurons from energy failure and oxidative stress. None are approved specifically for FARS2 deficiency yet, but they may appear in future trials.

6. Clinical trial drugs and repurposed agents
Some trials test drugs already approved for other conditions (drug repurposing) to see if they help mitochondrial disease, including agents that improve mitochondrial biogenesis or antioxidant defenses. When appropriate, families can discuss clinical trial participation with their specialists. This is the safest way to access experimental regenerative or “booster” treatments.

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Surgeries and procedures

1. Gastrostomy tube (G-tube) placement
If feeding by mouth is unsafe or not enough, surgeons can place a gastrostomy tube directly into the stomach. This allows reliable delivery of calories, water, and medicines, and reduces the risk of aspiration pneumonia from repeated choking. The procedure is usually done under general anesthesia with careful planning because of the mitochondrial disease.

2. Tracheostomy
In severe cases with chronic breathing failure or repeated aspiration, a tracheostomy (a breathing tube in the neck) may be needed. This allows better airway clearance and connection to ventilators. It is a major decision and requires intensive training and support for families, but can improve comfort and safety in selected patients.

3. Orthopedic surgery for contractures and scoliosis
Children with long-standing spasticity or weakness can develop joint contractures, hip dislocation, or scoliosis. Orthopedic surgery (such as tendon lengthening, hip reconstruction, or spinal fusion) may improve seating, caregiving, and pain. The goals are comfort and function, not cure of the underlying disease. Anesthesia plans must account for mitochondrial risk.

4. Botulinum toxin injections
While not a “surgery,” botulinum toxin injections into specific spastic muscles are often delivered in operating or procedure rooms. They temporarily weaken overactive muscles, making stretching, bracing, and physiotherapy more effective. Effects last a few months and can be repeated. This can improve gait or ease of care in spastic paraplegia.

5. Implantation of intrathecal baclofen pump
For severe generalized spasticity, an intrathecal baclofen pump can be surgically placed to deliver baclofen directly into the spinal fluid. This allows lower doses than oral treatment and better spasticity control in some patients. It requires regular refills and pump checks. The decision depends on overall health, life expectancy, and family goals.

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Prevention and lifestyle strategies

1. Prompt treatment of infections – Early medical review and treatment of fever, cough, or vomiting reduce the risk of metabolic crises and regression.

2. Avoidance of prolonged fasting – Following a sick-day plan with extra carbohydrates and shorter fasting times helps prevent hypoglycemia and lactic acidosis.

3. Keeping vaccinations up to date – Routine and additional vaccines lower the chance of serious infections that might destabilize mitochondrial function.

4. Adequate sleep and seizure trigger management – Good sleep hygiene and regular medication schedules can reduce seizure frequency and daytime fatigue.

5. Safe, gentle physical activity – Within limits, regular low-intensity movement prevents deconditioning, improves mood, and may support mitochondrial biogenesis.

6. Sun and heat safety – Extreme heat or dehydration can increase metabolic stress; families should ensure shade, fluids, and rest in hot weather.

7. Avoiding smoking and secondhand smoke – Tobacco smoke increases oxidative stress and harms lungs and vessels, which is especially harmful in mitochondrial disease.

8. Careful planning for anesthesia and surgery – Carrying a written mitochondrial anesthesia plan helps prevent use of higher-risk drugs and ensures close monitoring.

9. Regular dental and oral care – Good oral health reduces infection risk and supports safe feeding, important in children with swallowing problems.

10. Family education and emergency letters – Written emergency letters and training for teachers and caregivers ensure everyone knows what to do during seizures or illness.

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When to see a doctor

People with FARS2 deficiency should have regular planned visits with their metabolic and neurology teams even when stable. However, urgent review is needed if there is a prolonged seizure, repeated seizures without full recovery, new breathing difficulty, vomiting and inability to keep fluids down, very poor feeding, sudden loss of skills, severe sleepiness, or unusual behavior change. Parents are often given clear thresholds (for example, seizure lasting more than 5 minutes, or fever with poor intake) that should trigger emergency care.

Any discussion about new medicines, supplements, or major diet changes should also happen with the team first, because some “natural” products can interfere with prescribed drugs or stress the liver or kidneys.

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Diet: what to eat and what to avoid

1. Prefer regular, small meals with complex carbohydrates to provide steady energy and avoid long gaps without food.

2. Include good-quality protein (eggs, fish, poultry, legumes) in each meal to support muscle repair and enzyme production.

3. Use healthy fats such as olive oil and omega-3-rich fish to support brain and nerve health, unless contraindicated for other reasons.

4. Add fruits and vegetables for natural vitamins, minerals, and antioxidants that help combat oxidative stress.

5. Ensure enough fluids (water and oral rehydration solutions during illness) to prevent dehydration and support circulation and kidney function.

6. Avoid long fasting periods, especially overnight in young children; some may need a late-evening snack or specialized feeds.

7. Limit ultra-processed foods high in sugar and trans fats, which can increase oxidative stress and provide “empty” calories.

8. Be cautious with very high-protein or ketogenic diets unless prescribed by a metabolic specialist for a specific reason, because they can stress kidneys or worsen acidosis in some mitochondrial conditions.

9. Avoid unregulated herbal supplements that claim to “cure” mitochondrial disease; some may harm the liver or interact with anti-seizure medicines.

10. Work closely with a metabolic dietitian, who can tailor the diet to the individual’s age, growth, activity level, and lab results.

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Frequently asked questions (FAQs)

1. Is FARS2 deficiency curable?
Right now, FARS2 deficiency is not curable. The underlying genetic change cannot yet be permanently fixed in routine care. Treatment focuses on controlling seizures, supporting nutrition and development, and preventing complications. Research into gene and amino acid-based therapies is active, and future treatments may change the outlook, but they are not yet ready for general use.

2. What is the life expectancy in FARS2 deficiency?
Life expectancy is very variable and depends on the severity of the brain involvement, seizure control, feeding and breathing problems, and access to supportive care. Some infants with severe epileptic encephalopathy have a poor prognosis, while others with later-onset spastic paraplegia may live into adulthood with significant disability. It is best to ask your team about the individual situation.

3. Does every FARS2 variant cause the same symptoms?
No. Different FARS2 mutations affect the enzyme in different ways, and other genetic and environmental factors also influence the phenotype. Some variants are linked mainly to early-onset epileptic encephalopathy, while others are more associated with spastic paraplegia, and some show overlapping features.

4. How is FARS2 deficiency diagnosed?
Diagnosis usually involves clinical evaluation, brain MRI, lactate and metabolic tests, and genetic testing using panels or exome sequencing. Enzyme studies and muscle biopsy are sometimes used. Genetic results confirming two pathogenic FARS2 variants inherited from each parent support the diagnosis.

5. Are there special tests to monitor treatment?
Doctors may monitor seizure frequency, developmental milestones, growth charts, lactate, liver enzymes, and carnitine levels. They may also repeat MRI or EEG studies to judge disease progression. For experimental therapies like L-phenylalanine, standardized motor and quality-of-life tests have been used in research.

6. Can children with FARS2 deficiency attend school?
Many children can attend school with supports, such as special education services, one-to-one aides, assistive devices, and flexible schedules. The level of participation depends on motor and cognitive abilities. Early collaboration between parents, therapists, and schools helps create an effective education plan.

7. Is it safe to vaccinate my child with FARS2 deficiency?
In general, vaccines are strongly recommended, because preventing infections is critical in mitochondrial disease. There are rare situations where certain live vaccines may be delayed or modified, so decisions should be made with the metabolic and primary care teams, but avoiding vaccines completely usually increases risk.

8. Are there medicines that must be avoided?
Some medicines, such as high-dose valproate, prolonged high-dose propofol, or certain aminoglycoside antibiotics, may be more risky in mitochondrial disease. However, the list is not the same for every patient. Families should carry an updated medication list and a mitochondrial safety card from their specialist.

9. Will my other children also have FARS2 deficiency?
If both parents are carriers of a non-working FARS2 gene, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier child, and 25% chance of a non-carrier child. Genetic counseling and testing can clarify the situation for each family member.

10. Can diet alone treat FARS2 deficiency?
Diet is very important but cannot cure the genetic defect. A good diet and careful feeding plan can reduce metabolic stress, support growth, and make other treatments more effective, but it must be combined with medical care, therapy, and sometimes medicines.

11. Should we try L-phenylalanine supplementation?
L-phenylalanine showed promising results in a single detailed case study, but evidence is still limited. This therapy should only be considered in partnership with a metabolic specialist, ideally within a research protocol, so that benefits and risks can be carefully monitored. Families should not start amino acid supplements on their own.

12. What is the difference between FARS2 deficiency and other mitochondrial diseases?
FARS2 deficiency specifically affects mitochondrial phenylalanyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that “charge” tRNAs with amino acids. Other mitochondrial diseases may affect the respiratory chain complexes directly, mitochondrial DNA, or other enzymes. Symptoms can overlap, but the underlying gene and enzyme defect differ.

13. Are there international support groups for FARS2 deficiency?
Because FARS2 deficiency is rare, families often connect through mitochondrial disease foundations, aminoacyl-tRNA synthetase disorder groups, or rare disease networks rather than FARS2-only groups. Specialists and genetic counselors can point families toward reliable organizations and online communities.

14. How can we help research?
Families can consent to share clinical data with registries, donate samples for biobanking, and participate in observational studies or clinical trials when eligible. Even small numbers of participants are extremely valuable in rare diseases like FARS2 deficiency. Discuss options with your care team or a rare disease center.

15. What is the most important message for families?
While FARS2 deficiency is serious and often life-limiting, supportive care makes a real difference. Good seizure control, nutrition, therapies, and infection prevention can improve comfort, function, and quality of life. Families are not alone: multidisciplinary teams, rare disease organizations, and ongoing research are all working toward better care and future treatments.

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.