Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (often shortened to PNSED) is a very rare genetic disease that mainly affects the nerves, muscles, and brain. In this disease, the long nerves in the arms and legs do not work properly, so signals between the brain, spinal cord, and muscles become slow or weak. This causes weakness, reduced feeling, and problems with walking and balance. [1]
PNSED is a mitochondrial disease. Mitochondria are tiny “power stations” inside almost every cell. In PNSED, the mitochondria cannot make energy in a normal way, so the body has less fuel, especially in tissues that need a lot of energy, such as brain, nerves, heart, and skeletal muscles. This energy lack explains symptoms like exercise intolerance, fatigue, and slow development in many children with this condition. [2]
The disease is autosomal recessive. This means a child gets one faulty copy of the gene from each parent. The key gene is called TRMT5. Changes (mutations) in TRMT5 disturb a chemical change on mitochondrial transfer RNA (tRNA). This small change blocks normal oxidative phosphorylation, the main pathway that mitochondria use to make energy (ATP). [3]
Other names
In medical databases, this disease appears under several names. These all describe the same or very closely related conditions. [4]
Other names (synonyms)
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Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) [4]
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Combined oxidative phosphorylation deficiency 26 (COXPD26) [5]
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Combined oxidative phosphorylation defect type 26 [5]
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TRMT5-related combined oxidative phosphorylation deficiency [6]
Clinical types
Doctors often talk about “phenotypes” instead of strict types, because symptoms can vary even inside the same family. Three broad patterns are commonly described. [7]
1. Early-onset severe developmental type
In this pattern, symptoms start in infancy. Babies may have low muscle tone (feel “floppy”), poor head control, and slow or absent milestones such as sitting or walking. Growth can be poor, and spasticity (stiff, tight muscles) may appear early. Many of these children have seizures or cerebellar signs (poor coordination), and they may never walk on their own. [8]
2. Childhood-onset mixed type
Here, children may reach some milestones, but progress is slower than usual. Over time they develop weakness, peripheral neuropathy, stiffness in the legs, and problems with running or climbing stairs. School learning may be delayed, and they may tire very easily with physical activity. This pattern is “mixed” because both development and exercise tolerance are affected. [9]
3. Later-onset exercise-intolerance type
Some people do not show clear problems until teenage years or young adulthood. They may have normal early development, but later notice leg pain, heavy feeling in the muscles, or shortness of breath when they exercise. Weakness and neuropathy may slowly appear. In these milder cases, thinking and learning can be normal, but physical endurance is low. [10]
Causes and mechanisms
The true root cause is inherited TRMT5 gene mutation. The “causes” below explain how that gene change leads to body changes and what factors can make symptoms worse.
1. TRMT5 gene mutation
The main cause is a harmful change in both copies of the TRMT5 gene. This gene encodes a tRNA methyltransferase, an enzyme that modifies mitochondrial tRNA. When the gene is faulty, the enzyme does not work well, and mitochondrial protein building is disturbed. [11]
2. Defective mitochondrial tRNA methylation
TRMT5 normally adds a small chemical group (a methyl group) to specific positions in mitochondrial tRNA. Without correct methylation, the tRNA cannot help build proteins in the normal way. This leads to mis-translated or unstable proteins inside the mitochondria. [12]
3. Impaired oxidative phosphorylation
Because mitochondrial proteins are faulty, the chain of enzymes that makes ATP (the respiratory or oxidative phosphorylation chain) does not work at full power. Cells cannot produce enough energy, especially under stress such as activity or illness. [13]
4. Reduced ATP in peripheral nerves
Peripheral nerves are long and need constant energy to maintain their membranes and move signals quickly. Low ATP makes nerve fibers vulnerable to damage, causing the peripheral neuropathy that is central in this disease. [14]
5. Demyelination of peripheral nerves
In many patients, the neuropathy is demyelinating, meaning the insulating myelin layer around nerves is damaged. This slows nerve conduction and causes weakness, numbness, and reduced reflexes. [15]
6. Axonal degeneration
Some nerve fibers lose part of their axon (the long “wire” of the nerve). This axonal damage further reduces signal strength and can cause permanent loss of sensation or muscle strength, especially in the feet and hands. [16]
7. Brain involvement and developmental delay
Mitochondrial dysfunction affects developing brain cells. When these cells cannot get enough energy, connections between neurons form more slowly or abnormally. This can lead to global developmental delay, learning problems, and sometimes seizures. [17]
8. Spinal cord and motor-pathway damage
Spasticity usually comes from damage or dysfunction in upper motor pathways (for example, corticospinal tracts). In PNSED, mitochondrial failure in these pathways can cause overactive reflexes and stiff, tight muscles in the legs. [18]
9. Muscle fiber energy failure
Skeletal muscle cells need high ATP for contraction and relaxation. In this disease, they may show “myopathic” changes and reduced respiratory chain complex activity. As a result, muscles fatigue quickly, explaining the exercise intolerance. [19]
10. Lactic acidosis
When mitochondria cannot use pyruvate in the respiratory chain, the body converts more pyruvate into lactate. This can raise blood and sometimes cerebrospinal fluid lactate, a sign of mitochondrial disease. High lactate can cause nausea, headache, and worsening fatigue. [20]
11. Multisystem organ involvement
Because mitochondria are present in nearly all cells, many organs can be affected: heart, pancreas, kidney, and eyes (optic atrophy) have all been reported in some PNSED patients. This multi-organ stress adds to fatigue and overall disability. [21]
12. Genetic modifier effects
Other genes can change how severe the disease is. For example, variants in other mitochondrial or nuclear genes may make the respiratory chain slightly better or worse, leading to very different symptoms in people with the same TRMT5 mutation. [22]
13. Intercurrent infections as triggers
Infections like flu raise body temperature and energy demand. In someone with PNSED, this sudden extra demand can temporarily worsen weakness, fatigue, and lactic acidosis, though infection does not cause the disease itself. [23]
14. Fasting or poor nutrition
Long periods without food or low calorie intake reduce energy stores. The body must rely more on mitochondria to make fuel from fat and protein. In PNSED, this can reveal or worsen symptoms because the mitochondria are already struggling. [24]
15. Physical over-exertion
Very hard exercise demands a sudden increase in ATP production. People with PNSED may feel muscle pain, heavy legs, or shortness of breath quickly, and over-exertion can lead to prolonged fatigue or muscle breakdown in severe cases. [25]
16. Certain medications (potential stressors)
Some drugs that affect mitochondria or nerves (for example, some antibiotics or chemotherapy agents) may further stress energy production or nerve health. Doctors try to avoid known mitochondrial-toxic drugs when treating patients with mitochondrial disease. [26]
17. Fever and high body temperature
High temperature speeds up metabolism. In PNSED, this can push already weak mitochondria to their limit, worsening weakness, spasticity, or confusion during illness. Symptoms often improve as the fever resolves. [27]
18. Sleep deprivation
Poor sleep reduces the body’s ability to repair cells and manage energy. For people with mitochondrial disease, lack of rest can increase fatigue, slow thinking, and lower exercise tolerance the next day. [28]
19. Psychological stress
Chronic stress hormones can affect metabolism and muscle tone. In PNSED, stress does not cause the disease but may make spasticity, pain, or fatigue feel worse, and can lower resilience to illness and physical activity. [29]
20. Aging of cells with mitochondria damage
Over time, damaged mitochondria may accumulate, and natural repair systems may weaken. This can make symptoms slowly progress with age, even if the genetic mutation has been present since birth. [30]
Symptoms and clinical features
Not every person has all of these symptoms, but these are commonly reported in PNSED and related TRMT5-linked mitochondrial disease. [31]
1. Peripheral neuropathy
This means damage to the nerves outside the brain and spinal cord. People may feel tingling, burning, numbness, or “pins and needles,” often starting in the feet and later in the hands. They may trip easily or have trouble feeling the ground. [32]
2. Distal muscle weakness and wasting
Muscles in the feet, lower legs, hands, and forearms can become weak and smaller. This can cause foot drop, difficulty climbing stairs, gripping objects, or lifting the front of the foot while walking. [33]
3. Spasticity
Spasticity is abnormal stiffness and tightness of muscles, especially in the legs. Joints may feel hard to bend, and reflexes are often exaggerated. This can cause a scissoring gait, toe-walking, or difficulty with smooth movements. [34]
4. Exercise intolerance
People with PNSED get tired very quickly during physical activity. They may feel muscle pain, shortness of breath, or heaviness in the legs after only light walking or climbing a few stairs. Rest usually brings some relief, but recovery can be slow. [35]
5. Global developmental delay
Many children show slow progress in multiple skills: motor (sitting, standing, walking), speech and language, and sometimes social or learning skills. Some children may not reach certain milestones at all or do so much later than peers. [36]
6. Hypotonia (low muscle tone) in infancy
Babies may feel floppy when held, with poor head control and delayed rolling or sitting. Low tone reflects weakness and poor energy supply to the muscles early in life. [37]
7. Growth retardation or short stature
Some children with PNSED are smaller and grow more slowly than expected. Chronic energy shortage, feeding problems, or involvement of hormone systems may all contribute to reduced height or weight gain. [38]
8. Cerebellar signs (poor coordination)
Damage to or dysfunction of cerebellar pathways can cause clumsiness, unsteady walking, and trouble with tasks that need fine coordination, such as writing, buttoning clothes, or rapidly alternating movements. [39]
9. Seizures
Some patients develop epileptic seizures. These are bursts of abnormal electrical activity in the brain that can cause staring spells, jerking movements, or loss of consciousness. Seizures often indicate more severe brain involvement. [40]
10. Contractures
When joints stay bent for a long time due to spasticity or weakness, the muscles and tendons can shorten and joints can become “fixed.” These contractures can make standing and walking more difficult and may require therapy or surgery. [41]
11. Sensory loss
Because sensory nerves are affected, people may lose position sense, vibration sense, or pain and temperature feeling in their feet and hands. This can increase risk of injuries, burns, or pressure sores because the person does not feel normal warning signals. [42]
12. Fatigue and low stamina
Even at rest, many people feel a constant lack of energy. Simple daily tasks, such as dressing or moving around the house, may feel exhausting. This fatigue is a classic sign of mitochondrial disease. [43]
13. Cardiomyopathy (in some cases)
A few patients have thickened heart muscle (hypertrophic cardiomyopathy). This can cause shortness of breath, chest discomfort, or fainting, especially during exertion, and needs careful heart monitoring. [44]
14. Optic atrophy or visual problems
Mitochondrial dysfunction in the optic nerve can cause slowly progressive loss of vision. Patients may notice blurred vision, difficulty reading, or problems with color vision. Not everyone with PNSED has eye involvement, but it is reported in more severe forms. [45]
15. Elevated lactate-related symptoms
High lactate can cause abdominal pain, vomiting, fast breathing, or confusion during metabolic stress. These episodes may be seen during infections or after heavy exertion in some patients with PNSED. [46]
Diagnostic tests:
Physical examination and bedside tests
In total, doctors may use at least 20 different tests. Below are examples, grouped by type.
1. General neurological examination (physical exam)
The doctor checks strength, reflexes, muscle tone, coordination, and balance. They look for signs of neuropathy (reduced reflexes, sensory loss) and spasticity (increased reflexes, stiffness). This basic exam guides which further tests are needed. [47]
2. Developmental assessment
In children, structured tools are used to assess motor skills, speech, and cognitive abilities. The clinician compares these to age-based norms to document global developmental delay or specific learning problems. [48]
3. Gait and balance evaluation
The doctor watches how the person walks, turns, and stands on one leg. They may ask the patient to walk on heels or toes. Problems such as toe-walking, scissoring gait, or wide-based unstable walking suggest neuropathy, spasticity, or cerebellar involvement. [49]
4. Muscle strength and tone testing
Using simple manual resistance, the examiner grades strength in different muscle groups. They also gently move joints to feel for spastic catch or stiffness. This helps map out which muscles are weak and how severe the spasticity is. [50]
5. Sensory testing
Light touch, pin prick, vibration (using a tuning fork), and position sense are tested in the hands and feet. Loss in a “stocking-glove” pattern is typical of peripheral neuropathy and supports the diagnosis. [51]
6. Romberg test (manual bedside test)
The patient stands with feet together and eyes closed. If they sway or fall when they close their eyes, it suggests poor position sense due to sensory neuropathy or cerebellar dysfunction. This is a simple but useful bedside test. [52]
7. Heel-to-toe (tandem) walking test
The person is asked to walk in a straight line, placing one foot directly in front of the other. Difficulty staying on the line can indicate balance problems related to cerebellar disease, neuropathy, or both. [53]
8. Six-minute walk test
This test measures how far a person can walk in six minutes on a flat surface. In PNSED, distance is often reduced because of fatigue, weakness, and exercise intolerance. It can be repeated over time to monitor disease progression. [54]
Laboratory and pathological tests
9. Basic blood tests (metabolic and organ function)
Blood glucose, kidney and liver function, and complete blood count are checked to rule out more common causes of neuropathy and to look for organ involvement. These tests are not specific for PNSED but are part of a complete work-up. [55]
10. Serum lactate and pyruvate
Raised blood lactate and an abnormal lactate-to-pyruvate ratio suggest mitochondrial respiratory chain problems. These results support, but do not by themselves prove, a mitochondrial disease such as PNSED. [56]
11. Plasma amino acids and urine organic acids
These panels search for abnormal patterns that point toward mitochondrial or other metabolic diseases. Certain profiles can guide doctors toward more specific testing, such as gene panels or whole exome sequencing. [57]
12. Creatine kinase (CK) level
CK is an enzyme that rises when muscle fibers are damaged. In some mitochondrial myopathies, CK may be mildly elevated. A raised CK suggests muscle involvement and prompts further neuromuscular evaluation. [58]
13. Muscle biopsy with respiratory chain enzyme studies
A small piece of muscle is taken surgically and studied under the microscope. Special stains and spectrophotometric tests can measure the activity of complexes I–IV in the respiratory chain. Low activity supports a diagnosis of mitochondrial respiratory chain disorder. [59]
14. Histological assessment for ragged-red fibers and mitochondrial changes
Under the microscope, the biopsy may show abnormal clusters of mitochondria called ragged-red fibers or other structural changes. These are classic signs of mitochondrial myopathy and help confirm that mitochondria are the main problem. [60]
15. Genetic testing for TRMT5 and mitochondrial genes
Targeted gene panels for neuropathy or mitochondrial disease, or whole exome/genome sequencing, can identify TRMT5 mutations and other relevant variants. Finding two pathogenic TRMT5 variants in an autosomal recessive pattern provides strong confirmation of PNSED. [61]
Electrodiagnostic tests
16. Nerve conduction studies (NCS)
Small electrical pulses are delivered to nerves, and the speed and strength of the response are recorded. In PNSED, NCS often show a demyelinating or mixed neuropathy, with slowed conduction and reduced amplitudes. These results help distinguish types of neuropathy. [62]
17. Electromyography (EMG)
A thin needle electrode is inserted into muscles to measure their electrical activity at rest and during contraction. EMG can show patterns of neuropathy or myopathy and helps separate nerve and muscle contributions to weakness. [63]
18. Combined EMG/NCS electrodiagnostic assessment
Most centers perform EMG and NCS together. This combination gives a detailed picture of peripheral nerve and muscle function and is considered a key tool in diagnosing peripheral neuropathy and guiding further tests. [64]
Imaging tests
19. Brain and spinal cord MRI
Magnetic resonance imaging can show structural changes in the brain or spinal cord, such as cerebellar atrophy or white-matter changes, which may be seen in mitochondrial disorders. MRI can also help rule out other causes of spasticity and developmental delay. [65]
20. Cardiac imaging (echocardiography or cardiac MRI)
If there are signs of heart involvement (shortness of breath, abnormal exam, or ECG changes), heart ultrasound or MRI can check for cardiomyopathy. Early detection allows closer monitoring and treatment of heart problems, which can be serious in some mitochondrial diseases. [66]
21. Nerve or skin imaging/biopsy for small-fiber assessment (optional extra test)
In some cases, a skin biopsy is used to study small nerve fibers under the microscope. This can confirm small-fiber neuropathy when standard conduction tests are normal but symptoms are present. While not always needed in PNSED, it can add useful detail in complex cases. [67]
Non-pharmacological treatments
These treatments do not use medicines. They support the child’s function, reduce complications, and improve quality of life. They must be tailored by a specialist team (neurology, physio, rehab, dietitian, genetics). [3]
1. Individualised physiotherapy and stretching
Regular physiotherapy uses gentle stretching, range-of-motion exercises, balance work, and guided movement practice. The purpose is to keep muscles flexible, prevent joint stiffness and contractures, and maintain as much walking and sitting ability as possible. It works by repeatedly lengthening tight muscles and training the central nervous system to use better movement patterns, which slowly reduces spasticity and improves control. [4]
2. Occupational therapy (OT) for daily activities
Occupational therapists help the child manage daily self-care like dressing, feeding, writing, and using the bathroom. The purpose is to keep independence for as long as possible. OT works by simplifying tasks, teaching energy-saving methods, and introducing special tools like adapted cutlery, writing grips, and bathroom aids. [5]
3. Speech and language therapy
Some children have delayed speech, swallowing difficulties, or drooling. Speech therapists assess communication, swallowing, and safety while eating. The purpose is to improve speech clarity, support understanding, and prevent choking or aspiration. Therapy uses simple mouth, tongue, and breathing exercises and may add communication boards or devices if speech is very limited. [6]
4. Orthotic devices (braces and splints)
Ankle-foot orthoses (AFOs), wrist splints, and hand splints help position joints correctly, reduce toe-walking, and prevent deformities. The purpose is to stabilise weak or spastic limbs and make walking or standing safer. Orthoses work by providing constant support and gentle stretch to muscles, which decreases abnormal muscle pull over time. [7]
5. Mobility aids (walkers, wheelchairs, standing frames)
As neuropathy and spasticity progress, many children need walkers, crutches, or wheelchairs. The purpose is to allow safe movement, prevent falls, and reduce fatigue. Standing frames or supported standing devices help keep bones strong and hips aligned by putting weight through the legs even when the child cannot stand alone. [8]
6. Task-specific strengthening and coordination training
Low-load, carefully planned strengthening exercises help maintain muscle mass without worsening fatigue. The purpose is to improve function for important tasks, like standing up from a chair or climbing a small step. Task-specific practice works by training the exact movements the child needs in daily life, so the brain and muscles learn them more efficiently. [9]
7. Aquatic (water) therapy
Therapy in a warm pool lets the child move more freely with less gravity and joint stress. The purpose is to practice walking, balance, and stretching in a safer, more comfortable setting. Buoyancy supports the body, while gentle water resistance provides soft strengthening and helps relax spastic muscles. [10]
8. Respiratory physiotherapy and breathing exercises
If muscle weakness affects breathing or swallowing, respiratory physio and breathing exercises may be used. The purpose is to keep lungs clear, improve cough strength, and reduce infections. Techniques include deep breathing, supported cough, and sometimes airway-clearance devices. These support oxygen levels and energy. [11]
9. Pain management with physical and psychological methods
Neuropathic pain, muscle cramps, and joint pain are common. Non-drug approaches include heat packs, gentle massage, relaxation techniques, and mindfulness. The purpose is to reduce pain signals and muscle tension. Cognitive behavioural therapy (CBT) helps the child understand pain, reduce fear, and use coping skills to make pain less overwhelming. [12]
10. Energy conservation and fatigue management
Exercise intolerance means the child tires quickly. Occupational therapists teach pacing, planned rest breaks, and “activity banking” (saving energy for important tasks). The purpose is to prevent over-exertion crashes and allow more stable function. It works by balancing activity with rest so muscles and mitochondria are not overloaded. [13]
11. Structured, supervised aerobic activity
Gentle, supervised aerobic exercise, like slow cycling or walking, may improve mitochondrial function and fitness when carefully monitored. The purpose is to keep the heart and muscles as healthy as possible. Short, low-intensity sessions with rest reduce the risk of worsening fatigue while encouraging better oxygen use. [14]
12. Developmental and special education support
Developmental delay often affects learning and behaviour. Early intervention teachers and special educators create individual education plans. The purpose is to support language, problem-solving, social skills, and school participation. Structured routines, visual schedules, and small, achievable steps help the brain build new connections. [15]
13. Assistive communication technology
If speech is difficult, tablets with communication apps, picture boards, or eye-gaze devices may be used. The purpose is to give the child a clear “voice” to express needs and feelings. These tools work by replacing spoken words with pictures or text, which greatly lowers frustration and behaviour issues. [16]
14. Positioning, seating, and pressure-care management
Correct seating systems, cushions, and bed supports prevent pressure sores and spinal deformities. The purpose is to keep the spine as straight as possible and avoid painful skin breakdown. Good positioning spreads pressure evenly and reduces abnormal muscle pull on bones. [17]
15. Behavioural and psychological support
Living with a chronic, disabling disease is stressful for the child and family. Psychologists can offer counselling, play therapy, and coping strategies. The purpose is to treat anxiety, sadness, and frustration and support healthy family communication. Psychological support works by helping the child feel heard and teaching practical emotion-regulation skills. [18]
16. Social work and disability support services
Social workers help families access financial support, home care, school resources, and respite services. The purpose is to reduce caregiver burnout and ensure the child’s needs are met. These services make it easier for families to keep the child at home safely and maintain daily life. [19]
17. Genetic counselling for the family
Because this is an inherited condition, parents and relatives benefit from genetic counselling. The purpose is to explain inheritance, carrier testing, and options for future pregnancies. Counselling works by providing clear information about risks and discussing possible prenatal diagnosis or pre-implantation genetic testing if available. [20]
18. Sleep hygiene and night-time support
Muscle spasms and pain can disturb sleep. Sleep hygiene includes consistent bedtimes, calming routines, limiting screens, and comfortable positioning. The purpose is to improve sleep quality, which directly improves mood, learning, and pain tolerance the next day. [21]
19. Fall-prevention and home modification
Simple changes at home—grab bars, non-slip floors, better lighting, and removing clutter—reduce falls. The purpose is to prevent fractures, head injuries, and fear of walking. This works by making the environment safer so the child can move with more confidence. [22]
20. Community, peer, and patient-support groups
Connecting with other families facing mitochondrial or neuropathic conditions helps reduce isolation. The purpose is emotional support and shared practical tips. Peer groups work by providing role models, realistic hope, and a sense that the family is not alone. [23]
Drug treatments
All medicines below are examples used to treat symptoms like neuropathic pain, spasticity, seizures, mood problems, or mitochondrial dysfunction. In such a rare TRMT5-related disease, almost all use is off-label and must be decided by a specialist who knows the child, age, weight, and other illnesses. Never start, stop, or change doses without a doctor. [24]
1. Gabapentin
Gabapentin is an anticonvulsant often used to treat neuropathic pain. For adults, FDA labels suggest titrating from 300 mg once daily up to 300 mg three times daily, with a usual effective range 1800–3600 mg/day; children use weight-based dosing chosen by the doctor. It binds to α2δ subunits of calcium channels, dampening abnormal nerve firing and reducing burning or shooting pain. Common side effects are dizziness, sleepiness, weight gain, and swelling; breathing problems are a concern in vulnerable patients. [25]
2. Pregabalin
Pregabalin is closely related to gabapentin and is FDA-approved for neuropathic pain in diabetic neuropathy, postherpetic neuralgia, and spinal cord injury, and for partial seizures in adults. Typical adult doses for neuropathic pain start at 150 mg/day divided into two or three doses and may increase up to 300–600 mg/day, adjusted for kidney function. It reduces calcium entry into nerve endings, lowering release of pain-signalling chemicals. Side effects include dizziness, sleepiness, weight gain, and swelling, and it must be tapered off slowly. [26]
3. Duloxetine
Duloxetine is a serotonin–noradrenaline reuptake inhibitor (SNRI) approved for diabetic peripheral neuropathic pain, fibromyalgia, depression, and anxiety. Usual adult dosing for neuropathic pain is 60 mg once daily, sometimes started at 30 mg for a week. It works by increasing serotonin and noradrenaline in the spinal cord, which helps the brain dampen pain signals. Nausea, dry mouth, sleepiness or insomnia, sweating, and small blood-pressure changes are common side effects. [27]
4. Amitriptyline
Amitriptyline is a tricyclic antidepressant, widely used (often off-label) for chronic neuropathic pain and migraine. Doses for pain are usually lower than for depression, often starting at 10–25 mg at night and slowly increasing as tolerated. It blocks reuptake of serotonin and noradrenaline and also affects other receptors, which helps pain but causes side effects like dry mouth, constipation, weight gain, and drowsiness. It must be used very carefully in young people due to overdose and mood-related risks. [28]
5. Oral baclofen
Baclofen is a muscle relaxant that acts on GABA-B receptors in the spinal cord to reduce spasticity. It is FDA-approved for spasticity due to multiple sclerosis and spinal cord disease. Typical adult dosing slowly increases up to a maximum of about 80 mg/day split into several doses; children receive weight-based dosing. It reduces flexor spasms, clonus, and stiffness, but may cause sleepiness, weakness, low blood pressure, or mood changes. Abrupt stopping can be dangerous and must be avoided. [29]
6. Tizanidine
Tizanidine is another oral antispasticity drug that stimulates α2-adrenergic receptors, reducing muscle tone by acting mainly in the spinal cord. It is usually given several times per day, starting with very low doses and increasing slowly. Side effects include drowsiness, low blood pressure, dry mouth, and sometimes liver-function abnormalities, so monitoring is needed. [30]
7. Diazepam or other benzodiazepines
Diazepam and similar medicines like clonazepam can reduce severe spasticity and help with muscle cramps or seizures. They enhance GABA-A activity in the brain, giving a strong muscle-relaxing and anti-seizure effect. Doses and timing are carefully chosen by a specialist. Side effects include drowsiness, breathing depression, and dependence, so long-term daily use is usually limited. [31]
8. Intrathecal baclofen (ITB)
In severe spasticity not controlled by tablets, baclofen can be delivered through a pump into the spinal fluid. This allows much lower doses directly to the spinal cord with fewer whole-body side effects. ITB can greatly reduce stiffness and pain, but requires surgery, strict pump management, and careful monitoring for infection or withdrawal if the pump fails. [32]
9. Botulinum toxin injections
Botulinum toxin type A can be injected into over-active muscles to reduce local spasticity, improve joint position, and ease care. It blocks release of acetylcholine at the neuromuscular junction. Effects begin over a few days, last about 3–4 months, and then wear off. Side effects include weakness of nearby muscles, pain at the injection site, and rarely flu-like symptoms. [33]
10. Topical lidocaine patches or gels
For localised neuropathic pain, lidocaine patches or gels numb the skin and reduce nerve firing in that area. They are usually applied for several hours per day to the painful region. The purpose is to provide local pain relief without many systemic side effects. Skin irritation is the main problem; serious side effects are rare when used correctly. [34]
11. Topical capsaicin preparations
High-concentration or repeated low-dose capsaicin creams can reduce local neuropathic pain by desensitising TRPV1 pain receptors in the skin. After an initial burning feeling, nerve endings send fewer pain signals. Treatment must be supervised, especially with high-dose patches. Side effects are mostly local burning and redness. [35]
12. Simple analgesics (paracetamol / acetaminophen)
Paracetamol helps background musculoskeletal aches and is often used in combination with other treatments. Dosing must follow strict limits to avoid liver damage. It works centrally to reduce pain perception but does not treat neuropathic pain directly, so it is a supportive, not main, therapy. [36]
13. Non-steroidal anti-inflammatory drugs (NSAIDs)
Medicines like ibuprofen reduce inflammation and mild–moderate pain from joints, muscles, or orthopaedic problems. They are not strong for neuropathic pain but may help after surgery or during painful contractures. They can irritate the stomach and kidneys, so doctors carefully weigh risks and benefits, especially with long-term use. [37]
14. Levetiracetam
Levetiracetam is a modern anti-seizure medicine often preferred in mitochondrial disease because it generally has fewer mitochondrial-toxic effects than some older drugs. It binds to synaptic vesicle protein SV2A to stabilise neuronal firing. Doses are weight-based and split twice daily. Side effects include irritability, mood changes, and sleep problems, which need close monitoring in children. [38]
15. Lamotrigine
Lamotrigine is another anti-seizure drug used in some mitochondrial disorders. It blocks voltage-gated sodium channels and reduces glutamate release. It must be started very slowly to lower the risk of serious skin rashes such as Stevens–Johnson syndrome. It can also help mood in some patients. [39]
16. Selective serotonin reuptake inhibitors (SSRIs)
Living with chronic disability can lead to depression and anxiety. SSRIs like sertraline or fluoxetine may be used to treat mood symptoms. They increase serotonin in the brain, which can improve mood, appetite, and sleep. Doctors monitor for side effects like stomach upset, sleep changes, and, in young people, rare increases in suicidal thoughts. [40]
17. Magnesium supplements or medicines for cramps
If muscle cramps are prominent, magnesium or other cramp-reducing medicines may be tried. Magnesium helps stabilise nerve and muscle function. Too much can cause diarrhoea or, in kidney disease, serious toxicity, so dosing must be guided medically. [41]
18. Intravenous immunoglobulin (IVIG) in selected cases
If a person with this mitochondrial disorder also has an autoimmune neuropathy, IVIG may be considered. It consists of pooled antibodies from donors and is given through a vein over several days. It modulates the immune system and can improve some autoimmune neuropathies, but it is expensive and not standard for TRMT5 disease itself. Side effects include headache, clotting risk, and kidney strain. [42]
19. Anti-spasticity agents in combination (e.g., baclofen plus tizanidine)
Sometimes low doses of two different spasticity medicines give better relief with fewer side effects than a high dose of one drug. Doctors may combine baclofen with tizanidine or benzodiazepines, carefully watching for sedation, weakness, and low blood pressure. [43]
20. Short courses of corticosteroids for overlapping inflammatory problems
If there is evidence of overlapping autoimmune disease or inflammatory neuropathy, short courses of steroids like prednisone may be used. They dampen the immune response and can reduce inflammation and pain. Side effects include weight gain, mood changes, high blood sugar, and bone thinning, so long-term use is avoided whenever possible. [44]
Dietary molecular supplements
These supplements are often used as part of a “mitochondrial cocktail.” Evidence is mixed, but many are considered reasonably safe under medical supervision. They can interact with medicines, so doses must be set by a metabolic or mitochondrial specialist. [45]
1. Coenzyme Q10 (CoQ10)
CoQ10 is a key part of the mitochondrial electron transport chain and also an antioxidant. In theory it supports ATP production and reduces oxidative damage. Typical doses in mitochondrial disease are often 5–30 mg/kg/day split into two or three doses, but exact dosing is specialist-guided. It is generally well tolerated; main side effects are stomach upset and headache. [46]
2. L-carnitine
Carnitine helps fatty acids enter mitochondria to be used as fuel. In some mitochondrial and fatty-acid oxidation disorders, supplementation improves muscle function and reduces fatigue. Doses often range around 50–100 mg/kg/day in divided doses. Side effects include fishy body odour, diarrhoea, and, rarely, arrhythmias if used in very high doses or in certain conditions. [47]
3. Riboflavin (vitamin B2)
Riboflavin is a cofactor for several mitochondrial enzymes, including complex I and II of the respiratory chain. Supplementation, often 50–400 mg/day depending on age and indication, has helped some patients with specific riboflavin-responsive mitochondrial myopathies. It is usually safe, with bright yellow urine as a harmless side effect. [48]
4. Thiamine (vitamin B1)
Thiamine is essential for pyruvate dehydrogenase and other energy-producing enzymes. Some mitochondrial or metabolic disorders respond dramatically to high-dose thiamine. Doses are quite variable; many protocols use 50–300 mg/day under supervision. It is generally safe, but rare allergy-type reactions can occur with injections. [49]
5. Alpha-lipoic acid
Alpha-lipoic acid is both an antioxidant and a cofactor in mitochondrial energy metabolism. It has shown benefit in some studies of diabetic neuropathy and is proposed for mitochondrial dysfunction. Doses often range around 300–600 mg/day in adults, with lower weight-based doses in children. Side effects can include nausea, rash, or hypoglycaemia in people on diabetes drugs. [50]
6. Vitamins C and E
These antioxidant vitamins help neutralise free radicals produced by damaged mitochondria. They are sometimes combined in mitochondrial cocktails with other agents. Doses vary with age and condition; excess can cause stomach upset or, with very high vitamin E, bleeding risk, so they must not be megadosed without guidance. [51]
7. Biotin
Biotin is a cofactor for carboxylase enzymes and is included in some mitochondrial supplement regimens. It is usually well tolerated at doses from a few milligrams up to 10 mg/day or more, but very high doses can interfere with some lab tests, especially thyroid and cardiac assays. [52]
8. Creatine
Creatine acts as an energy buffer in muscle and brain by storing high-energy phosphate bonds. In some neuromuscular and mitochondrial disorders, it may improve strength and fatigue. Adult doses often total 3–5 g/day; paediatric regimens are weight-based. Side effects include weight gain and, rarely, kidney strain at high doses or with dehydration. [53]
9. NADH / B-complex combinations
NADH and B-vitamins are used to support many mitochondrial enzymes. They may slightly improve fatigue and cognitive symptoms in some patients, though data are limited. Doses are small (often in dietary supplement ranges), but combining many products can be expensive and should be coordinated by one clinician. [54]
10. Vitamin D
Vitamin D supports bone health and immune function. Children with reduced mobility and chronic illness are at high risk for low vitamin D and fragile bones. Supplement dosing is based on blood levels and age. Excessive vitamin D can cause high calcium and kidney damage, so testing and medical oversight are important. [55]
Immunity-booster, regenerative and stem-cell–related drugs
These options are not standard treatment for TRMT5-related disease. They are mentioned because they may be considered in very specific situations or clinical trials. Decisions must be made by highly specialised teams. [56]
1. Intravenous immunoglobulin (IVIG)
In clearly proven autoimmune neuropathies (like Guillain–Barré syndrome or CIDP), IVIG can improve weakness and reduce disability. It works by modulating the immune system and blocking harmful antibodies. In rare patients who have both mitochondrial disease and autoimmune neuropathy, IVIG may be used. It is given in high doses over several days and may be repeated monthly. Side effects include headache, blood clots, kidney strain, and infusion reactions. [57]
2. Hematopoietic stem cell transplantation (HSCT) in selected disorders
HSCT is mainly used for blood cancers and a few inherited metabolic diseases like Krabbe disease. In those settings it can improve peripheral nerve conduction and slow disease progression. It works by replacing the patient’s bone-marrow-derived cells with donor cells. HSCT carries major risks, including infection, graft-versus-host disease, and new neuropathies, so it is not a routine treatment for TRMT5 disease and is only considered in research or special combined conditions. [58]
3. Mesenchymal stem cell therapies (experimental)
Mesenchymal stem cells from bone marrow or other sources are being studied for many neurological diseases. They may release growth factors and anti-inflammatory signals that support nerve repair. At present, strong evidence in mitochondrial neuropathies is lacking, and many commercial offers are unregulated. Any use should be within approved clinical trials, where dosing and safety are carefully monitored. [59]
4. Vatiquinone (EPI-743)
Vatiquinone is a vitamin-E-like molecule being studied as a mitochondrial antioxidant and “redox modulator” in conditions such as Leigh syndrome and other mitochondrial diseases. It may protect cells from oxidative stress and improve energy metabolism, but trials have had mixed results and it is not yet widely approved. Dosing and side effects are defined only inside clinical trials. [60]
5. Idebenone
Idebenone is a synthetic CoQ10 analogue approved in some regions for Leber hereditary optic neuropathy, another mitochondrial disease. It acts as an antioxidant and electron carrier, bypassing complex I in the respiratory chain and helping protect retinal ganglion cells. Typical adult doses in LHON studies are around 300 mg three times daily. Side effects include mild stomach upset and liver-enzyme changes. Its role in TRMT5 disease is unknown and would be research-based. [61]
6. Future gene-therapy and cell-based approaches
Researchers are exploring gene therapy, mitochondrial-targeted gene editing, and cell-based treatments for mitochondrial disease. These aim to correct the underlying genetic defect or improve mitochondrial function in affected tissues. For TRMT5 disease, such strategies are still theoretical and confined to laboratory or very early clinical research. Families should be cautious about unproven “stem-cell cures” offered outside regulated studies. [62]
Surgical options
Surgery does not cure the mitochondrial defect, but it can correct fixed deformities, reduce pain, and make care easier in severe spasticity. [63]
1. Soft-tissue tendon lengthening or release
When spastic muscles keep joints in abnormal positions (like toe-walking or bent knees), orthopaedic surgeons may lengthen tendons or release tight muscles. This reduces contractures, improves joint alignment, and makes walking or bracing easier.
2. Orthopaedic surgery for hip dislocation or subluxation
Spasticity can gradually pull hips out of their sockets. Reconstructive hip surgery re-positions the hip joint, reduces pain, and helps sitting and hygiene. Without surgery, long-term pain and sitting problems can be severe.
3. Spinal fusion for severe scoliosis
Weak and spastic trunk muscles can lead to a curved spine. When scoliosis becomes large and progressive, spinal fusion with metal rods may be recommended. This stabilises the spine, prevents further curvature, and improves sitting balance and lung function.
4. Selective dorsal rhizotomy (SDR)
In carefully selected children with mainly spasticity and enough strength, neurosurgeons may cut selected sensory nerve roots in the spine to permanently reduce spasticity. SDR can improve walking and comfort but carries risks like weakness, bladder changes, or sensory loss and is usually reserved for conditions like cerebral palsy; its use in mitochondrial disease is rare and requires expert assessment.
5. Intrathecal baclofen pump implantation
This is both a surgery and a drug therapy. A pump is implanted under the skin with a catheter into the spinal fluid. It continuously delivers baclofen directly to the spinal cord to control severe generalised spasticity. Surgery carries infection and hardware risks, and families must attend regular refill and maintenance visits.
Prevention and lifestyle tips
For a genetic mitochondrial disease, we cannot fully prevent the condition, but we can lower complications and slow decline:
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Avoid prolonged fasting and dehydration – give regular meals, snacks, and good fluid intake to reduce metabolic stress. [64]
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Prevent infections with vaccines and hygiene – routine vaccines, flu and pneumonia shots when advised, and careful handwashing help avoid illness that can worsen weakness. [65]
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Avoid known mitochondrial-toxic medicines where possible – some drugs (for example, valproate in certain mitochondrial disorders) can be harmful; doctors choose safer alternatives. [66]
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Use paced, gentle physical activity instead of complete rest or intense workouts – short, low-intensity exercise with rest helps fitness without overloading mitochondria. [67]
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Keep good sleep habits – regular sleep improves energy, mood, and pain tolerance. [68]
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Protect joints and spine with early physio and bracing – starting PT and orthotics early can delay or reduce the need for surgery. [69]
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Treat seizures, pain, and spasticity early – good symptom control prevents deconditioning, falls, and loss of skills. [70]
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Monitor nutrition and growth regularly – dietitians can adjust calories, protein, and supplements to meet needs and avoid malnutrition. [71]
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Plan for heat, cold, and stress – extreme temperatures and emotional or physical stress can worsen fatigue; planning rest and appropriate clothing helps. [72]
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Use genetic counselling for future pregnancies – this prevents recurrence in families by explaining carrier testing and reproductive options. [73]
When to see a doctor urgently
You should seek urgent medical care or contact the treating team immediately if the person with this condition has:
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New or rapidly worsening weakness, especially sudden loss of the ability to stand or walk. [74]
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Loss of previously learned skills (regression), such as losing head control or words.
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Severe or prolonged seizures, or a first seizure.
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Sudden changes in breathing, blue lips, or trouble waking up.
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High fever with unusual sleepiness, stiffness, or confusion.
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Sudden, severe pain, swelling, or obvious deformity in a limb or joint.
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Signs of severe dehydration (very little urine, dry mouth, sunken eyes).
Regular check-ups with neurology, metabolic, physio, and rehab teams are also essential even when the child seems stable. [75]
Diet – what to eat and what to avoid
Diet must always be personalised by a dietitian or metabolic specialist, but general ideas are:
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Eat regular, balanced meals with complex carbohydrates (whole grains), lean protein, and healthy fats to give steady energy and avoid long fasting. [76]
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Include plenty of fruits and vegetables for natural antioxidants, vitamins, and fibre.
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Use adequate protein (beans, lentils, eggs, fish, lean meat, dairy if tolerated) to support muscle repair and immune function.
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Prefer healthy fats such as olive oil, nuts, and seeds rather than trans fats and deep-fried foods.
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Encourage frequent small snacks between meals when exercise intolerance is strong, to avoid energy crashes. [77]
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Limit very high-sugar foods and drinks (sodas, sweets) that cause rapid blood-sugar swings and do not give long-lasting energy.
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Avoid extreme fad diets (very low-carb, high-fat, or prolonged fasting diets) unless specifically recommended by a specialist for another condition.
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Reduce processed and salty foods to protect heart and kidneys, especially if mobility is limited.
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Ensure enough fluids – water and, if needed, oral rehydration solutions during illness, unless fluid restriction is prescribed. [78]
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Discuss any new supplement or herbal product with the medical team first, because some can interact with medicines or stress the liver or kidneys.
Frequently asked questions
1. Is this condition always serious?
The severity can vary widely. Some children are very affected early in life, while others may have milder symptoms that appear later. Because mitochondria are in almost all cells, the disease is considered serious and needs long-term follow-up, but supportive care can greatly improve quality of life. [79]
2. Can peripheral neuropathy and spasticity improve over time?
Symptoms can sometimes improve with good rehabilitation, pain and spasticity control, and careful management of energy and nutrition. However, the underlying genetic problem remains, so careful monitoring is needed to catch any new decline early.
3. Will every child eventually need a wheelchair?
Not always. Some may always walk short distances with support; others may need a wheelchair mainly for long distances or later in life. Early and continuous physio, orthotics, and surgeries when needed can preserve mobility for longer. [80]
4. Can this disease affect thinking and learning?
Yes. Developmental delay and sometimes intellectual disability can occur. Early special education, speech therapy, and supportive technologies can help children reach their own best level of learning and communication.
5. Is there a cure today?
At present there is no cure that corrects the TRMT5 gene or fully restores mitochondrial function. Treatment focuses on symptoms and prevention of complications. Research into gene therapy and mitochondrial-targeted drugs is active and may provide better options in the future. [81]
6. Do supplements like CoQ10 replace medicines?
No. Supplements may support mitochondrial function and may slightly improve fatigue or strength in some people, but they do not replace anti-seizure drugs, pain medicines, or spasticity treatments. They are an add-on to, not a substitute for, standard care.
7. Are all family members at risk?
Parents are usually healthy carriers. Each pregnancy between two carriers has a 25% chance of an affected child, a 50% chance of a carrier child, and a 25% chance of a non-carrier. Other relatives may also be carriers and can consider genetic testing. [82]
8. Can regular exercise damage mitochondria more?
Very intense or prolonged exercise can trigger severe fatigue and sometimes regression. However, carefully planned, low-intensity, paced exercise supervised by physio can actually improve fitness without harming mitochondria. The key is slow, gradual progression and listening to symptoms. [83]
9. Is anaesthesia safe for surgery in this disease?
Many people with mitochondrial disease undergo surgery safely, but anaesthesia needs special planning. The anaesthetist should know the diagnosis, avoid certain drugs if possible, and monitor blood sugar, temperature, and acid–base balance carefully. Pre-operative planning with the metabolic team is important.
10. Can infections permanently worsen the condition?
Severe infections can cause temporary or sometimes long-lasting loss of skills in mitochondrial disease. Fast treatment of infections, good vaccination, and early hospital care when the child is very unwell help reduce the risk of permanent worsening. [84]
11. Are vaccinations safe?
In most cases, vaccines are recommended and important to prevent serious infections. The team may space vaccines or avoid live vaccines only in special situations. Decisions are made case-by-case with neurology, metabolic, and primary-care doctors.
12. What about school and social life?
Many children can attend school with support, such as reduced schedules, extra rest breaks, aids for writing or speaking, and help with mobility. Social inclusion is very important for emotional health, so families and schools should work together to adapt the environment.
13. How often are check-ups needed?
Typically, regular visits with neurology, rehabilitation, and metabolic teams are scheduled every 3–12 months, depending on age and severity, with extra visits during acute problems. Physio and OT sessions are usually more frequent, especially in periods of rapid growth or change. [85]
14. Can diet alone control this disease?
No. A healthy, carefully planned diet can support energy and general health but cannot correct the genetic problem. Diet is one piece of the treatment plan, along with therapies, medicines, and sometimes surgery.
15. Where can families find more support?
Families can contact mitochondrial disease foundations, rare-disease organisations, and local disability services. These groups offer education materials, peer support, and sometimes help accessing clinical trials or expert centres. Online communities must be used carefully, checking information with the medical team. [86]
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 20, 2025.
