Charcot-Marie-Tooth Disease Caused by Mutation in YARS

Charcot-Marie-Tooth disease caused by mutation in YARS is a very rare, inherited nerve disease that damages the long nerves to the feet, legs, hands, and arms. Doctors call this form Charcot-Marie-Tooth disease, dominant intermediate C (CMTDIC). It happens when one copy of the YARS1 gene, which makes an enzyme called tyrosyl-tRNA synthetase, has a harmful change (mutation). This enzyme is needed for normal protein building inside nerve cells. When the YARS1 enzyme does not work properly, nerve cells cannot keep their long extensions (axons) healthy, so signals from brain to muscles and from skin back to brain become weak. People slowly develop weakness, wasting of muscles, foot deformities, and reduced feeling, usually beginning in childhood or adult life. Nerve tests show “intermediate” speeds, between typical demyelinating CMT and axonal CMT. ScienceDirect+4MalaCards+4ZFIN+4

Charcot-Marie-Tooth disease caused by a mutation in the YARS gene is a rare, inherited nerve disease. The YARS gene gives instructions for an enzyme called tyrosyl-tRNA synthetase, which helps cells build proteins correctly. When this gene is changed (mutated), long nerves in the arms and legs work poorly. This form is often called dominant intermediate CMT (DI-CMT C) and usually causes weakness, thin muscles, foot deformities and numbness in the feet and hands. There is no cure, so treatment focuses on symptoms, function and quality of life. ScienceDirect+3MalaCards+3arupconsult.com+3

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Another names

Charcot-Marie-Tooth disease caused by mutation in YARS is known in the medical literature by several other names. All of the names below describe the same or very closely related condition:

1. Charcot-Marie-Tooth disease, dominant intermediate C (CMTDIC)
This is the most common official name. “Dominant intermediate” means the disease is inherited in an autosomal dominant pattern and the nerve conduction speed is between the slow demyelinating type and the normal-speed axonal type. The letter C marks this specific subtype in the intermediate group. MalaCards+1

2. Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
This longer name explains clearly that one changed copy of the gene is enough to cause disease (autosomal dominant) and that it is an intermediate-type CMT of type C. It is often used in genetic and neurology reports. MalaCards+1

3. Charcot-Marie-Tooth neuropathy, dominant intermediate C
Here, the word neuropathy simply means “disease of the peripheral nerves.” This synonym is used in genetic databases and research papers to stress that the main problem is with motor and sensory nerves. MalaCards+1

4. CMTDIC
This is a short code used in many genetic databases, where “CMT” stands for Charcot-Marie-Tooth disease, “DI” for dominant intermediate, and “C” for subtype C. It is useful in lab reports and research indexing. MalaCards+1

5. DI-CMTC (dominant intermediate Charcot-Marie-Tooth type C)
This is another abbreviation used in early mapping and gene discovery papers. It refers to the same group of families in which YARS1 mutations were first linked to this neuropathy. MalaCards+1

6. Charcot-Marie-Tooth disease caused by mutation in YARS
Some databases list this exact phrase as an alias to clearly show that the disease is due to a pathogenic change in the YARS1 gene, located on chromosome 1p35. MalaCards+1

7. YARS Charcot-Marie-Tooth disease / YARS1-associated CMT
These names are often used in research to distinguish this form from other gene-related CMT types (for example, MFN2-CMT or GJB1-CMT). It reminds clinicians that the key gene is YARS1, a member of the aminoacyl-tRNA synthetase family. ScienceDirect+1

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Types

Doctors and researchers describe several clinical patterns within YARS1-related Charcot-Marie-Tooth disease. They are not always given separate official codes, but they help to understand how the disease can look in different people.

1. Classic autosomal dominant intermediate CMT type C due to YARS1
This is the “typical” form, caused by a heterozygous (one-copy) mutation in YARS1. It shows slowly progressive weakness and wasting in the feet and legs, later in the hands, with reduced sensation and intermediate nerve conduction speeds (about 25–45 m/s in median motor nerve studies). MalaCards+1

2. Early-onset YARS1-related intermediate CMT
In some families, symptoms appear in childhood with delayed walking, frequent falls, and early foot deformities. The same gene change may cause different ages of onset in different relatives, which shows variable expressivity even within the same mutation. MalaCards+1

3. Late-onset mild YARS1-related CMT
Other people with YARS1 mutations develop symptoms only in adult life, sometimes after age 40–50, with milder weakness and less disability. Nerve tests still show intermediate conduction, but daily function may stay almost normal for many years. MalaCards+1

4. YARS1-related CMT with mainly lower-limb involvement
In some reported cases, the disease mainly affects the peroneal muscles and other lower-leg muscles, with foot drop and high arches, while hand weakness stays mild or appears late. This “peroneal pattern” is typical for CMT in general and is also seen in YARS1-related forms. MalaCards+1

5. YARS1-related multisystem disorder with neuropathy
Recent reports describe children with biallelic (two-copy) YARS1 variants who have neuropathy plus other problems such as growth delay, hearing problems, or organ involvement. These cases show that YARS1 can cause a wider multisystem disease, where CMT-like neuropathy is one part of a more complex picture. Frontiers+1

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Causes

For this disease, the main root cause is a pathogenic mutation in the YARS1 gene. The other “causes” below describe genetic mechanisms, cell-level changes, and factors that can worsen or modify the neuropathy in a person who already carries a YARS1 mutation.

1. Pathogenic heterozygous YARS1 mutation
The primary cause is a harmful change in one copy of the YARS1 gene. This mutation changes the structure of the tyrosyl-tRNA synthetase enzyme, so it cannot support normal nerve cell function. This single-gene defect is enough to cause autosomal dominant intermediate CMT type C in many families. MalaCards+1

2. Autosomal dominant inheritance from an affected parent
Most patients inherit the mutation from a mother or father who also has, or once had, CMT signs. Each child of an affected person has a 50% chance to receive the changed gene. This clear family pattern is typical for CMTDIC. MalaCards+1

3. De novo YARS1 mutation
In some cases, the YARS1 mutation appears for the first time in the affected child, due to a new change in the egg or sperm or early embryo. The parents have normal genes and no symptoms, but the child develops CMT because of this fresh mutation. MedlinePlus+1

4. Missense mutation in the catalytic domain of TyrRS
Many reported YARS1 changes are missense mutations that alter a single amino acid in the active (catalytic) part of the enzyme. This can reduce its normal tRNA-charging activity and disturb many proteins needed for long nerve fibers. PNAS+1

5. Mutations in the tRNA-binding domain of YARS1
Other mutations affect the region that binds the tRNA molecule. This can make the enzyme attach poorly or abnormally to its tRNA partner, which again disrupts normal protein building in neurons and leads to nerve degeneration. PNAS+1

6. Misfolding and mis-localization of mutant YARS protein
Mutant YARS protein can fold incorrectly and be sent to the wrong places inside the cell. Instead of helping normal protein synthesis in the cytoplasm, it may form clumps or build up in axons, which stresses the cell and damages nerve fibers. PNAS+1

7. Toxic gain-of-function of mutant YARS1
Evidence suggests that many aminoacyl-tRNA synthetase-related CMT forms, including YARS1, are not just “loss of function” but also gain of toxic new functions. The changed enzyme starts to bind to other molecules and receptors it normally would not, which harms neurons. ScienceDirect+1

8. Disrupted aminoacylation of tRNA-Tyr and protein synthesis
The central job of tyrosyl-tRNA synthetase is to attach the amino acid tyrosine to its tRNA. When this step fails, many proteins cannot be built correctly or on time. Long peripheral nerves, which rely on constant protein supply along their length, are especially sensitive to this disruption. ScienceDirect+1

9. Impaired axonal transport and mitochondrial distribution
Mutant synthetase proteins can interfere with the transport of materials inside axons, including mitochondria. If mitochondria cannot reach the nerve endings, energy supply drops and distal axons start to degenerate, a key feature of CMT. ScienceDirect+1

10. Disturbed VEGF / neuropilin-1 signaling pathway
Some research shows that mutant aminoacyl-tRNA synthetases, including YARS-related forms, can bind abnormally to the VEGF / neuropilin-1 signaling pathway, which is important for neuron survival and blood vessel support. This abnormal interaction may promote motor neuron and axon damage. ScienceDirect+1

11. Secondary axonal degeneration with mixed demyelinating features
Intermediate CMT shows both axonal loss and some demyelination. The YARS1 defect may first harm axons, and then myelin-forming Schwann cells become affected, leading to further slowing of conduction and nerve fiber loss. MalaCards+1

12. Biallelic YARS1 variants in multisystem disease
When both copies of YARS1 carry variants (biallelic), a more severe, multisystem disorder may appear with neuropathy plus other organ involvement. In those patients, the combined effect of two gene changes can cause earlier and broader nerve damage. Frontiers+1

13. Other genetic modifiers of nerve vulnerability
The exact severity in each person can differ even with the same YARS1 mutation, which suggests that other genes involved in myelin, axons, or repair pathways can modify how strongly the disease expresses itself. MedlinePlus+1

14. Increasing age and cumulative nerve stress
As people with YARS1-related CMT get older, ongoing minor injury, metabolic stress, and lifetime use of nerves gradually add damage. Age does not cause the disease, but it helps explain why symptoms often slowly get worse over decades. Wikipedia+1

15. Metabolic problems such as poorly controlled diabetes
If someone with YARS1-CMT also develops diabetes, high blood sugar can further harm peripheral nerves. This is not the original cause of the disease, but it can greatly increase numbness, pain, and weakness, making the CMT more severe. Mayo Clinic+1

16. Vitamin B12 or other nutrient deficiencies
Lack of vitamin B12, folate, or other nutrients needed for nerve health can worsen neuropathy in any patient, including those with CMT. This can add additional nerve injury on top of the YARS1-related damage. ARUP Consult+1

17. Exposure to neurotoxic medications
Certain chemotherapy drugs and some other medicines can damage peripheral nerves. In a person who already has fragile nerves due to YARS1 mutation, these drugs may trigger faster progression or a sudden jump in symptoms. ARUP Consult+1

18. Chronic alcohol misuse
Heavy, long-term alcohol use can cause alcoholic neuropathy. For someone with YARS1-CMT, alcohol-related nerve damage can stack on top of the inherited neuropathy and lead to much more severe weakness and loss of sensation. Mayo Clinic+1

19. Repeated mechanical pressure or injury to feet and legs
People with CMT often have abnormal foot shape and unstable ankles. Frequent sprains, pressure from ill-fitting shoes, and repeated minor injuries can worsen pain, deformity, and walking problems, although they do not change the gene itself. Wikipedia+1

20. Lack of early rehabilitation and orthopedic support
If helpful treatments such as physical therapy, ankle-foot orthoses, and foot care are not used, contractures and deformities can increase stress on already weak nerves and muscles. This does not cause the genetic disease but contributes to greater disability. Wikipedia+1

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Symptoms

Symptoms of YARS-related CMT are similar to other forms of CMT, but with intermediate nerve conduction speeds and often a classic “distal” pattern that starts in the feet and legs. MalaCards+2Wikipedia+2

1. Slowly progressive weakness in feet and ankles
The most common early sign is weakness in small muscles of the feet and ankles. People may notice difficulty climbing stairs, standing on toes, or pushing off when walking. This weakness slowly gets worse over years because motor nerves cannot send strong signals to these muscles. Wikipedia+1

2. Foot drop and frequent tripping
Because the muscles that lift the front of the foot become weak, the toes may drag on the ground, a problem called foot drop. Patients trip easily, especially on uneven ground, and may develop a high-stepping “steppage” gait to keep from catching their toes. Wikipedia+1

3. High-arched feet (pes cavus)
Over time, an imbalance between weak and stronger muscles pulls the foot into a high arch position. This deformity, called pes cavus, is very common in CMT and can cause shoe-fitting problems, calluses, and ankle instability. Wikipedia+1

4. Hammertoes or claw toes
The small muscles that straighten and bend the toes become weak, while other muscles stay relatively stronger. This imbalance bends the toes into a “hammer” or “claw” shape, which may rub in shoes and cause pain or skin breakdown. Wikipedia+1

5. Wasting of lower-leg muscles (“stork leg” appearance)
As the disease progresses, the muscles on the front and sides of the lower legs shrink (atrophy). The legs may look thin below the knees, with more normal thigh size, giving a “stork leg” appearance. This is a typical sign of longstanding CMT. Wikipedia+1

6. Numbness and tingling in the feet
Sensory nerves are also affected, so people often feel numbness, tingling, or “pins and needles” in the toes and soles. They may have trouble feeling small objects under the foot or may not notice minor injuries, which increases the risk of skin problems. Wikipedia+1

7. Reduced ability to feel vibration, temperature, or pain
Detailed testing shows reduced vibration sense at the ankles and toes, and sometimes reduced awareness of heat, cold, or sharp pain. This loss of protective sensation makes it easier to get burns, blisters, or unnoticed wounds. Wikipedia+1

8. Neuropathic pain or burning in feet and legs
Some patients report burning, shooting, or electric shock-like pain in the feet and lower legs. This neuropathic pain comes from damaged sensory nerves sending abnormal signals to the brain. It may be worse at night. Wikipedia+1

9. Weakness in hands and fingers
With time, weakness often travels upward to the hands. People may have difficulty with fine tasks such as buttoning clothes, writing, using tools, or opening jars. The small hand muscles may look hollow and thin. Wikipedia+1

10. Poor grip and loss of fine motor control
Even when hand strength is only mildly reduced, coordination is often affected. Patients may drop objects more easily, feel clumsy, or tire quickly when doing detailed work such as sewing or typing. Wikipedia+1

11. Balance problems and unsteady walking
Loss of sensation in the feet plus muscle weakness makes balance harder, especially in the dark or on uneven surfaces. People may sway, especially when standing with feet together and eyes closed, and they are at higher risk of falls. Wikipedia+1

12. Reduced or absent tendon reflexes
During the neurological exam, ankle and sometimes knee reflexes are reduced or absent. This is because nerve signals do not travel normally through the reflex arc that connects muscle, nerve, and spinal cord. MalaCards+1

13. Fatigue with walking or standing
Even at early stages, many patients feel that walking long distances or standing for a long time is tiring. Weak muscles and abnormal gait make each step more effortful, so daily activities may cause fatigue sooner than in healthy people. Wikipedia+1

14. Skeletal deformities such as scoliosis in some patients
In some CMT types, including intermediate forms, the spine may curve abnormally (scoliosis) or other skeletal deformities may appear. This is less common than foot deformity but can add back pain and posture problems. Wikipedia+1

15. Mild autonomic features (cold feet, reduced sweating)
Some patients notice cold, pale feet or changes in sweating. These mild autonomic features reflect involvement of small nerve fibers that control blood vessels and sweat glands in the skin. Wikipedia+1

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Diagnostic tests

Diagnosing Charcot-Marie-Tooth disease caused by YARS1 mutation needs a combination of clinical examination, electrodiagnostic tests, genetic testing, and sometimes imaging or nerve biopsy. The goal is to confirm a hereditary neuropathy, define it as an intermediate type, and prove a YARS1 mutation. ARUP Consult+2Wikipedia+2

Physical exam tests

1. Full neurological examination
The neurologist checks muscle bulk, strength, reflexes, sensation, and coordination in all four limbs. They look for distal weakness, loss of ankle reflexes, sensory changes in a “stocking-glove” pattern, and foot deformities, which strongly suggest CMT rather than a brain or spinal cord disorder. Wikipedia+1

2. Gait and posture observation
The doctor watches how the person stands and walks, looking for foot drop, high-stepping gait, ankle instability, and uneven shoe wear. They may ask the patient to walk on heels and toes and turn quickly. These simple observations help show the typical distal pattern of weakness in CMT. Wikipedia+1

3. Muscle strength grading with MRC scale
Using the Medical Research Council (MRC) scale from 0 to 5, the examiner grades strength in key muscles such as ankle dorsiflexors, plantar flexors, and finger extensors. The pattern of strongest and weakest muscles helps distinguish CMT from other muscular diseases. Wikipedia+1

4. Detailed sensory examination
Light touch, pinprick, vibration (with a tuning fork), and position sense are tested in toes, ankles, fingers, and wrists. Distal loss with proximal sparing is typical of length-dependent hereditary neuropathies such as CMT, including YARS1-related forms. Wikipedia+1

Manual tests and functional assessments

5. Romberg balance test
The patient stands with feet together, first with eyes open, then closed. Increased sway or loss of balance when eyes are closed suggests impaired position sense in the legs, which is common in sensory neuropathy like CMT. Wikipedia+1

6. Heel-walk and toe-walk tests
Walking on heels tests the muscles that lift the feet, while toe-walking tests the calf muscles. Difficulty, especially with heel-walking, is a simple bedside sign of distal weakness and possible foot drop. Wikipedia+1

7. Manual muscle testing of intrinsic foot and hand muscles
The examiner asks the patient to spread the toes, flex and extend toes and fingers, and resist pressure from the examiner’s hand. Weakness in these small intrinsic muscles is a very sensitive sign of distal hereditary neuropathy. Wikipedia+1

8. Timed walking tests (10-meter walk or 6-minute walk)
Simple timed walking tests measure how long it takes to walk a short distance or how far the patient can walk in six minutes. These tests give an objective measure of walking capacity and can be repeated over time to track disease progression or treatment response. ARUP Consult+1

Lab and pathological tests

9. Basic blood tests to exclude other causes of neuropathy
Tests such as fasting glucose, HbA1c, vitamin B12, folate, thyroid function, kidney and liver panels are done to rule out acquired neuropathies. In YARS-CMT, these tests are usually normal, which supports a hereditary cause. ARUP Consult+1

10. Nerve biopsy (usually sural nerve)
In unclear cases, a small piece of sensory nerve may be taken from the leg and examined under the microscope. In intermediate YARS-related CMT, biopsy can show reduced numbers of large myelinated fibers, axonal degeneration, and segmental demyelination without classic “onion bulbs.” MalaCards+1

11. Genetic testing panel for CMT genes
Modern testing often uses a multi-gene CMT panel that includes many neuropathy genes (PMP22, MPZ, MFN2, GJB1, and others) along with YARS1. Finding a pathogenic variant in YARS1 with a matching clinical picture confirms the diagnosis of YARS-related CMTDIC. ARUP Consult+1

12. Targeted YARS1 sequencing or exome / genome sequencing
If a panel is negative or if the family is unusual, more extensive tests such as whole-exome or whole-genome sequencing can be used. These methods have identified new YARS1 variants and clarified that some patients have either dominant CMT or recessive multisystem disease linked to YARS1. Frontiers+1

Electrodiagnostic tests

13. Motor nerve conduction studies (NCS)
Electrodes are placed on the skin over nerves and muscles, and small electrical pulses are used to measure how fast and how strongly signals travel. In YARS-CMTDIC, motor velocities are intermediate (about 25–45 m/s), which is slower than normal but faster than in classic demyelinating CMT1, helping define the “intermediate” category. MalaCards+1

14. Sensory nerve conduction studies
Similar tests are done on sensory nerves (such as the sural nerve), measuring sensory action potentials. Amplitudes may be reduced, and velocities mildly to moderately slowed, showing sensory involvement typical of hereditary motor and sensory neuropathy. MalaCards+1

15. Electromyography (EMG)
A fine needle electrode is inserted into selected muscles to record their electrical activity at rest and during contraction. EMG in CMT shows chronic denervation and reinnervation patterns, confirming that weakness is mainly due to a neuropathy rather than a primary muscle disease. ARUP Consult+1

16. F-wave and H-reflex studies
Special nerve conduction techniques such as F-waves and H-reflexes test the whole length of motor neurons and reflex arcs. These measurements can show prolonged latencies or absent responses, giving extra information about the extent of motor nerve involvement. ARUP Consult+1

Imaging tests

17. X-ray of feet and ankles
Plain X-rays show bone shape and alignment. In CMT, they often reveal high arches, hammertoes, and other deformities. These images help orthopedic surgeons plan braces or corrective surgery when needed. Wikipedia+1

18. X-ray of spine
If the physical exam suggests scoliosis or other spinal curvature, X-rays of the spine are done to measure the angle and monitor progression. This is important in planning physiotherapy or bracing and, in rare cases, surgery. Wikipedia+1

19. MRI of peripheral nerves or plexus
In selected cases, MRI can show the size and structure of peripheral nerves or nerve roots. While not needed in every patient, it can help rule out other conditions such as nerve root compression or tumor if the picture is not typical. ARUP Consult+1

20. High-resolution nerve ultrasound
Ultrasound can non-invasively show the cross-sectional area and pattern of peripheral nerves. In hereditary neuropathies, nerves may have characteristic enlargement or texture. This tool is increasingly used to support the diagnosis and to distinguish inherited from acquired neuropathies. ARUP Consult+1

General Treatment Goals in YARS-Related Charcot-Marie-Tooth Disease

In Charcot-Marie-Tooth disease from YARS mutation, the main goals are to keep you moving, reduce pain and prevent complications. Doctors and therapists try to slow contractures, maintain joint range, keep balance as safe as possible, and protect feet from pressure and wounds. Because this is a genetic neuropathy, medicines cannot “fix” the gene, but careful rehabilitation, bracing, pain control, surgery when needed, diet, mental health support and regular check-ups can greatly improve daily life and independence. nhs.uk+3Physiopedia+3ScienceDirect+3

Important safety note (especially for you as a teen): All medicine doses and treatment plans must be chosen by a qualified doctor who knows the patient personally. The details below are general education only, not a personal prescription. Never start, stop or change any drug without your doctor.

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Non-Pharmacological Treatments (Therapies and Others)

Below are 20 non-drug treatments often used in Charcot-Marie-Tooth disease. They are also useful in YARS-related CMT because the pattern of weakness and deformity is similar. ScienceDirect+3PMC+3cmt.org.au+3

1. Physical therapy for strength and flexibility
Physical therapy uses gentle, repeated exercises to keep muscles as strong and flexible as possible. The purpose is to slow muscle wasting, prevent joint stiffness and improve walking. The therapist chooses safe movements that work around weak muscles instead of over-tiring them. Over time, this helps nerves and muscles use what strength they still have in the most efficient way, so everyday tasks like standing, stepping and climbing stairs become easier and safer. PMC+1

2. Stretching and contracture prevention
Regular stretching of the calves, hamstrings, hips, hands and fingers keeps joints moving smoothly. The purpose is to prevent contractures, where a joint becomes locked in a bent position. The mechanism is simple: slow, steady stretches lengthen tight muscles and ligaments and protect the joint capsule. If done every day, stretching reduces pain, keeps the ankle closer to a normal position and makes walking and bracing easier. PMC+1

3. Occupational therapy for hand and daily activities
Occupational therapists (OTs) help with weakness in the hands and arms, and problems with dressing, writing, cooking, school work and computer use. The purpose is to keep you independent. The OT may teach joint-protecting techniques, suggest different grips and handles, and recommend adaptive equipment like built-up pens or button hooks. This works by reducing stress on weak muscles, using stronger muscle groups and smart tools instead of pure muscle power. Charcot-Marie-Tooth Association+1

4. Balance and gait training
Balance training focuses on standing, turning and walking without falling. The purpose is fall prevention and confidence. Therapists use simple tasks such as standing on different surfaces, walking in straight lines and practicing safe turning. These exercises retrain the brain to make better use of visual and inner-ear (vestibular) input to compensate for poor sensory feedback from the feet, which is common in CMT. PMC+1

5. Ankle-foot orthoses (AFOs)
AFOs are light braces worn in the shoes or on the legs to control foot drop and ankle instability. The purpose is to lift the toes, prevent tripping and support weak ankle muscles. By holding the ankle in a more neutral position, AFOs let the knee and hip move in a smoother pattern and reduce energy use when walking. They also help prevent long-term deformities by keeping joints better aligned. nhs.uk+2Charcot-Marie-Tooth Disease+2

6. Custom footwear and insoles
People with CMT often have high-arched feet, hammer toes and pressure points. Custom shoes and soft insoles spread body weight more evenly. The purpose is to protect the skin, reduce calluses and prevent ulcers. The mechanism is mechanical: well-fitted footwear cushions sharp bony areas, stabilizes the heel and improves the line of force from the hip down to the ground with every step. nhs.uk+1

7. Hand splints and thumb supports
Splints and supports for the wrist, fingers and thumb help people who have weak grip, poor pinch or joint laxity. The purpose is to allow tasks like holding a pen, using a phone or handling cutlery with less strain and pain. The splints work by stabilizing joints, placing them in a functional position and letting stronger muscles do the fine control instead of over-stretching loose joints. Charcot-Marie-Tooth Association+1

8. Aquatic (water) therapy
Water therapy uses a pool so that the body is partly supported by buoyancy. The purpose is to allow exercise with less load on weak legs and joints. Warm water relaxes tight muscles, and the gentle resistance of water helps build strength without sudden impacts. This mechanism makes it easier for someone with CMT to practice walking patterns, balance and leg exercises in a safe, low-gravity environment. PMC+1

9. Energy-conservation and fatigue management training
Because nerves and muscles are weak, people with CMT often tire easily. Therapists teach pacing, planning tasks, using rests and arranging the home or school environment to reduce unnecessary steps. The purpose is to save limited energy for what truly matters. This works by matching activity levels to what the nervous system can handle and preventing the “boom-and-bust” cycle of over-doing and then crashing with severe fatigue. PMC+1

10. Pain psychology, CBT and relaxation techniques
Chronic nerve pain and disability can cause anxiety, sadness and sleep problems. Cognitive-behavioural therapy (CBT), relaxation breathing, mindfulness and biofeedback are non-drug techniques that help the brain handle pain signals more calmly. The purpose is to reduce suffering even when pain cannot fully disappear. These methods work by changing pain-related thoughts, reducing body tension and improving sleep, which all lower pain sensitivity over time. ScienceDirect+1

11. Podiatry and regular foot care
A podiatrist looks after nails, calluses and footwear. The purpose is to avoid foot wounds, infections and ulcers that can develop because of numbness and foot deformities. Routine trimming, removing hard skin and checking for pressure marks works by catching problems early, before they become deep sores that are hard to heal in a person who might not feel early pain signals. nhs.uk+1

12. Home safety changes and fall-prevention strategies
Simple home changes like removing loose rugs, adding grab bars, improving lighting and using non-slip mats can greatly reduce falls. The purpose is safety and independence. These changes work by lowering the physical demands on weak legs and poor balance, and by giving extra points of support so that a small mis-step does not turn into a serious fall or fracture. ScienceDirect+1

13. Use of canes, walkers or wheelchairs when needed
Mobility aids such as canes, walkers, scooters or wheelchairs are tools, not failures. Their purpose is to maintain freedom, not to “give up walking.” They work by taking some of the load off weak muscles and by widening the base of support. This reduces pain and fatigue and often lets a person move farther and more safely than they could without the device. Physiopedia+1

14. Respiratory and speech therapy (in selected patients)
A small number of people with more severe CMT may have breathing muscle weakness or voice and swallowing problems. Respiratory and speech therapists test lung function, cough strength, voice and swallow safety. The purpose is to prevent chest infections and choking. They work by teaching breath support exercises, safe swallowing strategies and, when needed, recommending cough-assist devices or feeding changes. Physiopedia+1

15. Vocational and school-based rehabilitation
Vocational rehab and school adaptation help students and workers match their abilities with the demands of tasks. The purpose is to keep education and employment possible. This may include modified schedules, ergonomic chairs, voice-to-text software and rest breaks. The mechanism is social and environmental: the world around the person is adjusted so they can succeed despite physical limits. Charcot-Marie-Tooth Association+1

16. Nutrition counselling and healthy weight management
Dietitians help keep a healthy weight and muscle mass. Extra weight makes walking and balance much harder on weak legs. The purpose is to provide enough protein, vitamins and calories without excess. Good nutrition supports nerve health indirectly by reducing strain on joints and lowering the risk of diabetes and vascular disease, which could worsen neuropathy. Physiopedia+1

17. Gentle yoga, Pilates or Tai Chi (adapted)
Gentle forms of yoga, Pilates or Tai Chi, adapted for safety, can improve body awareness, breathing control and flexibility. The purpose is to build a stronger core, better posture and calmer mind. These exercises work at low intensity and focus on slow, controlled movements, which help people with CMT use remaining muscles more efficiently without over-straining them. PMC+1

18. Peer support groups and patient organizations
CMT support groups and patient organizations give emotional support, practical tips and updated information about research. The purpose is to reduce isolation and build coping skills. The mechanism is psychosocial: seeing others successfully manage similar problems changes expectations, boosts hope and gives access to shared problem-solving and advocacy resources. Charcot-Marie-Tooth Association+1

19. Sleep hygiene and posture management
Good sleep routines, a comfortable mattress and proper night-time positioning of legs and feet help reduce cramps and morning stiffness. The purpose is to let the nervous system rest and repair as much as possible. Sleep hygiene works by synchronizing the body clock and lowering pain perception, while cushions and supports keep joints in neutral positions overnight. PMC+1

20. Regular neurological follow-up and monitoring
Regular visits to a neurologist or neuromuscular clinic allow early detection of changes such as worsening foot deformity, new scoliosis, breathing problems or severe pain. The purpose is timely intervention with bracing, surgery or new therapies. Monitoring works by comparing strength, sensation and walking over time so that the team can adjust the plan before complications become permanent. Physiopedia+1

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Drug Treatments

There is no FDA-approved disease-modifying drug specifically for YARS-related CMT. Medicines are used to treat neuropathic pain, muscle cramps, mood problems and sleep, borrowing evidence from other neuropathic pain conditions. All doses and schedules must be individualized by a doctor. Physiopedia+2ScienceDirect+2

Below are examples of 20 commonly used drug options with information based on FDA labels and major reviews. Government of British Columbia+5FDA Access Data+5NCBI+5

1. Gabapentin (Neurontin and others – anti-seizure / neuropathic pain drug)
Gabapentin is an anti-seizure medicine approved for post-herpetic neuralgia and seizures, and often used off-label for nerve pain in CMT. It calms over-excited nerve cells by binding to calcium channels in the nervous system. In adults, labels describe step-up dosing over several days; doctors start low and increase slowly to balance pain relief and side effects like sleepiness and dizziness. Always follow the exact plan given by the neurologist. FDA Access Data+2HPSJ/MVHP+2

2. Pregabalin (Lyrica – anti-seizure / neuropathic pain drug)
Pregabalin is approved for several forms of neuropathic pain and seizures. It works in a similar way to gabapentin, stabilizing nerve activity. FDA labeling describes starting doses around 150 mg/day in adults, adjusted up carefully depending on effect and kidney function, but the doctor must choose the right amount for each person. Common side effects include dizziness, sleepiness, swelling and weight gain. It should not be stopped suddenly without medical advice. Drugs.com+3FDA Access Data+3FDA Access Data+3

3. Duloxetine (Cymbalta – SNRI antidepressant for pain)
Duloxetine is an antidepressant that also treats chronic neuropathic pain, like diabetic nerve pain and fibromyalgia. It increases serotonin and norepinephrine levels in pain pathways, which helps the brain “turn down” pain signals. FDA labels describe typical adult doses near 60 mg/day, adjusted for other conditions and side-effect risk; doctors set the exact dose. Side effects can include nausea, dry mouth, sweating and, rarely, liver or blood pressure issues, so medical monitoring is important. FDA Access Data+3FDA Access Data+3FDA Access Data+3

4. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline)
Old antidepressants like amitriptyline and nortriptyline are often used at low doses for nerve pain. They block re-uptake of serotonin and norepinephrine, which modifies pain processing in the spinal cord and brain. Doctors usually start with very small bedtime doses in adults and go up slowly. Side effects such as dry mouth, constipation, sleepiness and heart rhythm changes mean they must be used carefully, especially in people with heart disease or in young patients. Government of British Columbia+1

5. Topical lidocaine 5% patch (Lidoderm)
Lidocaine patches are approved for post-herpetic neuralgia but can help localized burning or shooting pain in CMT feet. The patch numbs the skin by blocking sodium channels in small nerve fibers. FDA labeling describes applying patches to intact skin for limited hours per day, with a maximum number of patches at one time; dosing and schedule must follow the label and doctor’s advice. Side effects are usually local skin irritation or numbness beyond the painful spot. FDA Access Data+2FDA Access Data+2

6. Topical capsaicin 8% patch (Qutenza)
High-strength capsaicin patches are approved for certain neuropathic pain conditions. Capsaicin temporarily over-stimulates pain receptors (TRPV1) in the skin, leading to reduced sensitivity for weeks. The patch is applied in a clinic by trained staff under careful safety steps because it can cause intense burning at first. In CMT, it may be used off-label for severe localized pain. Side effects are mainly burning, redness and temporary increased pain right after treatment. FDA Access Data+2FDA Access Data+2

7. Simple analgesics (paracetamol / acetaminophen)
Acetaminophen is a common pain reliever for mild musculoskeletal pain. It works in the brain to reduce pain and fever but does not directly fix nerve damage. It may be used alone or with other medicines to reduce overall pain levels. Doctors must ensure the total daily dose stays within safe limits to avoid liver damage, especially when combined with other medicines that contain acetaminophen. Government of British Columbia+1

8. Non-steroidal anti-inflammatory drugs (NSAIDs e.g., ibuprofen, naproxen)
NSAIDs reduce inflammation in joints and soft tissues and can help secondary pains from altered walking, such as knee, hip or back pain. They work by blocking COX enzymes that make prostaglandins. FDA-approved products have specific adult dosing ranges, but a doctor chooses the right dose and duration to limit side effects such as stomach irritation, bleeding risk, kidney strain and effects on blood pressure or heart disease risk. Government of British Columbia+1

9. Muscle relaxants (e.g., baclofen)
Baclofen is approved for muscle spasticity and sometimes used in CMT patients who develop painful cramps. It acts on GABA-B receptors in the spinal cord to reduce muscle tone. FDA labels describe divided daily dosing in adults, started low and raised slowly, but only a doctor can decide if it is appropriate. Side effects can include sleepiness, weakness and dizziness; sudden withdrawal can be dangerous, so tapering is important. FDA Access Data+3FDA Access Data+3FDA Access Data+3

10. Short-term opioids or tramadol (with great caution)
In some cases of severe acute pain (for example, after surgery), short-term use of tramadol or other opioids may be considered. They work by binding to opioid receptors and changing how the brain senses pain. Because of strong risks of dependence, overdose and sedation, especially in teens and young adults, these medicines are usually a last resort and carefully monitored. They are not a routine long-term solution for CMT neuropathic pain. Government of British Columbia+1

11. Sleep aids for severe insomnia (e.g., melatonin, low-dose sedating antidepressants)
Chronic pain and cramps can disturb sleep. Sometimes doctors use low-dose sedating drugs or melatonin to help reset sleep. The purpose is to improve rest, which can indirectly reduce pain and fatigue. Because these medicines can interact with other drugs and affect breathing or mood, especially in people with neuromuscular disease, they must be chosen and monitored carefully. NCBI+1

12. Mood-stabilizing antidepressants or anti-anxiety medicines
Living with a lifelong neuropathy can lead to depression or anxiety. Selective serotonin reuptake inhibitors (SSRIs) or SNRIs like duloxetine may be used to treat mood and pain together. They work by adjusting neurotransmitters that affect both mood and pain circuits. Doses and timing depend on the individual and must be supervised because of side effects and the risk of sudden stopping, which can cause withdrawal symptoms. FDA Access Data+2FDA Access Data+2

(Other medicines, such as different anti-seizure drugs or combinations, may be used, but the above list covers many of the key evidence-based options for neuropathic pain and related symptoms.)

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Dietary Molecular Supplements

There is limited direct evidence for specific supplements in YARS-related CMT, but some nutrients may support general nerve and muscle health. Always discuss supplements with a doctor, especially if you take prescription medicines. Physiopedia+1

1. Alpha-lipoic acid – An antioxidant used in diabetic neuropathy studies; it may help protect nerve cells from oxidative stress and improve small-fiber function. Typical adult research doses are in the hundreds of milligrams per day, but exact dosing must be individualized.

2. Acetyl-L-carnitine – Involved in energy production in mitochondria. It may help nerve regeneration and reduce neuropathic pain in some studies. It is usually taken in divided doses, but long-term safety and ideal dose in hereditary neuropathies are still being studied.

3. Omega-3 fatty acids (EPA/DHA) – Found in fish oil; they support cell membranes and have anti-inflammatory effects. They may indirectly protect nerves by improving blood vessel health and lowering inflammation.

4. Vitamin B12 (methylcobalamin) – Essential for myelin and nerve repair. If blood levels are low, replacing B12 can improve neuropathy; if levels are normal, extra B12 has uncertain benefit. Doses and route (oral vs injection) depend on lab results.

5. Vitamin B1 (thiamine) or benfotiamine – Important for energy metabolism in nerves. Deficiency can cause neuropathy. Correcting low levels and ensuring enough intake may help nerve function, though it does not cure genetic CMT.

6. Vitamin D – Supports bone health and muscle function. Low vitamin D is common in people with limited mobility and can worsen weakness and fracture risk. Supplementing to reach normal blood levels is often recommended.

7. Magnesium – May help with cramps in some people by affecting muscle contraction and nerve excitability. Too much can cause diarrhea or, in kidney problems, serious issues, so dosing must be careful.

8. Coenzyme Q10 – Supports mitochondrial energy production. It has been explored in some neuromuscular disorders; evidence in CMT is limited but it is sometimes tried as an adjunct.

9. Curcumin (from turmeric) – Has anti-inflammatory and antioxidant properties. Laboratory work suggests possible nerve-protective effects, but human evidence is modest; it is usually used as a gentle supportive measure.

10. Probiotics and gut-health support – A healthy gut can improve nutrient absorption and possibly inflammation levels. Probiotics do not directly repair nerves but may support overall health, which is important for living with chronic neuropathy. Physiopedia+1

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Drugs for Immunity, Regeneration and Stem-Cell-Related Approaches

At present, no FDA-approved “immunity booster” or stem-cell drug exists specifically for YARS-related CMT. Research is ongoing into neuro-regeneration, gene therapy and stem cells for inherited neuropathies. Any such treatment is experimental and should only be used in clinical trials. PMC+2ScienceDirect+2

1. Neurotrophic factor–based therapies (research)
Some research looks at substances that support nerve survival, such as nerve growth factor (NGF) or other neurotrophins. These aim to protect or regrow damaged axons. So far, trials have been limited, and safety and long-term effects are still being studied.

2. Gene-targeted therapy (research)
Because YARS mutations directly cause DI-CMT C, gene-editing or gene-replacement strategies are being explored in laboratories and early animal models. The idea is to correct the defective gene or balance its activity. This is promising but not yet available as routine care for people. PMC+2PNAS+2

3. Stem-cell-based nerve repair (research)
Stem cell therapy aims to replace or support damaged Schwann cells or neurons. Several small studies in other neuropathies exist, but there is not yet strong, routine evidence for inherited CMT. Such treatments must be given only in well-regulated trials, because unproven commercial stem-cell clinics can be unsafe. ScienceDirect+1

4. Immunoglobulin (IVIG) and steroids (not standard for pure genetic CMT)
IVIG and steroids help in immune-mediated neuropathies like CIDP, not in typical genetic CMT. Sometimes, when doctors suspect both genetic and immune components, they may consider a monitored trial. These drugs change the immune system, so they carry important risks and are not used lightly. ScienceDirect+1

5. Antioxidant combinations in research protocols
Some clinical trials test cocktails of antioxidants and metabolic supporters in CMT (e.g., CMT1A). These try to protect nerves from stress related to faulty myelin or axons. Evidence is still emerging, so they are not standard prescriptions, but they show how future “disease-modifying” strategies may look. ScienceDirect+1

6. Supportive vaccines and infection prevention
While not a “regenerative drug,” staying up to date with vaccines protects overall health and reduces hospitalizations, which can worsen weakness. Preventing serious infections helps maintain strength and independence, especially in people who already have limited reserves because of neuropathy. Physiopedia+1

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Surgical Options

Surgery does not cure YARS-related CMT, but it can correct deformities and improve function. Physiopedia+2ScienceDirect+2

1. Foot deformity correction (osteotomy and tendon transfers)
Surgeons may cut and reposition bones (osteotomy) or move tendons to balance muscle forces in high-arched (cavus) feet. This makes the foot flatter and more stable, reducing pain and improving walking.

2. Achilles tendon lengthening
If the calf tendon is very tight and the heel cannot touch the ground, lengthening the Achilles tendon can bring the ankle closer to neutral. This helps walking and bracing and reduces risk of falls.

3. Fusion of severely unstable joints
In advanced deformity, fusing certain foot joints into a fixed but functional position can remove painful motion and improve stability in shoes and braces.

4. Hand surgery for clawed fingers or thumb problems
Tendon transfers or joint releases in the hand can improve grip and pinch when splints alone are not enough. This allows better independence with daily tasks.

5. Spine surgery for severe scoliosis
Rarely, scoliosis becomes so severe that it affects posture or breathing. In such cases, spinal fusion may be considered to straighten and stabilize the spine and protect lung function.

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Prevention Strategies (What Can Be Prevented)

You cannot prevent the YARS gene mutation itself, but you can reduce complications:

1. Avoid nerve-toxic drugs (some chemotherapy and certain antibiotics) unless absolutely necessary; always tell doctors you have CMT. ScienceDirect

2. Protect your feet with proper shoes, daily inspection and prompt care of blisters or sores. nhs.uk+1

3. Prevent falls by using braces, mobility aids and home safety changes. PMC+1

4. Maintain a healthy weight to reduce strain on weak legs and joints. Physiopedia+1

5. Stay physically active in safe ways (PT-guided exercise, aquatic therapy) to slow contractures. PMC+1

6. Keep vaccinations up to date to avoid serious infections and hospital stays. Physiopedia+1

7. Control other health risks like diabetes and smoking, which can worsen nerve damage. ScienceDirect+1

8. Use orthoses early when recommended, rather than waiting for severe deformity. Charcot-Marie-Tooth Disease+1

9. Get regular neurologist and therapist follow-up for early detection of complications. Physiopedia+1

10. Seek genetic counselling for family planning and understanding inheritance. MalaCards+1

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Diet: What to Eat and What to Avoid

What to eat:

• A balanced diet rich in fruits, vegetables, whole grains, lean proteins and healthy fats supports general nerve and muscle health.

• Adequate protein (fish, eggs, dairy, legumes) helps maintain muscle mass.

• Foods rich in B vitamins, vitamin D, calcium and magnesium support nerve and bone health when intake is not excessive.

• Omega-3 sources like fatty fish, flax and walnuts may help reduce inflammation. Physiopedia+1

What to avoid or limit:

• Excess junk food, sugar and sugary drinks, which promote weight gain and metabolic disease.

• Very high alcohol intake, which can damage nerves further.

• Crash diets or severe calorie restriction, which can cause muscle loss.

• Unproven “miracle” supplement cocktails advertised online without strong evidence, especially if expensive or not checked by your doctor. ScienceDirect+1

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When to See a Doctor

You should see a doctor or neuromuscular specialist regularly for routine follow-up. In addition, get medical help soon if you notice:

• Rapid worsening of weakness, walking or balance

• New severe pain, burning or electrical sensations that do not improve

• New breathing problems, morning headaches or trouble lying flat

• New scoliosis, hip or back pain that limits movement

• Foot ulcers, infections, colour changes or wounds that do not heal

• Major changes in mood, anxiety or sleep that affect daily life

Urgent or emergency care is needed if you have sudden severe breathing trouble, chest pain, high fever with weakness, or a serious fall or head injury. Physiopedia+2ScienceDirect+2

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Frequently Asked Questions (FAQs)

1. Can YARS-related Charcot-Marie-Tooth disease be cured?
Right now there is no cure for CMT caused by YARS mutation. Treatment focuses on symptoms and function with physical therapy, orthoses, pain control and sometimes surgery. Researchers are studying gene-targeted and regenerative therapies for inherited neuropathies, but these are not yet standard care. PMC+2ScienceDirect+2

2. Will everyone with a YARS mutation have the same severity?
No. Even in the same family, some people may have mild weakness and others more severe problems. The exact mutation, other genes and lifestyle factors all influence how the disease shows itself. MalaCards+2Breda Genetics srl+2

3. Does exercise make CMT worse?
Properly guided, low-to-moderate exercise usually helps maintain strength and flexibility. Over-training or very high-impact sports can over-tire weak muscles and strain joints. Working with a therapist familiar with CMT is the safest way to design an exercise plan. PMC+2cmt.org.au+2

4. Can diet alone treat YARS-related CMT?
Diet cannot change the gene mutation, but good nutrition supports energy, muscle and bone health and reduces the risk of other diseases that could worsen neuropathy. Supplements may help in cases of true deficiency, but they are not a stand-alone cure. Physiopedia+1

5. Are pain medicines like gabapentin and pregabalin safe long-term?
Gabapentin and pregabalin can be helpful but have side effects like dizziness, weight gain and sleepiness and can interact with other drugs. Doctors carefully balance dose and benefits and may adjust treatment over time. They must be tapered rather than stopped suddenly. Government of British Columbia+3FDA Access Data+3NCBI+3

6. Is surgery always needed for foot deformities?
No. Many people manage well with orthoses and footwear changes. Surgery is considered when deformity is rigid, painful or causes frequent falls and braces are not enough. Decisions are individual and made with an experienced orthopaedic or foot surgeon. Physiopedia+2ScienceDirect+2

7. Can children or teens with CMT still play sports?
Often yes, with adjustments. Low-impact sports like swimming or cycling are usually safer than high-impact contact sports. Braces, rest breaks and close monitoring reduce injury risk. The doctor or therapist can advise which activities are best. PMC+1

8. Will I end up in a wheelchair?
Many people with CMT never need a wheelchair full-time. Some may use one for long distances or when tired. Early treatment, bracing and therapy can help maintain walking for many years. Physiopedia+2ScienceDirect+2

9. Is pregnancy safe in someone with CMT?
Many people with CMT have successful pregnancies, but extra planning is needed. Weak muscles, balance changes and possible breathing issues must be monitored. Choice of pain medicines during pregnancy is very specific and must be handled by specialists. ScienceDirect+2FDA Access Data+2

10. Should my family members be tested for the YARS mutation?
Because this is usually an autosomal dominant inherited condition, close relatives may wish to discuss genetic testing with a genetic counsellor. Testing is a personal decision and should be paired with proper counselling. MalaCards+1

11. Are stem-cell clinics on the internet trustworthy for CMT?
Most commercial stem-cell clinics offering “cures” for CMT are not backed by strong evidence and may be unsafe or very expensive. Real stem-cell work is happening in controlled clinical trials, not in unregulated private clinics. ScienceDirect+1

12. Can CMT cause problems with the heart or breathing?
Some people can develop breathing issues if respiratory muscles or the spine are affected. Direct heart muscle disease is less common but must be checked if symptoms appear. Doctors may perform lung tests and sometimes heart tests as part of follow-up. Physiopedia+1

13. Does CMT affect thinking or intelligence?
Typical CMT, including YARS-related forms, mainly affects peripheral nerves, not the brain’s thinking centers. Intelligence is usually normal. However, chronic pain and fatigue can affect school or work performance, so support and accommodations are important. Physiopedia+1

14. How often should I see my neurologist?
Many experts suggest at least yearly visits, or more often if symptoms are changing. Children and teens may need more frequent check-ups while they are growing, to adjust braces and watch for scoliosis or rapid changes. PMC+2cmt.org.au+2

15. What is the long-term outlook (prognosis)?
CMT from YARS mutation is usually slowly progressive. Many people remain able to walk and live independent lives with the right supports. Early diagnosis, regular therapy, good foot care, smart use of medicines and surgery when needed all improve long-term function and quality of life. MalaCards+2Breda Genetics srl+2

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: December 23, 2025.