Charcot-Marie-Tooth Disease Dominant Intermediate E (CMTDIE)

Charcot-Marie-Tooth disease dominant intermediate E (CMTDIE) is a rare inherited nerve disease that mainly affects the long nerves in the legs and arms. It belongs to the big Charcot-Marie-Tooth (CMT) group of disorders, which cause slowly worsening weakness and loss of feeling, especially in the feet and hands. In CMTDIE, the damage is in the peripheral nerves (the “wires” that go from the spinal cord to muscles and skin).Wikipedia+2Cleveland Clinic+2

Charcot-Marie-Tooth disease dominant intermediate E (often shortened to CMTDIE) is a rare inherited nerve disease. It damages the long nerves that carry signals to and from the legs, arms, feet, and hands. People usually develop slowly progressive weakness in the feet and legs, balance problems, and numbness or tingling. In this subtype, nerve tests show “intermediate” speed, meaning the problem affects both the nerve insulation (myelin) and the inner wire (axon).cmtausa.org+1

CMTDIE is usually caused by a faulty copy of the INF2 gene, which is important for the actin “skeleton” inside cells. This mutation can affect both peripheral nerves and the kidneys, so some people also develop a kidney disease called focal segmental glomerulosclerosis (FSGS), with protein in the urine and, over time, possible kidney failure.malacards.org+1

Doctors call this form “dominant intermediate” because the problem in the nerves looks in-between the classic “demyelinating” type (damage mainly to the myelin insulation) and the “axonal” type (damage mainly to the nerve core or axon). In nerve conduction tests, the signal speed is not very slow and not normal, but in the middle, usually about 25–45 m/s.Muscular Dystrophy Association+2ScienceDirect+2

The “E” in CMTDIE is an alphabet letter used to show the exact genetic subtype. In this subtype, almost all known patients have a disease-causing change (mutation) in a gene called INF2. The same INF2 change can also cause a kidney disease called focal segmental glomerulosclerosis (FSGS), so some people with CMTDIE also develop kidney problems such as protein in the urine and gradual kidney failure.UniProt+3cmtausa.org+3NCBI+3

Other names

Doctors and researchers may use several different names for Charcot-Marie-Tooth disease dominant intermediate E. All of the names below describe the same basic condition:

1. CMTDIE (short form commonly used in expert and patient resources).cmtausa.org+1

2. Charcot-Marie-Tooth disease, dominant intermediate E (full English name).malacards.org+1

3. Autosomal dominant intermediate Charcot-Marie-Tooth disease type E (shows the inheritance pattern).monarchinitiative.org+1

4. Dominant intermediate Charcot-Marie-Tooth neuropathy due to INF2 mutation (emphasizes the gene).neurosci.cn+1

5. Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis / FSGS (used when kidney biopsy shows FSGS).NCBI+1

These slightly different names reflect the same core idea: an inherited mixed-type peripheral neuropathy linked to INF2, sometimes combined with serious kidney disease.cmtausa.org+2malacards.org+2

Types

Experts think about CMTDIE in the context of the larger intermediate CMT group and also in terms of how the disease looks in real life (phenotype). Intermediate CMT itself is rare and shows nerve conduction speeds that are neither clearly demyelinating nor clearly axonal. It can be divided into dominant (DI-CMT) and recessive (RI-CMT) forms; CMTDIE belongs to the dominant group.ScienceDirect+3cmtausa.org+3neurosci.cn+3

Within dominant intermediate CMT, several genes are known (for example MPZ, INF2, DNM2, YARS, GNB4, NEFL, MFN2). Each gene gets a letter label (A, B, C, etc.), and CMTDIE is the INF2-related subtype. Other dominant intermediate subtypes share common clinical features with CMTDIE but are genetically different.neurosci.cn+1

Clinically, doctors sometimes think of CMTDIE in a few “patterns,” even though these are not official separate types:

1. CMTDIE with mainly neuropathy – typical CMT signs (leg and foot weakness, numbness) without clear kidney problems.malacards.org+1

2. CMTDIE with neuropathy and kidney disease (FSGS) – classic nerve problems plus protein in urine, swelling, and gradual worsening kidney function.NCBI+2cmtausa.org+2

3. Early-onset CMTDIE – symptoms starting in childhood or teenage years, with more marked weakness and foot deformities.Wikipedia+2Cleveland Clinic+2

4. Adult-onset CMTDIE – first clear symptoms in early or mid-adult life, usually with milder or more slowly progressive signs.Cleveland Clinic+1

Causes

Because CMTDIE is a genetic disease, the true direct cause is a harmful change in the INF2 gene. Environmental or lifestyle factors cannot create CMTDIE by themselves, but they may make symptoms worse. The list below explains 20 closely related genetic and biological “causal” factors in simple language.

1. Pathogenic INF2 mutation – In almost all reported patients with CMTDIE, genetic testing finds a disease-causing mutation in the INF2 gene. INF2 encodes a protein that controls the actin skeleton inside cells, especially in nerve cells and kidney podocytes. A harmful mutation changes how this protein works and leads directly to the disease.cmtausa.org+2neurosci.cn+2

2. Autosomal dominant inheritance – CMTDIE follows an autosomal dominant pattern. This means a person usually needs only one changed copy of INF2 (from one parent) to develop the disease. Each child of an affected parent has a 50% chance of inheriting the mutation.MedlinePlus+2monarchinitiative.org+2

3. De novo (new) INF2 mutation – In some families, the INF2 change appears for the first time in a child with no prior family history. This “de novo” mutation is a new error in the gene that happened in the egg, sperm, or very early embryo, but it still causes the same disease.MedlinePlus+1

4. Mutations in key INF2 domains – Many CMTDIE mutations cluster in specific functional parts of INF2, such as the diaphanous inhibitory domain. A change in this sensitive region can strongly disturb actin regulation in nerves and kidneys, leading to neuropathy plus FSGS.neurosci.cn+2UniProt+2

5. Disruption of actin cytoskeleton in nerve cells – INF2 helps build and remodel actin filaments inside nerve cells. Mutations can make this system over-active or unstable, so axons and myelin support structures become fragile, which over time causes weakness and sensory loss in the limbs.Wikipedia+2Cleveland Clinic+2

6. Schwann cell and myelin involvement – In peripheral nerves, Schwann cells form myelin, the insulation around axons. Intermediate CMT, including CMTDIE, shows features of both myelin and axonal injury, so INF2-related changes likely affect not only neurons but also Schwann cell structure and support.ScienceDirect+2NCBI+2

7. Axonal degeneration – Over years, the stressed and damaged peripheral axons gradually degenerate. This axonal loss explains the slowly progressive weakness and wasting of distal muscles in the legs and arms typical of CMTDIE.Wikipedia+2Cleveland Clinic+2

8. Podocyte damage and FSGS – INF2 is also important in kidney podocytes, which are cells that filter blood. Mutations can cause podocyte foot process fusion and scarring of parts of the glomerulus (FSGS). This is why some people with CMTDIE also develop protein in the urine and kidney failure.NCBI+2monarchinitiative.org+2

9. Family clustering and founder effects – In some populations or families, the same INF2 mutation is seen in many relatives. This pattern suggests a founder effect, where a single ancestral mutation has been passed down to many descendants who then share similar CMTDIE features.neurosci.cn+2Wikipedia+2

10. Variable expressivity of INF2 mutations – Not everyone with the same INF2 mutation has exactly the same signs. Some family members may show mainly neuropathy, others mainly kidney problems, and some both. This “variable expressivity” is driven by the same genetic cause but shaped by other genes and background factors.NCBI+2monarchinitiative.org+2

11. Genetic modifiers in other CMT genes – Research shows that many genes can influence peripheral nerve health (such as MPZ, DNM2, MFN2). In a person with INF2 mutation, small changes in these other genes may modify how early symptoms start or how severe they become, even though INF2 remains the primary cause.neurosci.cn+2NCBI+2

12. Overlap with broader intermediate CMT mechanisms – Intermediate CMT as a group shows mixed demyelinating and axonal nerve pathology. Shared mechanisms such as abnormal myelin maintenance, disturbed axonal transport, and chronic low-grade inflammation may also contribute to nerve damage in CMTDIE.ScienceDirect+2PMC+2

13. Chronic nerve vulnerability to everyday stress – Nerves that are already weakened by INF2-related changes may be more sensitive to normal life stresses, such as minor injuries or repetitive strain. Over time, this added stress can worsen weakness and numbness, although it does not cause the disease by itself.Wikipedia+2Cleveland Clinic+2

14. Superimposed metabolic problems – Conditions like diabetes, poor kidney function, or vitamin deficiencies can cause their own neuropathies. In a person with CMTDIE, these extra metabolic problems may further damage nerves and make symptoms appear earlier or more severely.Cleveland Clinic+2arupconsult.com+2

15. Toxic nerve exposures in carriers – Some chemotherapy drugs, heavy metals, and alcohol can injure peripheral nerves. In someone with an INF2 mutation, these toxins may not start CMTDIE, but they can add damage on top of the inherited neuropathy.Cleveland Clinic+1

16. Long nerve length and distance from the spine – The longest nerves, especially those to the feet, are more vulnerable to any kind of neuropathy. In CMTDIE, this “length dependence” means symptoms usually start in the feet and ankles because those axons are most affected by the INF2-related damage.Wikipedia+2Cleveland Clinic+2

17. Age-related accumulation of nerve damage – CMTDIE progresses slowly. As the years go by, small ongoing axonal losses accumulate, and eventually muscle weakness, deformities, and sensory loss become more obvious, even though the root cause (INF2 mutation) has been present since birth.Wikipedia+2Cleveland Clinic+2

18. Incomplete penetrance and late recognition – Some people with INF2 mutations may show only very mild or late symptoms. This incomplete penetrance can hide the disease in earlier generations, making it seem “new” in a child even though the mutation was present in a parent.MedlinePlus+2NCBI+2

19. Kidney–nerve interaction in advanced disease – Severe FSGS and kidney failure can cause additional metabolic and nerve problems (for example, uremic neuropathy). In people with CMTDIE, this can further worsen nerve function and weakness, although the underlying INF2 mutation is still the starting cause.NCBI+2monarchinitiative.org+2

20. Unknown INF2-related pathways – Research is still uncovering how INF2 mutations translate into nerve and kidney damage. It is likely that changes in cell signaling, calcium handling, and other pathways also play a role, but these mechanisms are not fully understood yet.neurosci.cn+2UniProt+2

Symptoms

1. Distal leg weakness – The earliest and most common symptom is weakness in the muscles of the feet and lower legs. People may notice that they cannot run as fast, climb stairs easily, or stand on their toes. Over time, the lower leg muscles become thin.Wikipedia+2Cleveland Clinic+2

2. Foot drop and tripping – Weakness in the muscles that lift the front of the foot can cause “foot drop.” The toes drag when walking, leading to frequent tripping, especially on uneven ground or stairs. Many people develop a high-stepping “steppage” gait to avoid catching the toes.Wikipedia+2Cleveland Clinic+2

3. High arches and hammertoes – Over time, imbalanced muscle pull deforms the feet. The arch becomes very high (pes cavus), and the toes may curl (hammertoes). These fixed deformities can cause pain, pressure points, and trouble finding comfortable shoes.Wikipedia+2Cleveland Clinic+2

4. Ankle instability and frequent sprains – Weak muscles around the ankle and poor sensation in the feet can make the joints unstable. People with CMTDIE may twist their ankles easily, suffer repeated sprains, or feel afraid of walking on rough ground.Cleveland Clinic+2arupconsult.com+2

5. Hand weakness and fine motor problems – As the disease advances, weakness can spread to the hands. Simple tasks like buttoning clothes, writing, or opening jars become hard. Objects may slip from the hands because of both weakness and sensory loss.Wikipedia+2Cleveland Clinic+2

6. Muscle wasting of calves and forearms – Long-standing nerve damage leads to visible thinning of muscles, especially in the calves and later in the hands and forearms. The legs can look “inverted champagne bottle” in shape: thin calves with relatively normal thighs.Wikipedia+2Cleveland Clinic+2

7. Numbness and tingling in feet and hands – Damage to sensory fibers causes reduced feeling, pins-and-needles, or burning sensations. These abnormal feelings often start in the toes and soles and may slowly climb up the legs, and later affect the hands.Wikipedia+2Cleveland Clinic+2

8. Loss of vibration and position sense – People may have trouble sensing the position of their toes or feeling a tuning fork vibration. This makes it harder for the brain to know exactly where the foot is, which adds to balance problems, especially in the dark.Wikipedia+2Cleveland Clinic+2

9. Balance difficulty and falls – Because of weakness and sensory loss, standing and walking can become unstable. People may sway when standing with feet together, especially with eyes closed, and may fall more often than others.Wikipedia+2Cleveland Clinic+2

10. Reduced or absent reflexes – Tendon reflexes, such as the ankle jerk, are often weak or absent. Doctors usually find this during the neurologic exam. People do not usually notice this themselves, but it is an important clinical sign.Wikipedia+2Orthobullets+2

11. Neuropathic pain or discomfort – Some people with CMTDIE feel burning, aching, or shooting pains in the feet or legs. Others may feel only numbness. Pain levels vary widely between individuals and do not always match the degree of weakness.Cleveland Clinic+2Wikipedia+2

12. Fatigue and reduced endurance – Because walking and standing require extra effort from weakened muscles, people often tire quickly. Everyday activities like shopping, school, or work may feel exhausting, especially late in the day.Cleveland Clinic+2Wikipedia+2

13. Difficulty running and sports participation – Children or teens with CMTDIE may be slower than their peers in sports and may avoid running games. They might be seen as “clumsy” or unathletic before the diagnosis is recognized.Cleveland Clinic+2Wikipedia+2

14. Kidney-related symptoms in some patients – When FSGS is present, there may be swelling of the legs or face, frothy urine (due to protein), tiredness, and high blood pressure. These symptoms are not caused by the neuropathy itself but by the associated kidney disease linked to the same INF2 mutation.NCBI+2cmtausa.org+2

15. Emotional and social impact – Long-term physical disability and visible foot or leg deformities can lead to low mood, anxiety, or social withdrawal. People may feel embarrassed by braces, walking aids, or difficulty keeping up with others, even though the condition is not their fault.Cleveland Clinic+2arupconsult.com+2

Diagnostic tests

Physical exam–based tests

1. Full neurologic examination – The doctor checks muscle strength, tone, reflexes, and different types of sensation (touch, pain, vibration). In CMTDIE, the exam usually shows distal weakness, reduced reflexes, and sensory loss in a “stocking-glove” pattern. This clinical picture strongly suggests a peripheral neuropathy.Wikipedia+2Cleveland Clinic+2

2. Gait and posture assessment – Watching how the person walks and stands gives important clues. A high-stepping gait, ankle rolling, or difficulty walking on heels or toes suggests distal weakness and foot drop, as commonly seen in CMT.Wikipedia+2Cleveland Clinic+2

3. Foot and lower limb inspection – The doctor looks for high arches, hammertoes, calluses, and muscle wasting in the calves. These typical structural changes are common in CMT and help distinguish it from other causes of neuropathy.Wikipedia+2Cleveland Clinic+2

4. Manual muscle strength grading (MRC scale) – Muscles in the ankles, toes, and hands are tested against resistance and graded from 0 to 5. In CMTDIE, weakness is usually most pronounced in ankle dorsiflexion and toe movements, matching the pattern of length-dependent neuropathy.Wikipedia+2Cleveland Clinic+2

5. Deep tendon reflex testing – Using a reflex hammer, the doctor taps tendons at the ankle, knee, and elsewhere. Reduced or absent ankle reflexes are typical in CMT and help confirm that the peripheral nerves are not working normally.Wikipedia+2Orthobullets+2

Manual bedside tests

6. Romberg balance test – The person stands with feet together, first with eyes open, then closed. Increased swaying with eyes closed suggests impaired position sense in the legs, which is common in CMT. This simple test highlights the sensory component of the neuropathy.Wikipedia+2Cleveland Clinic+2

7. Heel-to-toe and tandem walking – Walking on heels, walking on toes, and walking in a straight line heel-to-toe are used to check distal strength and coordination. Difficulty performing these tasks is typical of length-dependent motor neuropathy such as CMTDIE.Wikipedia+2Cleveland Clinic+2

8. Vibration sense testing with tuning fork – A vibrating tuning fork is placed on bones in the feet and legs. In CMT, vibration sense is often reduced in the toes and ankles, reflecting involvement of large sensory fibers.Wikipedia+2Cleveland Clinic+2

9. Joint position sense (proprioception) testing – The examiner gently moves the patient’s toes or fingers up and down and asks them to say the direction with eyes closed. Poor performance points to large-fiber sensory neuropathy, which fits with the intermediate CMT picture.Wikipedia+2arupconsult.com+2

Lab and pathological tests

10. Routine blood tests to exclude mimics – Tests such as blood sugar, vitamin B12, thyroid function, and kidney and liver tests help rule out other common causes of neuropathy. While these are usually normal in CMTDIE, they are important so that treatable causes are not missed.arupconsult.com+2www.elsevier.com+2

11. Kidney function tests (creatinine, urea, electrolytes) – Because INF2 mutations can cause FSGS, checking blood kidney function is important. Rising creatinine or other abnormalities may suggest early kidney involvement in a person with CMTDIE.NCBI+2monarchinitiative.org+2

12. Urinalysis for proteinuria – A simple urine dipstick or laboratory test can detect protein in the urine. Persistent proteinuria is a warning sign of FSGS or other kidney damage and is a key clue that an INF2-related CMT subtype such as CMTDIE may be present.NCBI+2cmtausa.org+2

13. Targeted genetic testing for INF2 – Once intermediate CMT is suspected, a molecular test can look for mutations in INF2. Finding a clearly pathogenic INF2 variant in someone with typical clinical and electrodiagnostic features confirms the diagnosis of CMTDIE.cmtausa.org+2neurosci.cn+2

14. Next-generation sequencing CMT gene panel – In many centers, clinicians order a panel that includes many CMT-related genes (such as MPZ, INF2, DNM2, YARS, GNB4, NEFL, MFN2). This approach increases the chance of finding the exact genetic cause when the family history or clinical pattern is not straightforward.neurosci.cn+2www.elsevier.com+2

15. Kidney biopsy for FSGS – If kidney disease is suspected, a biopsy may be performed. Under the microscope, FSGS shows scarring in parts of some glomeruli. When this pattern is seen together with CMT and an INF2 mutation, the combined diagnosis of CMTDIE with FSGS becomes very likely.NCBI+2monarchinitiative.org+2

Electrodiagnostic tests

16. Nerve conduction studies (NCS) – Small electrical shocks are used to measure how fast and how strongly nerves conduct signals. In CMTDIE, motor nerve conduction velocities are usually in the intermediate range (about 25–45 m/s), and amplitudes may be reduced, showing both demyelinating and axonal features. This “intermediate” pattern is central to the diagnosis.ScienceDirect+2PMC+2

17. Electromyography (EMG) – A thin needle electrode is inserted into muscles to record their electrical activity. EMG in CMTDIE typically shows signs of chronic denervation and re-innervation, confirming a long-standing neuropathic process affecting distal muscles.Wikipedia+2Charcot-Marie-Tooth Disease+2

18. Late response studies (F-waves and H-reflexes) – These specialized nerve tests look at conduction along the entire length of motor pathways. Abnormal or delayed F-waves and H-reflexes support the presence of a generalized peripheral neuropathy such as CMTDIE.Orthobullets+2ScienceDirect+2

Imaging tests

19. Peripheral nerve ultrasound – High-resolution ultrasound can show changes in nerve size and structure. In some CMT forms, nerves may be mildly enlarged. While not specific, ultrasound can support the diagnosis of inherited neuropathy and help distinguish it from other causes.ScienceDirect+2arupconsult.com+2

20. Magnetic resonance imaging (MRI) of nerves or limbs – MRI may be used to look at muscle bulk, fatty replacement, or, in research settings, the nerves themselves. It can show patterns of chronic denervation in the lower legs and help rule out spinal cord or root problems that could mimic CMT.Wikipedia+2arupconsult.com+2

Non-pharmacological treatments (therapies and others)

1. Physiotherapy (physical therapy)
Physiotherapy is one of the most important non-drug treatments in CMTDIE. A physiotherapist teaches safe stretching, strengthening, and balance exercises to keep muscles working as well as possible and to prevent them from shortening (contractures). Regular therapy helps maintain walking, reduces stiffness, and slows joint deformities. Over time, this can delay disability and help people stay independent in daily life.nhs.uk+2Physiopedia+2

2. Stretching and range-of-motion exercises
Daily gentle stretches for the ankles, knees, hips, hands, and fingers help keep joints loose. In CMTDIE, weak muscles can pull joints into abnormal positions, especially the feet. Stretching counters this pull, makes walking smoother, and lowers the chance of painful contractures. The mechanism is simple: slow, repeated stretching signals muscles and tendons to stay flexible and not “shrink” over time.

3. Strength training with light resistance
Low-impact strength training focuses on the muscles that still have useful power. Using elastic bands, light weights, or water exercises, the therapist sets a safe program so muscles are challenged but not over-tired. In CMT, studies show that strength and endurance training can improve function and daily activities when done carefully and regularly, without overloading the weak nerves.PMC+1

4. Balance and gait training
Because weak ankle and foot muscles cause instability, physiotherapists use balance boards, tandem walking, and targeted stepping drills. These exercises train the brain and remaining nerves to react faster and more safely. The goal is to reduce falls, increase confidence, and make walking patterns (gait) smoother and more energy-efficient.

5. Aerobic (endurance) exercise
Low-impact activities like walking on flat ground, cycling, or swimming improve heart and lung fitness without heavy impact on weak feet. Aerobic exercise helps reduce fatigue, supports weight control, and benefits mood. The mechanism is improved blood flow and general conditioning, which can indirectly support nerve and muscle health and reduce overall tiredness.

6. Occupational therapy (OT)
Occupational therapists focus on daily activities, such as dressing, writing, working, and using tools. They suggest energy-saving strategies and adaptive devices like special grips, button hooks, or modified keyboards. The purpose is to keep independence in school, work, and home life by adapting the environment to the person, rather than forcing the person to fit a difficult environment.Muscular Dystrophy Association

7. Ankle-foot orthoses (AFOs)
AFOs are braces worn in the shoe and around the lower leg to lift the front of the foot (“foot drop”) and stabilize the ankle. In CMT, custom AFOs can improve walking, reduce tripping, and lower the risk of sprains and falls. The brace works by holding the foot in a safer, more neutral position so weak muscles do not have to do all the work.cmtausa.org+2Pod NMD+2

8. Foot orthoses and custom footwear
Soft insoles, arch supports, and special shoes help support high arches, hammertoes, or flat feet that are common in CMT. Foot orthoses spread pressure more evenly, reduce pain spots, and improve foot alignment. This mechanical support can make walking less painful and reduce calluses, ulcers, and deformity progression.

9. Walking aids (canes, crutches, walkers)
As CMTDIE progresses, some people benefit from a cane, crutch, or rollator. A walking aid provides extra points of contact with the ground, improving balance and reducing the risk of falls. It shifts part of the body weight from weak legs to the arms and device, making movement safer and less tiring.

10. Hand splints and wrist supports
If hand weakness is present, splints and wrist braces can stabilize joints and improve function. For example, a wrist support can help keep the hand in a better position for typing or holding objects. The mechanism is simple mechanical stabilization, which reduces strain on weak muscles and can lessen hand fatigue and pain.

11. Pain management techniques (non-drug)
Heat packs, cold packs, massage, gentle stretching, and relaxation breathing can reduce pain signals from muscles and joints. Methods like mindfulness and cognitive-behavioral techniques teach people to manage chronic pain more effectively. They work by changing the way the brain interprets pain, reducing stress hormones and muscle tension.

12. Psychological counseling and support groups
Living with a progressive neuropathy can lead to sadness, anxiety, or frustration. Counseling and peer support groups offer emotional tools, coping strategies, and a sense of community. This psychosocial support helps reduce isolation, improves adherence to therapy, and strengthens resilience when facing long-term disability or kidney issues.

13. Kidney-protective lifestyle counseling
Because CMTDIE can include kidney disease (FSGS), lifestyle advice is crucial. A renal dietitian and nephrologist may recommend limiting salt, avoiding dehydration, and managing blood pressure. These steps reduce strain on the kidneys and may slow kidney damage, protecting overall health and energy.NCBI+1

14. Fall-prevention home modifications
Simple changes at home—removing loose rugs, improving lighting, installing grab bars, and using non-slip mats—greatly reduce fall risk. The purpose is to match the environment to the person’s balance and strength level. This reduces injuries, hospital visits, and fear of moving around, which can otherwise lead to more weakness.

15. Sleep hygiene and fatigue management
Good sleep habits (regular bedtime, quiet dark room, limiting screens) help the nervous system recover daily. Planning rest breaks, pacing activities, and alternating heavy and light tasks prevent “boom and bust” fatigue. The mechanism is managing energy so nerves and muscles are not constantly overloaded.

16. Weight management and healthy nutrition
Maintaining a healthy weight reduces stress on weak legs and feet, making walking easier. A balanced diet rich in vegetables, fruits, whole grains, and lean protein supports general health, immunity, and kidney function. Good nutrition also helps the body respond better to infections and injuries.

17. Smoking cessation support
Smoking damages blood vessels and lowers oxygen delivery to nerves and muscles. Stopping smoking improves circulation and may help preserve remaining nerve function. Programs offering counseling, nicotine replacement, and support groups make quitting more successful and protect long-term health.

18. Genetic counseling
Because CMTDIE is usually autosomal dominant, each child of an affected person has a significant chance of inheriting the mutation. Genetic counselors explain the inheritance pattern, test options, and reproductive choices in simple language. This helps families make informed decisions and plan early monitoring for symptoms.Muscular Dystrophy Association+1

19. Education about safe medications
Some drugs are known to be toxic to peripheral nerves. A neurologist can provide a list of medicines to avoid or use with caution and send this information to other doctors. Educating patients and families prevents accidental use of strong neurotoxic drugs that could speed up nerve damage.

20. School and workplace accommodations
For students and workers, simple adjustments—extra time for walking between classes, ergonomic chairs, flexible schedules, or remote work—can make a big difference. These accommodations reduce physical strain and fatigue, allow rest breaks, and let people with CMTDIE stay active in education and employment for longer.

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Drug treatments

There is no FDA-approved drug that cures or specifically treats CMTDIE. Most medicines are approved for other conditions like neuropathic pain but are used “off-label” to manage symptoms in CMT, based on general nerve-pain evidence. Always follow a specialist’s prescription and never self-medicate.PMC+2FDA Access Data+2

1. Pregabalin
Pregabalin is an anticonvulsant approved for neuropathic pain in diabetes and other conditions.FDA Access Data+1 It binds to the α2-δ subunit of calcium channels in the nervous system and reduces the release of pain-signaling chemicals. Doctors use it to ease burning, stabbing, or electric-shock pains in CMT. The dose and timing are chosen individually, usually split over the day. Common side effects include dizziness, sleepiness, weight gain, and swelling of the legs.FDA Access Data+1

2. Gabapentin
Gabapentin works in a similar way to pregabalin, calming nerve activity and reducing abnormal firing in damaged nerves. It is widely used for neuropathic pain and can lessen tingling, shooting pains, and sleep disturbance. Doses are slowly increased by the doctor to find the best balance between pain relief and side effects like drowsiness, dizziness, and coordination problems.

3. Duloxetine
Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI) approved for diabetic peripheral neuropathic pain.FDA Access Data+2FDA Access Data+2 It increases levels of serotonin and norepinephrine in pain-modulating pathways in the brain and spinal cord. In CMT, it may be used off-label to reduce chronic nerve pain, especially when mood symptoms are also present. Side effects can include nausea, dry mouth, sweating, and sleep changes.

4. Amitriptyline
Amitriptyline is a tricyclic antidepressant used in low doses for chronic nerve pain. It blocks certain serotonin and norepinephrine reuptake pumps and dampens pain signals. Taken usually at night, it can improve sleep and pain together. Doctors watch for side effects like dry mouth, constipation, blurred vision, and daytime sleepiness, especially in older adults.

5. Nortriptyline
Nortriptyline is a related tricyclic with slightly fewer sedating and anticholinergic effects. It can be used when amitriptyline is not tolerated. The purpose is similar: reduce neuropathic pain and improve sleep quality. The mechanism is modulation of descending pain pathways and reduced sensitivity of overactive pain fibers.

6. Topical lidocaine patches or gels
Lidocaine patches or gels numb the skin over painful areas, such as the tops of the feet. They block sodium channels in local nerve endings, preventing pain signals from starting. Because the drug mostly stays in the skin, systemic side effects are low. They are useful when pain is localized and oral medicines cause too many side effects.

7. Topical capsaicin cream
Capsaicin, the active component in chili peppers, depletes substance P, a pain neurotransmitter, from nerve endings. Applied regularly, it can reduce burning pain in some people with neuropathic pain. At first it can cause warmth or stinging, but this usually settles with continued use. It should be used only on unbroken skin and away from eyes and mouth.

8. Non-steroidal anti-inflammatory drugs (NSAIDs)
Medicines like ibuprofen or naproxen do not treat nerve damage itself, but they can reduce pain from joints, tendons, and muscles that are overworked because of weakness and deformity. They block cyclo-oxygenase enzymes and reduce inflammatory prostaglandins. Long-term use must be monitored by doctors because of possible stomach, kidney, or heart side effects, especially in people with kidney disease.

9. Acetaminophen (paracetamol)
Acetaminophen is often used for mild musculoskeletal pain or headaches in CMT. It works mainly in the central nervous system to reduce pain and fever, though the exact mechanism is still being studied. It is generally safer for the stomach than NSAIDs, but high doses can damage the liver, so total daily dose limits set by the doctor must be respected.

10. Muscle relaxant – baclofen
Baclofen is a muscle relaxant that acts on GABA-B receptors in the spinal cord. It can reduce muscle spasms and stiffness in some people with neuropathies. In CMT, it may help if spasticity overlaps with neuropathy or if muscle tightness causes pain. Side effects include drowsiness, weakness, and dizziness, and it must not be stopped suddenly.

11. Tramadol (with caution)
Tramadol is a pain medicine that has weak opioid effects and also affects serotonin and norepinephrine. It may be used short-term for severe pain that does not respond to other treatments. Because it can cause dependence, drowsiness, and breathing problems, doctors use it carefully, at the lowest effective dose, and avoid it in many patients.

12. Strong opioids (rare, last resort)
In very severe, otherwise uncontrollable pain, strong opioids like morphine may be used for short periods under strict supervision. They work by binding to opioid receptors in the brain and spinal cord to block pain perception. Risks include dependence, constipation, hormonal changes, and overdose, so they are not routine in CMT and are usually avoided when possible.

13. Selective serotonin reuptake inhibitors (SSRIs)
SSRIs such as sertraline or fluoxetine are mainly antidepressants. They do not directly treat nerve pain but can improve mood, anxiety, and coping in people with chronic disease. Better mental health often leads to lower perceived pain and better participation in physiotherapy. Doses and choices depend on each person’s mental health needs.

14. Medications for restless legs or cramps
Some people with CMT have restless legs or painful night cramps. Low-dose dopamine agonists, magnesium supplements (if deficient), or quinine alternatives may sometimes be used, but only under specialist guidance because of possible side effects. The goal is to improve sleep quality and reduce night discomfort.

15. Blood pressure medicines for kidney protection
In CMTDIE with FSGS, drugs like ACE inhibitors or ARBs are commonly used (for example, in other kidney diseases) to lower blood pressure and reduce protein loss in urine. They work by relaxing blood vessels and reducing pressure inside the kidney filters, helping slow kidney damage. Doses and choices belong strictly to kidney specialists.

16. Diuretics for swelling (edema)
If kidney disease leads to fluid retention and swelling, diuretics (“water pills”) can help remove extra salt and water through the urine. This can improve comfort and breathing. However, they can affect blood pressure, electrolytes, and kidney function, so they must only be used under nephrologist supervision with regular blood tests.

17. Vitamin D medicines (if low)
When tests show low vitamin D, doctors may prescribe vitamin D tablets or drops. Vitamin D supports bone strength and muscle function. Correcting deficiency reduces fracture risk and may improve muscle performance. The dose depends on blood levels and must be guided by lab tests to avoid excess.

18. Statins (with caution)
If someone with CMTDIE has high cholesterol, statins may be used to reduce cardiovascular risk. They work by blocking HMG-CoA reductase in the liver and lowering cholesterol production. Very rarely, statins can cause muscle pain or injury, so doctors watch closely, especially in people with pre-existing neuromuscular disorders.

19. Experimental drug PXT3003 (for CMT1A, not standard for CMTDIE)
PXT3003 is a combination of baclofen, naltrexone, and sorbitol, granted orphan-drug and fast-track designation by the FDA and EMA for CMT1A.Charcot-Marie-Tooth News+5FDA Access Data+5PR Newswire+5 It aims to reduce PMP22 overexpression and improve nerve function. It is still investigational and not approved for CMTDIE but shows how targeted therapies are being developed.

20. Experimental drug NMD670 (for CMT in trials)
NMD670 is an investigational oral drug with FDA orphan-drug designation for CMT. It targets the skeletal muscle chloride channel ClC-1 to improve muscle responsiveness to weak nerve signals.Synapse+5Charcot-Marie-Tooth Disease+5NMD Pharma+5 It is only available in clinical trials and not yet an approved treatment, but it represents a hopeful future direction for CMT therapies.

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Dietary molecular supplements

No supplement can cure CMTDIE. Most of these are used to support general nerve and kidney health. Always ask your doctor before taking any supplement, especially with kidney disease or other medicines.

1. Vitamin C (ascorbic acid)
Vitamin C is an antioxidant that helps protect cells from oxidative stress. It was tested in CMT1A to see if it could reduce disease activity, but large trials did not show clear benefit for nerve function.PMC Still, adequate vitamin C from diet or modest supplements supports immune function, wound healing, and collagen in skin and blood vessels.

2. B-complex vitamins (B1, B6, B12)
B-vitamins are important for nerve metabolism and myelin production. Correcting any deficiency can improve neuropathy symptoms. For example, low B12 can cause numbness and balance problems. Supplement doses should be guided by blood tests, because very high B6 doses over long periods may actually damage nerves.

3. Vitamin D
Vitamin D supports bone strength, muscle function, and immunity. In people with weak muscles and limited mobility, vitamin D deficiency is common and increases fracture risk. Supplementation is tailored based on blood levels. Good vitamin D status helps muscles work more efficiently and supports overall health.

4. Omega-3 fatty acids (fish oil)
Omega-3 fats from fish oil have anti-inflammatory effects and may support heart and kidney health. They may slightly reduce triglycerides and help protect blood vessels. While they do not directly repair nerves, better vascular health may indirectly benefit nerve function. High doses can thin the blood, so medical advice is important, especially before surgery.

5. Alpha-lipoic acid
Alpha-lipoic acid is an antioxidant used in some countries for diabetic neuropathy. It helps reduce oxidative stress in nerves and may modestly improve symptoms like burning pain in some people. Evidence in CMT is limited, so it is considered an optional add-on only if the doctor agrees and monitors for side effects like stomach upset.

6. Coenzyme Q10
CoQ10 is involved in energy production in mitochondria. Some people use it hoping to support muscle and nerve energy. Evidence in CMT is still weak, but it is generally well tolerated at usual doses. People on blood thinners or other heart medicines must check with doctors, because CoQ10 can interact with some drugs.

7. Magnesium (if deficient)
Magnesium is important for muscle relaxation and nerve signaling. If blood tests show low magnesium, supplementation can reduce cramps and improve general muscle function. Too much magnesium, especially with kidney disease, can be dangerous, so doses must be tailored and monitored.

8. Curcumin (turmeric extract)
Curcumin has anti-inflammatory and antioxidant properties in lab studies. Some people use it to support joint comfort and general health. It may help reduce low-grade inflammation, though strong clinical evidence in CMT is lacking. It can interfere with blood thinners and bile duct diseases, so medical advice is needed.

9. Probiotics
Probiotics support gut health and may help with bowel problems related to reduced mobility or medicines. A healthy gut can improve nutrient absorption, which indirectly supports nerve and kidney health. Specific strains and doses depend on individual needs and should be chosen with a healthcare professional.

10. General multivitamin (if diet is limited)
For people who eat poorly or have reduced appetite due to illness or medications, a basic multivitamin may help cover small gaps in micronutrient intake. It is not a treatment for CMTDIE itself, but it supports overall resilience and recovery from infections or surgery. High-dose “megavitamins” are usually not needed and can be harmful.

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Regenerative / immune-related and stem-cell-type approaches

These are research areas, not standard treatments for CMTDIE. Most are available only in clinical trials.

1. Gene-targeted therapies (AAV gene therapy)
For some CMT types (like CMT4J), viral gene therapies using AAV9 to deliver a correct gene copy have received orphan-drug designation from the FDA.FDA Access Data The idea is to supply a healthy gene to nerve cells, allowing them to make normal proteins again. For CMTDIE, research would need to target INF2. These therapies are experimental, expensive, and currently limited to carefully controlled trials.

2. Small-molecule disease-modifying drugs (e.g., PXT3003)
PXT3003 is being studied in CMT1A to lower excess PMP22 protein and preserve myelin.NIHR Innovation Observatory+3PR Newswire+3European CMT Federation+3 This approach aims to modify the disease process, not just symptoms. Similar strategies might one day be adapted for other CMT subtypes like CMTDIE, if specific pathways are identified. At present, this is not standard care and is only used in trials.

3. Muscle-targeted drugs (e.g., NMD670)
NMD670, with orphan-drug designation for CMT, targets skeletal muscle chloride channels to improve muscle responsiveness to weak nerve signals.Pharmafile+6Charcot-Marie-Tooth Disease+6NMD Pharma+6 Rather than repairing the nerve, it tries to make muscles work better despite nerve damage. This may help with fatigue and weakness if proven safe and effective in larger studies.

4. Stem-cell-based nerve repair (experimental)
Researchers are studying different stem cells, such as Schwann-cell precursors or mesenchymal stem cells, to see whether they can support nerve repair or remyelination. So far, this work is mostly in animals or early-phase human studies. There is no approved stem-cell treatment for CMTDIE, and unregulated “stem cell clinics” can be risky and expensive.

5. Immune-modulating therapies (for overlapping immune disease)
If a person with CMTDIE also has immune-mediated kidney disease or another autoimmune condition, doctors sometimes use immune-modulating drugs like corticosteroids or other agents used in nephrology. These drugs calm overactive immune responses and may protect kidneys, but they do not fix the genetic neuropathy and can have serious side effects.

6. Kidney transplantation (for end-stage FSGS)
In advanced FSGS with kidney failure, transplant is sometimes considered. It replaces the damaged kidney with a healthy donor kidney to restore filtration and remove toxins. This improves overall health and energy but does not change the underlying INF2 mutation or nerve disease. It is a major procedure requiring lifelong immune-suppressing drugs.

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Surgeries

1. Foot deformity correction (osteotomy)
In severe high-arched (pes cavus) or twisted feet, orthopedic surgeons may cut and reposition bones (osteotomy) to place the foot in a more natural position. This helps spread weight more evenly, improve walking, and reduce pain and callus formation. Surgery is usually combined with ongoing physiotherapy and orthotics.

2. Tendon transfer surgery
In tendon transfer, a stronger working muscle’s tendon is moved to take over the job of a weaker one, such as lifting the foot. This surgery tries to balance forces around the ankle and improve foot control. It can reduce trips and falls and may delay or reduce the need for very bulky braces.

3. Joint fusion (arthrodesis)
If a joint is severely unstable or painful despite braces and physiotherapy, surgeons may permanently fuse it in a better position. For example, ankle fusion can create a stable, plantigrade foot for standing and walking. The joint no longer moves, but pain can decrease and shoes may fit better, improving function.

4. Hammertoe correction
Hammertoes occur when the toe joints bend abnormally, often due to muscle imbalance in CMT. Surgical straightening releases tight tissues and aligns the toes. This reduces pressure on the tops of the toes, lowers pain from rubbing shoes, and makes footwear more comfortable.

5. Kidney biopsy (diagnostic procedure) and transplant surgery
In suspected FSGS, a kidney biopsy is performed to confirm the diagnosis and guide treatment. Under imaging, a small piece of kidney is taken for microscopic examination. In end-stage disease, kidney transplant surgery, as mentioned above, replaces the failed organ to restore kidney function and improve survival and quality of life.

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Preventions

1. Avoid nerve-toxic medicines (when alternatives exist), following a neurologist’s written list.

2. Protect feet daily: inspect skin, nails, and between toes; treat small injuries early to avoid ulcers.

3. Use braces and footwear as prescribed to prevent deformities and falls.

4. Stay physically active within limits to prevent deconditioning and maintain flexibility.

5. Control blood pressure and blood sugar to protect kidneys and nerves.

6. Maintain a healthy weight to reduce stress on weak legs and feet.

7. Quit smoking and avoid second-hand smoke to protect blood vessels and nerves.

8. Keep up with vaccines (like flu and pneumonia) to reduce infections that could trigger hospital stays and extra weakness.

9. Plan pregnancies with genetic counseling, so families understand inheritance risks and options.

10. Attend regular follow-ups with neurology and nephrology teams to catch problems early.

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When to see doctors

You should see a doctor urgently (or go to emergency care) if you have any of these:

• Sudden or fast-worsening weakness, especially if you cannot walk or lift your foot.

• New trouble breathing, chest pain, or serious swallowing problems.

• Sudden severe back pain, loss of bladder or bowel control, or numbness around the groin.

• Strong swelling of the legs, puffiness around the eyes, or very little urine (possible kidney failure).

• Very high blood pressure, severe headache, or confusion.

You should book a planned visit with your neurologist or kidney specialist if you notice:

• Gradually worse balance or more frequent falls.

• New or worsening numbness, burning, or electric-shock pains.

• Changed shape of your feet or new pressure spots, calluses, or ulcers.

• Increased tiredness, nausea, itching, or foamy urine suggesting kidney changes.

Always tell your doctors about any new medicines, supplements, or alternative treatments before starting them.

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What to eat and what to avoid

1. Eat: plenty of vegetables and fruits
Colorful vegetables and fruits provide vitamins, antioxidants, and fiber. They support immune health, help control weight, and reduce cardiovascular risk, which is important when mobility is reduced.

2. Eat: whole grains
Whole-grain bread, rice, and pasta give slow-release energy and improve bowel function. Stable energy helps manage fatigue and keeps blood sugar steady, which is helpful for general nerve health.

3. Eat: lean protein
Fish, skinless poultry, beans, lentils, and tofu provide protein to maintain muscle mass. This is important when nerves are weak and muscles need all the support they can get from good nutrition.

4. Eat: healthy fats in moderation
Use small amounts of olive oil, nuts, seeds, and avocados. These provide essential fatty acids useful for cell membranes and overall cardiovascular health, which indirectly benefits nerves and kidneys.

5. Eat: kidney-friendly choices when advised
If kidney function is reduced, a renal dietitian may suggest limiting salt, some minerals (like potassium or phosphorus), and adjusting protein amounts. Following this advice can slow kidney damage and reduce swelling.

6. Avoid: very salty foods
Limit processed meats, instant noodles, salty snacks, and fast food. Too much salt raises blood pressure and strains the kidneys, increasing the risk of fluid retention and kidney damage.

7. Avoid: large amounts of added sugar
Sugary drinks, sweets, and desserts can cause weight gain and raise blood sugar. High blood sugar over time can damage nerves and kidneys, adding extra harm to already vulnerable systems.

8. Avoid: heavily processed, fried foods
Deep-fried chips, fried chicken, and processed snacks increase unhealthy fats and calories. They raise cardiovascular risk and can worsen fatigue and inflammation.

9. Avoid: excessive caffeine
Too much caffeine may worsen tremor, anxiety, or sleep problems. Poor sleep increases pain and fatigue. Moderate amounts may be fine, but balance is important, especially in teens and people with heart or kidney issues.

10. Avoid: any supplement or “herbal cure” without medical advice
Some “natural” products can harm the kidneys, interact with medicines, or be contaminated. Always check with your healthcare team before starting any new herb or supplement, even if advertised for nerves or immunity.

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Frequently asked questions (FAQs)

1. Is Charcot-Marie-Tooth disease dominant intermediate E curable?
No. At present, there is no cure that fixes the gene change in CMTDIE. Treatment focuses on symptom control, protecting function, and slowing complications through physiotherapy, braces, medications for pain, and kidney-protective care.

2. Will everyone with CMTDIE need a wheelchair?
Not always. Some people have mild symptoms and walk independently for most of their lives. Others may eventually need a cane, walker, or wheelchair, especially for longer distances. Early therapy, good bracing, and safety planning help delay mobility loss.

3. Does CMTDIE always cause kidney failure?
No. CMTDIE is linked with FSGS, but not every person will develop severe kidney disease. Regular urine and blood tests help catch problems early. Blood pressure control and kidney-protective treatment can slow progression in many people.NCBI+1

4. Can exercise make the disease worse?
Too much intense exercise can over-tire weak muscles, but carefully planned low-impact exercise is usually helpful. A physiotherapist designs a program that strengthens without overloading the nerves, improving balance and stamina instead of worsening damage.PMC+2ScienceDirect+2

5. Can children with CMTDIE play sports?
Many children can join sports with some adjustments, such as avoiding high-impact contact sports and using braces. The key is safety: no activities that greatly increase fall risk or ankle injuries. A pediatric neurologist and physiotherapist can advise which sports are safest.

6. Is pregnancy safe for someone with CMTDIE?
Many people with CMT have successful pregnancies, but careful planning is important. Extra strain on legs, changes in balance, and the genetic risk to the baby need discussion. Genetic counseling and pregnancy care with a high-risk obstetrician and neurologist are recommended.

7. Are there special medicines that people with CMTDIE must avoid?
Yes, some medicines can be toxic to peripheral nerves or kidneys. Your neurologist and nephrologist can provide a list and send it to all your doctors. Never stop a prescribed drug suddenly, but always ask before starting new ones.

8. Will gene therapy become available soon for CMTDIE?
Research in CMT gene therapy is moving forward, especially for specific subtypes. Orphan-drug designations for gene and small-molecule therapies show promise, but these are still in trials and not yet routine. It may take years before safe, widely available gene therapy for CMTDIE exists.FDA Access Data+2PR Newswire+2

9. Can diet alone treat CMTDIE?
No. Diet cannot fix the genetic nerve problem. However, a healthy, kidney-friendly diet can help control weight, protect blood vessels and kidneys, and support overall energy. It works best together with physiotherapy, braces, and medical care—not as a replacement.

10. Are over-the-counter vitamins safe to take?
Some basic vitamins at normal doses may be fine, especially if blood tests show a deficiency. But high-dose or multiple supplements can stress the kidneys or interact with medicines. Always ask your doctor before starting any new vitamin or supplement.

11. How often should I see my neurologist?
This depends on how active the disease is. Many people see a neurologist once or twice a year, and more often if symptoms change quickly. Kidney specialists may also plan regular visits, especially if protein is found in the urine or kidney function is reduced.

12. Can CMTDIE affect hearing or other senses?
Some intermediate CMT types can include mild hearing loss, and sensory problems like numbness and tingling are common. If you notice hearing changes, ringing in the ears, or new sensory symptoms, tell your doctor so tests and hearing support can be arranged.Orpha+1

13. Does CMTDIE shorten life expectancy?
For many people, life span is near normal, especially with good care and kidney protection. Quality of life may be affected by mobility limits and pain, but early interventions, safety planning, and emotional support can help maintain independence and well-being.

14. What kind of specialist should manage CMTDIE?
Ideally, care is shared between a neuromuscular neurologist, a nephrologist (kidney doctor), a physiatrist or rehabilitation doctor, physiotherapists, occupational therapists, and an orthotist for braces. This team approach covers nerves, kidneys, mobility, and daily living needs.

15. What can families do right now?
Families can learn about the disease, keep regular appointments, help with safe exercise, check feet and skin, support mental health, and advocate for school or workplace accommodations. Being informed, kind, and patient with each other makes living with CMTDIE easier and safer over the long term.

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 24, 2025.