Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2U (LGMD2U / LGMDR20, ISPD/CRPPA-related)

Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2U (LGMD2U / LGMDR20, ISPD/CRPPA-related) is a rare inherited muscle disease where both parents pass on a non-working copy of the same gene. The faulty gene is ISPD (now also named CRPPA), which is needed to add sugar “handles” (glycans) to a muscle-cell protein called α-dystroglycan. When α-dystroglycan is poorly glycosylated, muscle fibers can’t anchor well to their surrounding support matrix, so they are easily damaged with activity, leading over time to slowly progressive weakness of the hip–thigh (pelvic girdle) and shoulder (scapular) muscles. Children or teens typically show difficulty rising from the floor (Gowers’ sign), enlarged calves or thighs, and high CK levels; contractures (tight tendons) and reduced reflexes are common. There’s no disease-specific cure yet, so care focuses on rehabilitation, orthopedic, cardiac, and respiratory support. Researchers sometimes use the updated name LGMDR20-ISPD-related. MDPI+2platform.opentargets.org+2

ISPD/CRPPA helps make CDP-ribitol, a building block required to assemble the long “matriglycan” chain on α-dystroglycan. Without adequate matriglycan, the dystroglycan complex can’t grip the extracellular matrix, and contraction stress injures fibers. This dystroglycanopathy mechanism links LGMD2U to other glycosylation-related muscular dystrophies. MDPI

Autosomal recessive limb-girdle muscular dystrophy type 2U is a rare inherited muscle disease. It mainly weakens the muscles around the hips and shoulders (the “limb-girdle” muscles). The weakness usually starts in childhood and gets worse slowly. Many people notice a waddling walk, trouble running, climbing stairs, or getting up from the floor using their hands (a “Gowers’ sign”). Blood tests often show very high creatine kinase (CK), which means the muscles are leaking enzymes because their membranes are fragile. Some people develop tight heel cords (Achilles tendon contractures), reduced reflexes, and large calves or thighs. A few patients can also have heart, eye, or balance problems, but these are less common. Genetic & Rare Diseases Info Center

This disorder is caused by harmful changes (variants) in a single gene once called ISPD and now officially named CRPPA (CDP-L-ribitol pyrophosphorylase A). This enzyme helps make CDP-ribitol, a key building block needed to add special sugar chains to a protein called α-dystroglycan. When α-dystroglycan is not properly “glycosylated,” muscle fibers cannot anchor tightly to their support structures, so they get damaged with normal use. The result is chronic muscle fiber injury and weakness. MedlinePlus+2PMC+2

In older literature this condition is called LGMD2U (the old system). In the current system, all recessive LGMDs are written as LGMDR#, so LGMD2U ≈ LGMDR20 (ISPD/CRPPA-related). European Reference Network+2PMC+2

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Other names

• LGMD2U (old name)

• LGMDR20 (ISPD/CRPPA-related) (newer name)

• ISPD-related limb-girdle muscular dystrophy

• CRPPA-related limb-girdle muscular dystrophy

• Muscular dystrophy-dystroglycanopathy, type C7 (MDDGC7) – an older umbrella term used when α-dystroglycan glycosylation is defective
  These labels all refer to the same gene-based disorder affecting α-dystroglycan glycosylation. monarchinitiative.org+2glycosmos.org+2

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Types

Although the gene is the same, people can present in different ways. Think of these as clinical sub-types along one spectrum:

1. Childhood-onset LGMD form (most typical): Slow, mainly hip/shoulder weakness starting in school years; walking is kept for years; CK is high. Genetic & Rare Diseases Info Center

2. Adolescent or young-adult-onset mild form: Later onset, slower course, may be mistaken for “deconditioning”; still shows elevated CK and proximal weakness. (General LGMD patterns.) Cleveland Clinic+1

3. Intermediate CMD–LGMD overlap: Early hypotonia and delays like congenital muscular dystrophy (CMD), but later looks like LGMD. This has been described in CRPPA/ISPD-related disease. Frontiers

4. LGMD with “extra-muscle” features (variable): Some individuals show eye problems, rare cerebellar signs, or heart involvement. These are not constant but have been reported. Genetic & Rare Diseases Info Center

The different forms relate to how much α-dystroglycan function remains. When glycosylation is severely impaired, the picture can overlap with severe “dystroglycanopathies”; when it’s partially preserved, the picture is the milder LGMD pattern. MedlinePlus

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Causes

Core cause: biallelic (both copies) pathogenic variants in CRPPA (formerly ISPD). Below are 20 plain-English “causes” and contributors that explain how and why the disease happens or varies among people:

1. Loss-of-function CRPPA variants: Nonsense or frameshift changes stop the enzyme from being made correctly. Less enzyme → defective α-dystroglycan glycosylation → weak muscles. PMC

2. Missense CRPPA variants: Single-letter changes may reduce enzyme activity or stability, lowering CDP-ribitol production. genecards.org

3. Splice-site variants: Mutations at intron–exon borders can remove or misread exons, creating a faulty protein. Frontiers

4. Exonic deletions/duplications in CRPPA: Larger changes that remove or copy coding segments disrupt enzyme function. Frontiers

5. Promoter/regulatory variants (rare): Variants that lower gene expression can reduce enzyme amount. (General gene-regulation principle; reported across dystroglycanopathies.) search.clinicalgenome.org

6. Compound heterozygosity: Different pathogenic variants on each chromosome 7 copy together reduce function below a safe threshold. search.clinicalgenome.org

7. Complete enzyme deficiency: Very low CRPPA activity causes severe α-dystroglycan under-glycosylation and earlier, stronger symptoms. search.clinicalgenome.org

8. Partial enzyme deficiency: Some residual activity leaves α-dystroglycan partly functional, leading to later onset and milder LGMD. MedlinePlus

9. CRPPA’s key pathway step: CRPPA makes CDP-ribitol, which FKTN and FKRP use to decorate α-dystroglycan with ribitol-phosphate. Without CDP-ribitol, this step fails. MedlinePlus

10. Defective α-dystroglycan “sugar chains”: Poor glycosylation means α-dystroglycan cannot stick well to the surrounding matrix; muscle fibers tear more easily. Medscape

11. Muscle membrane fragility: Repeated small injuries from daily activity accumulate, causing CK leakage and weakness. (LGMD mechanism.) Medscape

12. Genetic background (modifiers): Other genes in the glycosylation network may slightly worsen or soften the picture in a given patient. (General dystroglycanopathy concept.) search.clinicalgenome.org

13. Founder variants in some populations: A specific pathogenic variant can be more common in a region or family line, increasing risk locally. (Widely observed across LGMD subtypes.) orpha.net

14. Parental consanguinity: When parents are related, both may carry the same rare CRPPA change, increasing the chance a child inherits two copies. (Autosomal recessive principle.) MedlinePlus

15. Alternative splicing differences: How cells process CRPPA RNA can change enzyme amounts slightly, modifying severity. genecards.org

16. Cell stress and inflammation: Damaged muscle releases signals that bring inflammation, which can speed up muscle fiber loss over time. (General LGMD biology.) Medscape

17. Impaired muscle repair: Satellite (stem) cell repair cannot keep up with ongoing damage, so weakness slowly progresses. (General muscular dystrophy biology.) Medscape

18. Reduced activity of connected enzymes (FKTN/FKRP): While not the cause of this subtype, shared pathway defects explain why CRPPA loss behaves like other α-dystroglycanopathies. MedlinePlus

19. Energy and metabolism strain in diseased muscle: Chronic membrane injury raises energy needs and waste products, contributing to fatigue and cramps. (General LGMD physiology.) Medscape

20. Time (aging): Over years, repeated micro-injury accumulates, so even mild variants can lead to noticeable weakness in adolescence or adulthood. (LGMD natural history.) Medscape

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Common symptoms and signs

1. Trouble rising from the floor or low chair: People often push on their thighs to stand (Gowers’ sign) because hip muscles are weak. Genetic & Rare Diseases Info Center

2. Waddling gait and easy tiring when walking: Pelvic muscle weakness makes the trunk sway; walks become short and slow. Genetic & Rare Diseases Info Center

3. Climbing stairs is hard: Hip and thigh muscles cannot lift the body easily, so steps feel heavy and require rails. Genetic & Rare Diseases Info Center

4. Shoulder weakness: Lifting objects overhead, hanging clothes, or carrying bags becomes difficult. (LGMD hallmark.) Medscape

5. Calf or thigh enlargement (pseudohypertrophy): Muscles may look big from fat and connective tissue changes, not true strength. Genetic & Rare Diseases Info Center

6. Muscle cramps or aches after activity: Fragile fibers are irritated by routine use, causing soreness. (General LGMD.) Medscape

7. Reduced reflexes (hyporeflexia): Knee or ankle reflexes can be weak because the muscle itself is weak. Genetic & Rare Diseases Info Center

8. Heel cord tightness (Achilles contracture): Calf imbalance and toe-walking can develop without stretching and physiotherapy. Genetic & Rare Diseases Info Center

9. Scapular winging: Shoulder girdle weakness causes the shoulder blades to stick out like “wings.” (LGMD pattern.) Medscape

10. Frequent falls: Weak hips and poor balance make tripping and falls more likely. (LGMD pattern.) Medscape

11. High CK on blood tests: CK often rises many times normal because damaged muscle leaks CK into the blood. Genetic & Rare Diseases Info Center

12. Breathing weakness (later or mild): Diaphragm and chest muscles may weaken slowly; shortness of breath or poor sleep can appear. (LGMD general.) Medscape

13. Heart involvement (uncommon but reported): Some patients can develop heart muscle changes and need periodic checks. Genetic & Rare Diseases Info Center

14. Eye problems (variable): A few patients have ocular findings in the dystroglycanopathy spectrum, so vision checks are reasonable. Genetic & Rare Diseases Info Center

15. Learning or coordination issues (rare): Some individuals show mild cerebellar or cognitive features, but many have purely muscle disease. Genetic & Rare Diseases Info Center

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Diagnostic tests

A) Physical examination

1. Pattern-focused neuromuscular exam: The clinician checks for proximal (hip/shoulder) more than distal weakness, posture, contractures, and reflexes; this pattern points toward LGMD. Medscape

2. Gowers’ maneuver assessment: Watching how a person stands from the floor helps detect classic hip/thigh weakness. Genetic & Rare Diseases Info Center

3. Gait observation: Waddling, toe-walking, and Trendelenburg sway suggest pelvic girdle weakness and tight calves. Genetic & Rare Diseases Info Center

4. Cardio-respiratory screen at bedside: Heart rate, rhythm, oxygen levels, and chest movement are checked to pick up silent heart or breathing involvement. (LGMD care norms.) Medscape

B) Manual/functional tests

5. Manual Muscle Testing (MRC scale): Grading strength in each muscle helps stage severity and follow change over time. (LGMD standard.) Medscape

6. Timed rise from floor / sit-to-stand: Simple time-based tasks capture day-to-day function and are easy to repeat in clinic. (LGMD practice.) Medscape

7. 6-Minute Walk Test: Measures endurance and safety while walking; useful for tracking progression. (LGMD practice.) Medscape

8. Contracture range-of-motion checks: Regular goniometry at the ankles, knees, and hips guides stretching programs. (LGMD care.) Medscape

C) Laboratory & pathological tests

9. Serum CK (creatine kinase): Usually markedly elevated, supporting active muscle damage. Genetic & Rare Diseases Info Center

10. Aldolase, AST/ALT: These enzymes can also rise from muscle injury and help confirm a muscle source. (General LGMD.) Medscape

11. Targeted gene testing / panels: Sequencing CRPPA/ISPD (and related α-dystroglycan genes) identifies the exact variants and confirms the diagnosis. invitae.com

12. Copy-number analysis (exonic CNV): Detects deletions/duplications in CRPPA if sequencing alone is negative. Frontiers

13. Muscle biopsy (when genetics is inconclusive): Shows a dystrophic pattern. Special stains and α-dystroglycan immunostaining reveal reduced glycosylation typical of dystroglycanopathy. Medscape

14. Western blot for α-dystroglycan: Confirms reduced glycosylation status and supports a CRPPA-pathway defect. Medscape

D) Electrodiagnostic tests

15. EMG (electromyography): Shows a myopathic pattern—small, brief motor unit potentials—supporting primary muscle disease, not nerve disease. (LGMD standard.) Medscape

16. Nerve conduction studies: Usually normal, helping rule out neuropathies and confirming a muscle-predominant problem. (LGMD standard.) Medscape

17. ECG/ambulatory rhythm monitoring: Screens for silent heart rhythm problems that can occur in some LGMD patients. Genetic & Rare Diseases Info Center

E) Imaging tests

18. Skeletal muscle MRI: Shows characteristic patterns of muscle fatty replacement (for example, hip and thigh groups), useful for diagnosis and tracking. (LGMD practice.) Medscape

19. Echocardiography or cardiac MRI: Evaluates heart muscle size and pumping function when cardiac involvement is suspected or for routine surveillance. Genetic & Rare Diseases Info Center

20. Spine/pelvic X-ray (selected cases): Looks for hip subluxation, scoliosis, or contracture-related changes that influence therapy and mobility planning. (LGMD care.) Medscape

Non-pharmacological treatments (therapies & other care)

1. Regular, gentle physical therapy (PT)
   Description (≈150 words): A skilled neuromuscular PT builds a long-term plan of range-of-motion, gentle strengthening, posture, and energy-conservation strategies tailored to your baseline power and contracture risk. They monitor hip, knee, ankle, shoulder, and elbow motion every few months; adjust home programs as weakness evolves; and teach safe transfers, fall-prevention, and pacing to avoid overwork. In LGMDs, low-impact aerobic work (e.g., stationary cycling, water exercise) can improve efficiency and reduce fatigue, while high-intensity, “to-exhaustion” or supramaximal efforts are avoided. PTs also coordinate bracing, mobility aids, and splinting with orthotists and occupational therapists. Periodic reassessment (often every 4–6 months) catches early contractures or scapular dyskinesis, so interventions remain proactive rather than reactive. Medscape+2Parent Project Muscular Dystrophy+2
   Purpose: Maintain mobility, delay contractures, reduce falls/fatigue. Medscape
   Mechanism: Gentle loading improves cardiovascular conditioning and neuromuscular efficiency without provoking overwork weakness. Medscape

2. Occupational therapy (OT) & energy conservation
   Description: OT evaluates daily living tasks (dressing, bathing, cooking), recommends adaptive tools (reachers, shower chairs, elevated toilet seats), and trains joint-protection and pacing. They assess home and school/work ergonomics and coach task simplification and assistive technology (voice input, ergonomic keyboards) to preserve independence and reduce overuse pain in shoulder girdles. myTomorrows
   Purpose: Keep self-care and work roles feasible, safely. myTomorrows
   Mechanism: Reduces biomechanical strain and fatigue by optimizing task setup and tools. myTomorrows

3. Night splints and serial stretching
   Description: Custom ankle-foot night splints hold the ankle in neutral stretch to slow Achilles tightness, while daily gentle stretching protects hamstrings and hip flexors. Splints and casting schedules are adjusted as growth or weakness evolves, often combined with daytime AFOs for gait stability. Evidence across neuromuscular disease shows benefit mainly when used consistently and for months. Parent Project Muscular Dystrophy
   Purpose: Delay contractures; maintain positioning for standing/walking or comfortable seating. Parent Project Muscular Dystrophy
   Mechanism: Prolonged low-load stretch remodels muscle–tendon units and preserves joint range. Parent Project Muscular Dystrophy

4. Low-impact aerobic exercise (water-based, cycling, walking to tolerance)
   Description: Programs use sub-maximal targets (talk-test or low Borg RPE) to avoid overwork while still improving endurance. Swimming and cycling minimize impact and reduce fall risk; sessions are short, frequent, and progressed slowly. Hydration and heat management are emphasized. Medscape
   Purpose: Improve stamina and quality of life without provoking muscle breakdown. Medscape
   Mechanism: Aerobic conditioning enhances mitochondrial efficiency and reduces perceived exertion at daily activity levels. Medscape

5. Respiratory surveillance and training
   Description: Annual (or more frequent) checks of spirometry, cough peak flow, nocturnal oximetry/capnography track evolving weakness. Early introduction of cough-assist and nocturnal non-invasive ventilation (usually BiPAP, not CPAP) improves secretion clearance and sleep quality; caregivers learn infection-prevention routines and airway clearance during colds. PMC+1
   Purpose: Prevent pneumonias, improve sleep, manage hypoventilation. PMC
   Mechanism: Assisted ventilation alleviates hypoventilation; mechanical insufflation–exsufflation raises cough flow. PMC

6. Cardiac surveillance (echo/ECG/Holter)
   Description: Some LGMDs develop cardiomyopathy or arrhythmia; even if ISPD-related risk is uncertain, baseline and periodic cardiology evaluations are standard. Early treatment with heart-failure regimens and implantable devices in the right scenarios improves outcomes. Medscape+1
   Purpose: Detect and treat cardiomyopathy/arrhythmia early. American Heart Association Journals
   Mechanism: Monitoring guides ACE-I/β-blockers and device timing before decompensation. American Heart Association Journals

7. Orthoses (AFOs, KAFOs) and gait aids
   Description: Ankle-foot orthoses improve foot clearance and stance stability; knee-ankle-foot orthoses may prolong standing/walking when quadriceps weaken. Canes, crutches, or walkers reduce fall risk; wheelchairs/scooters support mobility when distances exceed safe limits. Physiopedia
   Purpose: Preserve safe mobility and reduce falls. Physiopedia
   Mechanism: External support substitutes for weak proximal stabilizers and optimizes biomechanics. Physiopedia

8. Nutrition, weight management, and dysphagia support
   Description: No diet cures LGMD, but healthy weight lowers strain on weak muscles. Speech/OT may modify food textures and teach safe-swallow techniques; feeding tubes are considered if aspiration risk or weight loss threatens health. Vitamin D/calcium help bone health under steroid use or limited mobility; dosing is individualized. Muscular Dystrophy Association+1
   Purpose: Prevent malnutrition, fractures, and aspiration. Muscular Dystrophy Association
   Mechanism: Adequate macro/micronutrients support muscle and bone; texture/technique changes reduce aspiration. Muscular Dystrophy Association

9. Fall-prevention and home safety
   Description: OT/PT audit hazards (loose rugs, poor lighting), recommend grab bars, railings, non-slip mats, raised seats, and teach floor-recovery strategies. Wear supportive footwear and plan routes with rests. myTomorrows
   Purpose: Reduce fractures, head injury, and fear of falling. myTomorrows
   Mechanism: Environmental modification + training lowers exposure to trip/slip risks. myTomorrows

10. Education on safe activity dosing
    Description: People with LGMD often benefit from gentle, regular activity but should avoid max-effort, eccentric-heavy, or exhaustion-level workouts. Hydration and heat control matter, and planned rest days help. Medscape
    Purpose: Minimize overwork weakness and rhabdomyolysis risk. Medscape
    Mechanism: Sub-maximal loads stress-shield fragile fibers while maintaining conditioning. Medscape

11. Psychosocial support & peer networks
    Description: Counseling, patient groups, and educational resources help families adapt, navigate services, and stay current on trials and standards of care. TREAT-NMD+1
    Purpose: Improve coping, reduce isolation, aid decision-making. TREAT-NMD
    Mechanism: Social support and disease education improve adherence and quality of life. TREAT-NMD

12. Cough-assist device training
    Description: Teaching proper use of mechanical insufflation–exsufflation during respiratory infections can shorten illness and prevent hospitalizations. PMC
    Purpose: Augment weak cough. PMC
    Mechanism: Alternating positive/negative pressure mobilizes secretions. PMC

13. Sleep medicine evaluation
    Description: Screening for nocturnal hypoventilation and sleep-disordered breathing (snoring, daytime sleepiness) with overnight studies guides BiPAP initiation. PM&R KnowledgeNow
    Purpose: Improve sleep quality and daytime alertness. PM&R KnowledgeNow
    Mechanism: Pressure support targets hypoventilation from respiratory muscle weakness. PM&R KnowledgeNow

14. Bone-health program
    Description: Baseline vitamin D level, calcium intake review, fall prevention, and fracture risk mitigation—especially if on chronic steroids or limited weight-bearing. PMC
    Purpose: Reduce osteoporosis and fracture risk. PMC
    Mechanism: Adequate vitamin D/calcium supports bone remodeling; weight-bearing as tolerated helps. PMC

15. Vaccinations (influenza, pneumococcal, others per schedule)
    Description: Preventing respiratory infections is critical when cough strength is borderline; vaccinate household contacts too. PMC
    Purpose: Reduce pneumonia/exacerbation risk. PMC
    Mechanism: Population-level immunity decreases exposure; individual vaccination lowers severe disease. PMC

16. Scoliosis monitoring and timely spine referral
    Description: Progressive trunk weakness can lead to scoliosis; timely surgical correction in selected cases improves sitting balance and quality of life and may slow FVC decline. jss.amegroups.org+1
    Purpose: Preserve posture, comfort, and pulmonary mechanics. jss.amegroups.org
    Mechanism: Spinal stabilization restores alignment and chest mechanics. PubMed

17. Contracture clinics & selective orthopedic procedures
    Description: Multidisciplinary teams consider Achilles/gastrocnemius lengthening or multilevel soft-tissue releases when bracing and therapy fail, aiming to ease bracing or sitting and reduce pain—not to “cure” weakness. PubMed+1
    Purpose: Improve comfort, shoe wear, and function. PubMed
    Mechanism: Surgical lengthening reduces fixed equinus and rebalances levers for gait or seating. PubMed

18. Assistive communication & computer access
    Description: Hands-free and voice-assist tech offsets shoulder girdle weakness and maintains productivity and social connection. myTomorrows
    Purpose: Independence in school/work and social life. myTomorrows
    Mechanism: Technology substitutes for lost arm elevation/endurance. myTomorrows

19. Genetic counseling
    Description: Families learn autosomal recessive inheritance, carrier testing options for relatives, and reproductive choices. Genomics Education Programme
    Purpose: Informed family planning and risk assessment. Genomics Education Programme
    Mechanism: Explains 25% recurrence risk when both parents are carriers. Genomics Education Programme

20. Clinical-trial awareness (dystroglycanopathy research)
    Description: Though no approved disease-modifying therapy for ISPD-related LGMD exists, related dystroglycanopathy trials (e.g., ribitol in FKRP disease) and preclinical work (ribitol/ISPD strategies) inform future approaches. Discuss eligibility and risks with a neuromuscular specialist. Institut Myologie+2Nature+2
    Purpose: Access emerging options and contribute to knowledge. Institut Myologie
    Mechanism: Substrate or gene-targeted therapies aim to restore α-dystroglycan glycosylation. Nature

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Drug treatments

Important: No medicine is FDA-approved specifically for LGMD2U. Drugs below are commonly used off-label to manage symptoms or complications (pain, cramps/spasticity, heart or breathing issues, bone health, reflux while on NSAIDs/steroids, etc.). Always personalize with your neuromuscular/heart/lung clinicians.

1. Prednisone / Prednisolone
   Long description (≈150 words): Low-dose glucocorticoids can help some muscular dystrophies by dampening inflammation, improving muscle membrane stability, and transiently increasing strength; in ISPD-related disease, limited reports suggest low-dose prednisone may improve exercise ability, but benefits must be balanced against risks (bone loss, infection, weight gain, glucose intolerance). If used, clinicians monitor vitamin D/calcium, BP, glucose, mood, and infection risk, and adjust or taper carefully to avoid adrenal suppression. Prednisolone liquid or delayed-release prednisone (RAYOS®) formulations can tailor dosing. Use is off-label for LGMD. PMC+2FDA Access Data+2
   Class: Glucocorticoid. FDA Access Data
   Typical dosage/time: Highly individualized (e.g., 5–20 mg/day), morning dosing often preferred; taper to lowest effective dose. FDA Access Data
   Purpose: Reduce inflammation/pain; possibly modest strength benefit in select cases. PMC
   Mechanism: Genomic anti-inflammatory and membrane-stabilizing effects. FDA Access Data
   Side effects: Weight gain, mood changes, hyperglycemia, hypertension, infection risk, osteoporosis. FDA Access Data

2. Deflazacort (EMFLAZA®)
   Long description: Approved for DMD, sometimes extrapolated off-label to other dystrophies when steroid therapy is chosen. Compared with prednisone, deflazacort may cause less weight gain for some, but has similar steroid risks; clinicians monitor cataracts, bone health, infection signs. Dosing is individualized (e.g., ~0.9 mg/kg/day in DMD contexts), with tapering to minimize adrenal suppression. Not LGMD-specific approved. FDA Access Data+1
   Class: Glucocorticoid. FDA Access Data
   Dosage/time: Individualized daily dosing; taper as appropriate. FDA Access Data
   Purpose: Steroid option where benefits outweigh risks. FDA Access Data
   Mechanism: Anti-inflammatory effects similar to other corticosteroids. FDA Access Data
   Side effects: Cushingoid features, infection risk, cataracts, bone loss, behavior changes. FDA Access Data

3. ACE inhibitor (e.g., Enalapril)
   Long description: If cardiomyopathy or LV dysfunction emerges, ACE inhibitors are first-line heart-failure therapy to reduce afterload and remodeling. In dystrophies with cardiac involvement, early ACE-I may delay progression. In LGMD2U, use is based on cardiac status, not on the gene itself. Monitor BP, potassium, and kidney function. FDA Access Data
   Class: ACE inhibitor. FDA Access Data
   Dosage/time: Low dose up-titrated (e.g., enalapril 2.5–20 mg bid). FDA Access Data
   Purpose: Treat cardiomyopathy/afterload; improve outcomes. American Heart Association Journals
   Mechanism: Blocks angiotensin II production; decreases aldosterone. FDA Access Data
   Side effects: Cough, hyperkalemia, renal effects, angioedema (rare). FDA Access Data

4. ARB (e.g., Losartan) or ACE-I alternative
   Long description: If ACE-I intolerant (e.g., cough/angioedema), ARBs provide similar afterload-reducing and anti-remodeling benefits in cardiomyopathy. Kidney function and potassium monitoring remain essential. (Representative ACE-I label cited above.) FDA Access Data
   Class: Angiotensin receptor blocker. FDA Access Data
   Dosage/time: Titrate per heart-failure guidelines. American Heart Association Journals
   Purpose/Mechanism/Side effects: Similar to ACE-I but without ACE-related cough; watch hyperkalemia/renal function. American Heart Association Journals

5. β-blocker (e.g., Carvedilol)
   Long description: Standard heart-failure and arrhythmia therapy to reduce sympathetic drive, improve LV function, and lower sudden-death risk in selected cardiomyopathies. Start very low and uptitrate; monitor BP, HR, and signs of worsening HF during titration. FDA Access Data
   Class: Non-selective β-blocker with α-blockade. FDA Access Data
   Dosage/time: Start 3.125 mg bid, titrate to tolerance. FDA Access Data
   Purpose: Remodeling and rhythm benefits in LV dysfunction. American Heart Association Journals
   Mechanism: Blocks β-adrenergic receptors; reduces myocardial oxygen demand and arrhythmic triggers. FDA Access Data
   Side effects: Fatigue, bradycardia, hypotension. FDA Access Data

6. Mineralocorticoid receptor antagonist (eplerenone or spironolactone)
   Long description: Add-on for HFrEF to reduce fibrosis and hospitalization; choose eplerenone to minimize endocrine side effects or spironolactone as a time-tested option. Monitor potassium and renal function. FDA Access Data+1
   Class: Aldosterone antagonists. FDA Access Data+1
   Dosage/time: Eplerenone 25–50 mg daily; spironolactone 12.5–25 mg daily as tolerated. FDA Access Data
   Purpose: Anti-fibrotic and diuretic support in HF. FDA Access Data
   Mechanism: Block aldosterone’s cardiac and renal effects. FDA Access Data
   Side effects: Hyperkalemia; gynecomastia (spironolactone). FDA Access Data

7. Loop diuretic (Furosemide)
   Long description: For symptomatic fluid overload in HF (edema, dyspnea), loop diuretics improve comfort; doses are highly individualized and require electrolyte and renal monitoring. FDA Access Data
   Class: Loop diuretic. FDA Access Data
   Dosage/time: Titrate (e.g., 20–80 mg), adjust with daily weights. FDA Access Data
   Purpose: Decongestion in HF. FDA Access Data
   Mechanism: Inhibits Na-K-2Cl transporter in loop of Henle. FDA Access Data
   Side effects: Electrolyte loss, hypotension, renal effects, ototoxicity (high doses). FDA Access Data

8. Short-acting bronchodilator (Albuterol HFA)
   Long description: Not a muscle drug, but if reactive airways complicate respiratory infections, short-acting β2 agonists can relieve wheeze and improve airflow while cough-assist clears mucus. Use by inhalation with correct technique; overuse can cause tremor/palpitations. FDA Access Data
   Class: β2-agonist bronchodilator. FDA Access Data
   Dosage/time: 1–2 puffs every 4–6 h as needed (per label). FDA Access Data
   Purpose: Ease bronchospasm during infections. FDA Access Data
   Mechanism: β2-receptor activation relaxes airway smooth muscle. FDA Access Data
   Side effects: Tremor, tachycardia. FDA Access Data

9. Baclofen (oral; reserve intrathecal for severe spasticity)
   Long description: If spasticity (less typical in LGMD but can occur with contracture pain) limits care, baclofen reduces tone and spasms. Titrate slowly to the lowest effective dose; abrupt withdrawal can cause dangerous reactions. Intrathecal baclofen is for refractory severe cases managed by specialists. FDA Access Data+1
   Class: GABA-B agonist antispastic. FDA Access Data
   Dosage/time: Start low (e.g., 5–10 mg tid), titrate; intrathecal per specialist. FDA Access Data
   Purpose: Reduce spasticity/pain that hinders function. FDA Access Data
   Mechanism: Inhibits excitatory neurotransmission in spinal cord. FDA Access Data
   Side effects: Sedation, dizziness; withdrawal risk if stopped abruptly. FDA Access Data

10. Tizanidine
    Long description: A short-acting α2-agonist for spasticity “on demand” during activities; can cause sedation and hypotension. Dose titration and liver function checks are standard. FDA Access Data
    Class: Central α2-adrenergic agonist. FDA Access Data
    Dosage/time: Small doses up to q6–8h when needed. FDA Access Data
    Purpose: Task-specific tone reduction. FDA Access Data
    Mechanism: Reduces polysynaptic spinal reflex activity. FDA Access Data
    Side effects: Sleepiness, dry mouth, low BP, LFT elevations. FDA Access Data

11. Mexiletine (for painful cramps/myotonia in select contexts)
    Long description: A sodium-channel blocker used for arrhythmias, sometimes used off-label for painful muscle cramps/myotonia in neuromuscular disorders when conservative measures fail; ECG monitoring is advised, and drug interactions reviewed. FDA Access Data+1
    Class: Class IB antiarrhythmic. FDA Access Data
    Dosage/time: Divided doses (e.g., 150–200 mg tid) individualized. FDA Access Data
    Purpose: Reduce cramps/myotonia that impede sleep or therapy. FDA Access Data
    Mechanism: Inhibits abnormal membrane excitability. FDA Access Data
    Side effects: GI upset, tremor, arrhythmia risk (specialist oversight). FDA Access Data

12. Gabapentin (for neuropathic pain features)
    Long description: For burning/tingling neuropathic pain, gabapentin can improve sleep and comfort; dose titration is gradual and renal function considered. Dizziness and somnolence are common early effects. FDA Access Data
    Class: Anticonvulsant/neuropathic pain modulator. FDA Access Data
    Dosage/time: Titrate (e.g., 100–300 mg at night → bid/tid). FDA Access Data
    Purpose: Improve neuropathic pain and sleep. FDA Access Data
    Mechanism: Binds α2δ subunit of calcium channels, reducing excitatory neurotransmitter release. FDA Access Data
    Side effects: Drowsiness, dizziness, edema. FDA Access Data

13. Acetaminophen
    Long description: First-line analgesic/antipyretic for musculoskeletal aches with a favorable GI profile compared to NSAIDs; mind the total daily dose to avoid liver toxicity, especially if combined products are used. FDA Access Data+1
    Class: Analgesic/antipyretic. FDA Access Data
    Dosage/time: Typical adult max 3–4 g/day (per local guidance). FDA Access Data
    Purpose: Pain/fever relief with minimal GI risk. FDA Access Data
    Mechanism: Central COX inhibition (likely). FDA Access Data
    Side effects: Hepatotoxicity with overdose or chronic excess. FDA Access Data

14. NSAIDs (Ibuprofen/Naproxen)
    Long description: For activity-related aches or post-orthopedic pain, NSAIDs help short-term; they carry GI, renal, and cardiovascular risks, so use the lowest effective dose for the shortest time and consider a PPI if long courses are unavoidable. FDA Access Data+1
    Class: Nonsteroidal anti-inflammatory drugs. FDA Access Data+1
    Dosage/time: Follow OTC/Rx labels precisely. FDA Access Data
    Purpose: Short-term pain/anti-inflammatory effect. FDA Access Data
    Mechanism: COX inhibition → ↓ prostaglandins. FDA Access Data
    Side effects: GI bleeding/ulcer, kidney effects, ↑CV risk. FDA Access Data

15. Proton-pump inhibitor (Omeprazole) when needed
    Long description: If steroids/NSAIDs are needed, PPIs protect the stomach and manage reflux that can worsen at night in weak trunk muscles. Use the lowest effective dose and periodically reassess. FDA Access Data
    Class: Proton-pump inhibitor. FDA Access Data
    Dosage/time: Typical 20–40 mg daily course depending on indication. FDA Access Data
    Purpose: Reduce GI injury/GERD symptoms. FDA Access Data
    Mechanism: Blocks gastric H+/K+-ATPase. FDA Access Data
    Side effects: Headache, diarrhea; long-term use risks discussed individually. FDA Access Data

16. Vitamin D (a supplement, but often prescribed like a “drug”)
    Long description: Under steroid therapy or limited weight-bearing, clinicians often prescribe vitamin D to reach target serum 25-OH-D levels, helping bone health and fracture prevention combined with calcium and fall-prevention strategies. Dosing is individualized (often 800–1000 IU/day in adults, with higher repletion for deficiency). PMC+1
    Class: Vitamin/hormone. Bone Health & Osteoporosis Foundation
    Dosage/time: Per level and age; recheck labs. PMC
    Purpose/Mechanism: Support bone mineralization; reduce steroid-related bone loss. PMC
    Side effects: Hypercalcemia with overdosing—monitor. Bone Health & Osteoporosis Foundation

17. Calcium
    Long description: Paired with vitamin D for bone support when dietary intake is inadequate, especially with steroids or low weight-bearing. Dosing is tailored to dietary assessment to avoid kidney stone risk. Parent Project Muscular Dystrophy
    Class: Mineral supplement. Bone Health & Osteoporosis Foundation
    Dosage/time: Divide doses with meals for absorption. Bone Health & Osteoporosis Foundation
    Purpose/Mechanism: Substrate for bone; complements vitamin D. Parent Project Muscular Dystrophy
    Side effects: Constipation, kidney stones at high intake. Bone Health & Osteoporosis Foundation

18. Coenzyme Q10 (adjunct, investigational in dystrophies)
    Long description: Small studies (mostly in DMD) suggest CoQ10 can modestly improve muscle strength when added to steroids; evidence in LGMD is limited. Discuss risks/cost and avoid replacing proven supportive care. PMC+1
    Class: Mitochondrial cofactor supplement. PMC
    Dosage/time: Varied (e.g., 2–4 mg/kg/day in studies). PMC
    Purpose/Mechanism: Supports mitochondrial electron transport. PMC
    Side effects: Usually mild GI upset; interactions possible (discuss with clinician). PMC

19. Creatine monohydrate
    Long description: High-quality RCTs across muscular dystrophies show small but significant strength gains and better performance for some patients; generally well tolerated if kidneys are healthy and dosing sensible. Hydration is important. Cochrane+1
    Class: Nutraceutical/ergogenic supplement. PMC
    Dosage/time: Commonly 3–5 g/day (no loading needed). Cochrane
    Purpose/Mechanism: Increases phosphocreatine for quick energy buffering in muscle. PMC
    Side effects: Weight gain (water), GI upset in some. Cochrane

20. Pain & sleep adjuncts (tailored)
    Long description: Short-courses of acetaminophen/NSAIDs for musculoskeletal aches, judicious PPI protection if needed, and careful use of neuropathic agents (e.g., gabapentin) can improve comfort and participation in therapy. Always review polypharmacy and organ function. FDA Access Data+3FDA Access Data+3FDA Access Data+3
    Class: Symptom-based. FDA Access Data
    Dosage/time: As per individual labels and clinician guidance. FDA Access Data
    Purpose/Mechanism/Side effects: See individual agents above. FDA Access Data

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Dietary molecular supplements

None of these cures LGMD2U; consider them optional adjuncts discussed with your neuromuscular team.

1. Creatine monohydrate (3–5 g/day). Function: modest strength gain; Mechanism: phosphocreatine pool; Evidence: RCTs show small benefits in muscular dystrophies; monitor renal status. Cochrane+1

2. Coenzyme Q10 (e.g., 100–300 mg/day). Function: mitochondrial support; Mechanism: electron transport; Evidence: pilot DMD studies show strength improvements with steroids; extrapolation to LGMD is cautious. PMC+1

3. Vitamin D3 (dose per level, often 800–1000 IU/day adults). Function: bone health; Mechanism: Ca/P metabolism; Evidence: neuromuscular guidelines emphasize vitamin D sufficiency under steroids/immobility. PMC

4. Calcium (intake to RDA; supplement only if diet insufficient). Function: bone mineral; Mechanism: substrate for bone; Evidence: bone health guidelines in dystrophies. Parent Project Muscular Dystrophy

5. L-carnitine (e.g., 1–2 g/day if used). Function: fatty-acid shuttle; Mechanism: mitochondrial β-oxidation; Evidence: mixed/limited, mostly animal or small studies—use only with clinician oversight. PubMed+1

6. Omega-3 fatty acids (EPA/DHA) (1–2 g/day combined). Function: anti-inflammatory; Mechanism: membrane lipid mediators; Evidence: general anti-inflammatory data; disease-specific LGMD evidence limited—discuss risks (bleeding) with clinicians. Medscape

7. Ribitol (research setting; not standard OTC therapy). Function/Mechanism: substrate to increase CDP-ribitol and matriglycan in FKRP-related dystroglycanopathy; Evidence: animal and early clinical signals in FKRP disease—not established for ISPD/CRPPA-deficiency, where the enzyme that makes CDP-ribitol is defective. Nature+1

8. Ribose (research setting). Function/Mechanism: may increase CDP-ribitol pathways; Evidence: preclinical/early studies mainly in FKRP models; not proven in ISPD deficiency. Nature

9. Protein adequacy (whey/casein if diet low). Function: maintain lean mass; Mechanism: amino acid availability for repair; Evidence: general nutrition principles; pair with PT for best effect. Muscular Dystrophy Association

10. Antioxidant-rich foods/supplements (under guidance). Function: general oxidative stress support; Mechanism: scavenging ROS; Evidence: mixed—prioritize whole foods; supplements only if clinician recommends. Muscular Dystrophy Association

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Immunity-booster / regenerative / stem-cell” drugs

There are no FDA-approved regenerative or stem-cell drugs for LGMD2U. The items below are experimental concepts—discuss only within clinical trials.

1. Ribitol (BBP-418) – substrate enhancement (FKRP disease)
   ~100 words: Oral ribitol increases CDP-ribitol, enabling better α-dystroglycan glycosylation where FKRP retains function; animal and early human data are encouraging in FKRP-related disease. Not proven for ISPD/CRPPA deficiency, because the CRPPA enzyme that makes CDP-ribitol is itself impaired. Nature+1

2. ISPD/CRPPA gene therapy (preclinical concept)
   ~100 words: Delivering a correct CRPPA gene to muscle (e.g., AAV) could, in theory, restore CDP-ribitol synthesis and matriglycan; preclinical work combining ISPD overexpression with ribitol improved dystrophic phenotypes in models, but human trials are not yet available. Cell

3. Dystroglycanopathy-targeted gene therapy (platform research)
   ~100 words: Lessons from FKRP AAV studies and adjuvant ribitol suggest substrate-plus-gene strategies might be synergistic; these are gene-specific and have not yet been extended to ISPD in people. ScienceDirect

4. Cell-based therapies (mesoangioblasts/myoblasts – investigational)
   ~100 words: Various cell-delivery approaches have been tested in other dystrophies to repopulate muscle with healthier nuclei, but challenges (engraftment, immune response, distribution) remain, and no approved product exists for LGMD. Trials are disease- and center-specific. PMC

5. Myostatin-pathway inhibitors (class concept)
   ~100 words: Agents that block myostatin aim to increase muscle mass; trials in other neuromuscular diseases have had mixed results, and none is approved for LGMD2U. Risk–benefit remains under study. PMC

6. Metabolic mitochondrial adjuncts (e.g., CoQ10) – supportive
   ~100 words: While not regenerative, mitochondrial supports like CoQ10 are sometimes used adjunctively; evidence is modest and mostly from DMD. Use only as part of comprehensive care, not as a substitute for proven supportive therapies. PMC

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Surgeries (what they are; why done)

1. Achilles tendon lengthening / gastrocnemius recession
   Procedure: Lengthen tight heel cords to allow the ankle to reach neutral for bracing/standing.
   Why: Reduce painful equinus, improve shoe wear and orthosis fit, help standing transfers or short ambulation. Evidence shows deformity correction; expectations must be realistic regarding overall weakness. PubMed

2. Multilevel soft-tissue contracture releases
   Procedure: Address multiple tight muscle-tendon units (e.g., hamstrings/hip flexors) at once.
   Why: Improve seating posture, hygiene, orthotic fitting, and comfort when conservative care fails; combination with good medical therapy (e.g., GC in DMD) may have functional benefits. PMC

3. Spinal fusion for progressive scoliosis
   Procedure: Instrumentation and fusion to correct/stabilize scoliosis.
   Why: Improve sitting balance, comfort, and quality of life, and may slow forced vital capacity (FVC) decline compared with conservative care. jss.amegroups.org+1

4. Feeding tube (gastrostomy) when needed
   Procedure: Placement of PEG/GT for nutrition.
   Why: Secure calories and hydration when dysphagia/aspiration risk limits oral intake, preventing weight loss and chest infections. Muscular Dystrophy Association

5. Cardiac devices (pacemaker/ICD/CRT) in selected patients
   Procedure: Implantable devices for bradyarrhythmias or ventricular arrhythmia risk according to cardiology guidelines.
   Why: Reduce syncope/sudden-death risk and improve LV synchrony in appropriate cardiomyopathy phenotypes. American Heart Association Journals+1

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Preventions

1. Avoid exhaustion-level workouts; choose gentle, regular activity. Medscape

2. Daily stretching/night splints to slow contractures. Parent Project Muscular Dystrophy

3. Vaccinate (influenza, pneumococcal) and practice hand hygiene to prevent chest infections. PMC

4. Home safety changes (grab bars, rails, lighting) to prevent falls. myTomorrows

5. Bone health: vitamin D sufficiency, calcium as needed, fall-prevention, and weight-bearing as tolerated. PMC

6. Regular cardio-respiratory checkups with early use of cough-assist/BiPAP if indicated. PMC

7. Weight management to reduce strain on weak muscles and joints. Muscular Dystrophy Association

8. Ergonomic aids (OT-recommended) to protect shoulders and conserve energy. myTomorrows

9. Early orthopedic referral when contractures or scoliosis progress despite therapy. jss.amegroups.org

10. Genetic counseling for family planning and early detection in relatives. Genomics Education Programme

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When to see doctors (red flags)

• Falling more often, new tripping, or sudden loss of a skill → PT/neuromuscular review to adjust braces, therapy, and safety plan. Medscape

• Morning headaches, daytime sleepiness, or restless sleep → sleep/respiratory assessment for nocturnal hypoventilation and need for BiPAP. PM&R KnowledgeNow

• Weak cough, frequent chest infections, or difficulty clearing mucus → respiratory clinic for cough-assist training. PMC

• Palpitations, chest pain, dizziness/syncope, or swelling/shortness of breath → cardiology evaluation for arrhythmia or cardiomyopathy management. American Heart Association Journals

• Progressive contractures or worsening scoliosis → orthopedic/spine clinic to discuss bracing vs. surgery. jss.amegroups.org

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Foods to favor (and to limit/avoid)

Eat more of:

• Lean proteins (fish, eggs, poultry, legumes) to support muscle repair with PT. Muscular Dystrophy Association

• Calcium-rich foods (dairy, fortified plant milks) if intake is low. Parent Project Muscular Dystrophy

• Vitamin-D sources (fortified foods; supplements if deficient per clinician). PMC

• Fruits/vegetables (color variety) for antioxidants and fiber. Muscular Dystrophy Association

• Whole grains for steady energy and gut health. Muscular Dystrophy Association

Limit/avoid:

• Ultra-processed, high-sugar snacks/drinks that add weight without nutrition. Muscular Dystrophy Association

• Very high-salt foods if heart failure or edema is present. FDA Access Data

• Excess alcohol, which worsens balance and muscle recovery. Medscape

• NSAIDs without a plan if used frequently; ask about PPI protection. FDA Access Data

• Unreviewed supplements that could interact with heart or seizure medicines. FDA Access Data

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FAQs

1. Is LGMD2U the same as LGMDR20?
   Yes. Newer naming calls it LGMDR20 (ISPD/CRPPA-related); both refer to the same ISPD gene-related condition. MDPI

2. How is it inherited?
   Autosomal recessive—both parents are carriers; each pregnancy has a 25% chance of an affected child. Genomics Education Programme

3. What symptoms usually appear first?
   Trouble rising from the floor, climbing stairs, or lifting arms overhead; enlarged calves/thighs can be seen; CK is often high. Global Genes

4. Is there a cure?
   No disease-specific cure yet; supportive, proactive care improves quality of life and safety. Medscape

5. What specialists should be on my team?
   Neuromuscular neurologist/physiatrist, PT/OT, pulmonologist, cardiologist, orthopedic/spine surgeon, genetic counselor, and dietitian. TREAT-NMD

6. Can exercise help or harm?
   Gentle, regular aerobic work helps; avoid exhaustion-level or high-intensity eccentric training. Medscape

7. Will I need breathing support?
   Some people benefit from cough-assist and nighttime BiPAP as weakness progresses; screening catches needs early. PMC+1

8. Is the heart affected?
   Risk varies by subtype; surveillance is standard, and ace-inhibitors/β-blockers or devices may be used if cardiomyopathy/arrhythmias appear. American Heart Association Journals

9. Are steroids used?
   Sometimes off-label, balancing modest functional goals with side-effects; decisions are individualized. FDA Access Data+1

10. What about ribitol or gene therapy?
    Ribitol has early promise mainly in FKRP-related disease; ISPD/CRPPA-deficient LGMD would need CRPPA gene correction—currently preclinical. Institut Myologie+1

11. Do supplements work?
    Creatine shows small strength gains; CoQ10 has limited supportive data in DMD; vitamin D/calcium for bone health if deficient or on steroids. Cochrane+2PMC+2

12. When are surgeries considered?
    For fixed contractures altering function or pain, and progressive scoliosis affecting sitting balance or lung mechanics. PubMed+1

13. Could my child outgrow it?
    No; it is genetic and lifelong, but progression is variable and support can be highly effective. MDPI

14. Is pregnancy possible?
    Many women with LGMD carry pregnancies with specialist care; genetic counseling is important, and anesthesia teams should be informed of neuromuscular disease. Genomics Education Programme

15. Where can I learn about standards of care and trials?
    See Treat-NMD/LGMD Care guides and neuromuscular centers; discuss trial listings with your specialist. TREAT-NMD+1

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: October 11, 2025.

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