What is muscular dystrophy in children, including its definition, classification, epidemiology, genetics, molecular pathogenesis, clinical features, diagnosis, management, and prognosis?

Muscular Dystrophy in Children: Comprehensive Overview

Definition and Core Pathophysiology

Muscular dystrophies are primary hereditary diseases of muscle caused by mutations in more than 40 genes, characterized by progressive muscle wasting, weakness, and replacement of functional muscle tissue with fat and connective tissue over time. 1, 2

The dystrophic process involves myofiber shrinkage, net loss of cytoplasm and organelles, overall protein degradation, fiber size variability, fiber necrosis, regeneration, inflammation, and connective tissue deposition 3, 4.

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Classification and Types

Major Forms of Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD)

• Most common and severe X-linked inherited muscular dystrophy of childhood 1
• Affects approximately 1 in 3,000 to 1 in 5,000 live male births 1
• Caused by mutations in the dystrophin gene resulting in absent or severely reduced dystrophin protein 2

Becker Muscular Dystrophy (BMD)

• Milder allelic variant of DMD with later onset and slower progression 2
• Results from in-frame mutations allowing production of partially functional dystrophin 2

Limb-Girdle Muscular Dystrophies (LGMD)

• Heterogeneous group affecting proximal limb muscles 5
• Caused by mutations in genes encoding sarcolemmal proteins (sarcoglycans, dysferlin, caveolin-3), cytosolic proteins (calpain-3, TRIM32), and sarcomeric proteins (telethonin, myotilin, titin) 5

Congenital Muscular Dystrophies (CMD)

• Early onset disorders with muscle weakness present at birth or within first months of life 6
• Often involve brain and eye abnormalities 6
• Caused by mutations in genes encoding extracellular matrix proteins (alpha2 laminin, collagen VI) and glycosylation pathway enzymes (fukutin, fukutin-related proteins) 5

Emery-Dreifuss Muscular Dystrophy

• Characterized by early contractures, slowly progressive muscle weakness, and cardiac conduction defects 5
• Caused by mutations in nuclear envelope proteins (emerin, lamin A/C) 5

Facioscapulohumeral Muscular Dystrophy (FSHD)

• Affects facial, shoulder girdle, and upper arm muscles 2
• Typically presents in adolescence or early adulthood 2

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Molecular Pathogenesis

Dystrophin Gene and Dystrophin-Glycoprotein Complex (DGC)

The dystrophin protein is a huge cytosolic protein that links intracellular F-actin filaments to members of the dystrophin-glycoprotein complex, connecting the muscle cell cytoskeleton to the extracellular matrix. 7, 5

• Dystrophin deficiency results in absence or reduction of DGC components that are degraded through ubiquitin-proteasome pathways 7
• Loss of this structural link causes sarcolemmal instability, increased membrane permeability, calcium influx, and progressive muscle fiber degeneration 2
• The E3/E4 ubiquitylation enzyme CHIP plays a critical role in muscle wasting and degeneration through proteasome-mediated degradation 7

Genotype-Phenotype Correlation

Full characterization of the mutation is required to correlate the predicted effect on the reading frame, which determines disease progression and eligibility for mutation-specific therapies. 8

• Out-of-frame deletions/duplications typically cause DMD (severe phenotype) 8
• In-frame mutations typically cause BMD (milder phenotype) 2
• The reading frame rule predicts phenotype severity in approximately 90% of cases 2

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Epidemiology and Genetics

Inheritance Patterns

DMD/BMD: X-linked recessive inheritance

• Affects primarily males; females are typically carriers but may have mild symptoms 1
• Approximately one-third of cases result from de novo mutations 2

LGMD: Autosomal recessive or dominant inheritance 5

CMD: Primarily autosomal recessive 6

EDMD: X-linked or autosomal dominant 5

FSHD: Autosomal dominant 2

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Age of Onset and Clinical Features Stage-Wise

Duchenne Muscular Dystrophy Progression

Early Stage (Birth to 3 years)

• Delayed motor milestones (sitting, crawling, walking) 8
• May walk later than 18 months 1
• Calf pseudohypertrophy may be present 8
• CK levels markedly elevated (>10,000 U/L) even before symptoms 8

Ambulatory Stage (3-12 years)

• Progressive proximal muscle weakness affecting lower limbs more than upper limbs 3, 8
• Gowers' sign: child uses hands to "climb up" their own legs when rising from floor, indicating proximal lower extremity weakness 3
• Waddling gait, difficulty climbing stairs, frequent falls 3
• Toe-walking due to Achilles tendon contractures 1
• Calf pseudohypertrophy (firm, enlarged calves due to fat and connective tissue replacement) 8
• Motor skills plateau or decline between 4-6 years 8
• Loss of ambulation typically occurs between 7-13 years without corticosteroid treatment 1

Non-Ambulatory Stage (12+ years)

• Wheelchair dependence 1
• Progressive upper limb weakness 1
• Scoliosis development 3
• Respiratory muscle weakness requiring ventilatory support 1
• Cardiac involvement progressing to dilated cardiomyopathy 1

Red Flag Signs Requiring Urgent Evaluation

• Persistently elevated CK levels (>3,500 U/L) in infants or young children 8
• Delayed walking beyond 18 months with proximal weakness 1
• Gowers' sign in a boy over 3 years of age 3
• Calf pseudohypertrophy with weakness 8
• Family history of affected males or carrier females 8

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Cardiac and Respiratory Involvement

Cardiac Complications

Cardiac involvement progresses to dilated cardiomyopathy in the majority of DMD patients and is the leading cause of death. 1

• Cardiomyopathy develops in nearly all patients by late teens 1
• Arrhythmias and conduction abnormalities occur 3
• Early introduction of cardiac medication (ACE inhibitors and beta-blockers) can delay onset and/or slow progression of cardiomyopathy 1, 3
• Regular cardiac assessments are recommended to monitor disease progression 1

Respiratory Complications

Respiratory complications are the second most frequent cause of death in DMD, after cardiac failure. 1

• Progressive loss of respiratory muscle strength leads to restrictive lung disease 1
• Ventilatory support is frequently required after loss of ambulation, initially overnight but later may be needed 24 hours/day 1
• Nocturnal hypoventilation occurs first, followed by daytime respiratory insufficiency 1
• Respiratory infections pose significant risk 1

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Cognitive Associations

Cognitive impairment occurs in approximately one-third of DMD patients, with mean IQ approximately one standard deviation below normal. 2

• Verbal abilities are more affected than performance abilities 2
• Learning disabilities, particularly in reading and language, are common 2
• Attention deficit disorders may occur 2
• Cognitive function does not decline progressively 2

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Differential Diagnosis

Conditions to Consider

Neurogenic atrophy:

• Spinal muscular atrophy (anterior horn cell disease) 3
• Peripheral neuropathies 3
• Distinguished by EMG/NCS showing neurogenic patterns 3

Other myogenic conditions:

• Congenital myopathies 3
• Metabolic myopathies 3
• Inflammatory myopathies (elevated CRP, different biopsy findings) 8

Endocrine and metabolic causes:

• Hypothyroidism, Cushing syndrome 3
• Glycogen storage diseases 3

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Diagnostic Approach

Initial Clinical Evaluation

In children less than 5 years of age, a normal muscle examination cannot completely exclude DMD, and a boy older than 10 years with normal muscle function is highly unlikely to have DMD. 8

Key clinical assessments:

• Motor development evaluation including sitting, crawling, walking milestones 8
• Muscle tone and strength using manual muscle testing (MRC scale) or quantitative myometry 8
• Range of motion assessment using goniometry 8
• Standardized timed function tests 8
• Evaluation for calf pseudohypertrophy 8
• Detailed family history including affected males and potential carrier females 8

Laboratory Testing

Creatine Kinase (CK) Levels

• In DMD patients, CK concentration is usually >10,000 U/L and these levels remain permanently high 8
• CK levels in DMD remain permanently high and do not show temporary fluctuations associated with exercise 8
• In healthy individuals, maximal exercise can increase CK to >3,000 U/L, but this returns to normal within 24-120 hours 8
• High CK levels should not be attributed to "only exercise effect" in suspected DMD—CK should be re-measured after at least 48-72 hours of rest 8
• Continuous high CK levels (3,500-16,000 U/L) are strong evidence for DMD 8

Genetic Testing

Proceed directly to genetic testing for dystrophin gene deletions/duplications from a blood sample—this is always necessary even if muscle biopsy is performed. 8

• Dystrophin gene deletion/duplication analysis should be performed immediately from blood sample 8
• Detects approximately 65-70% of DMD mutations 2
• If deletion/duplication testing is negative, proceed to full gene sequencing 2
• Full characterization of the mutation is required to determine eligibility for mutation-specific therapies 8

Electromyography (EMG) and Nerve Conduction Studies

EMG helps differentiate between myopathic and neurogenic processes. 3

• Myopathic pattern: short-duration, low-amplitude, polyphasic motor unit potentials 3
• Neurogenic pattern: long-duration, high-amplitude potentials with reduced recruitment 3

Muscle Biopsy

Muscle biopsy is the gold standard for confirming diagnosis and differentiating inflammatory from noninflammatory myopathy. 1, 3

• Shows dystrophic changes: fiber size variability, necrosis, regeneration, inflammation, connective tissue deposition 4
• Immunohistochemistry for dystrophin protein: absent in DMD, reduced/patchy in BMD 2
• If genetic testing is negative, muscle biopsy may be necessary to evaluate dystrophin protein expression 8
• Can identify other muscular dystrophies through specific protein staining 2

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Screening and Prevention

Screening of Siblings

Genetic counseling should be provided to the family, especially potential carrier female family members. 8

• Male siblings should undergo CK testing and genetic analysis 8
• Female siblings and maternal relatives should undergo carrier testing 8
• Carrier females may have mild symptoms and elevated CK 2

Prenatal Diagnosis

Available for families with known mutations:

• Chorionic villus sampling (10-12 weeks gestation) 2
• Amniocentesis (15-20 weeks gestation) 2
• Preimplantation genetic diagnosis for IVF pregnancies 2

Newborn Screening

Early diagnosis allows for timely initiation of glucocorticoid treatment and slows disease progression. 8

• Some regions have implemented newborn screening for DMD using CK or genetic testing 2
• Enables early intervention and family planning 8

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Disease Progression and Natural History

DMD Natural History

Without treatment, progressive loss of muscle strength results in loss of ambulation (7-13 years), loss of respiratory muscle strength, and death typically from respiratory insufficiency or cardiac failure. 1

• Median life expectancy: 29-30 years with comprehensive care 1
• Ambulation lost between 7-13 years without corticosteroids 1
• Scoliosis develops in most non-ambulatory patients 3
• Respiratory failure typically occurs in late teens to twenties 1
• Cardiac failure becomes predominant cause of death 1

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Complications

Major Complications

Respiratory:

• Nocturnal hypoventilation 1
• Respiratory infections and pneumonia 1
• Respiratory failure requiring mechanical ventilation 1

Cardiac:

• Dilated cardiomyopathy 1
• Arrhythmias and conduction defects 3
• Heart failure 1

Orthopedic:

• Scoliosis (occurs in >90% of non-ambulatory patients) 3
• Joint contractures (ankles, knees, hips, elbows) 1
• Pathologic fractures due to osteoporosis 3

Nutritional:

• Early obesity due to reduced mobility 1
• Later malnutrition and dysphagia 1

Psychosocial:

• Depression and anxiety 2
• Social isolation 2
• Educational challenges 8

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Prognosis and Causes of Death

Prognosis

With comprehensive multidisciplinary care including corticosteroids, cardiac management, and respiratory support, median life expectancy has improved to 29-30 years. 1

• Corticosteroid treatment prolongs ambulation by 2-5 years 1
• Early cardiac intervention improves cardiac outcomes 1, 3
• Non-invasive ventilation extends survival significantly 1

Causes of Death

Primary causes:

1. Cardiac failure (most common) 1
2. Respiratory insufficiency (second most common) 1
3. Respiratory infections and pneumonia 1
4. Sudden cardiac death from arrhythmias 3

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Quality of Life

Multidisciplinary care models with coordinated comprehensive care can improve survival and quality of life for children with muscular dystrophy. 3

• Prolonged ambulation improves independence and reduces complications 1
• Psychosocial support addresses mental health needs 2
• Educational accommodations enable academic success 8
• Assistive technology enhances communication and mobility 2
• Family support and respite care reduce caregiver burden 2

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Management: Pharmacologic Treatment

Corticosteroids

Corticosteroids are routinely recommended from a young age because they slow the rate of decline in muscle function and prolong ambulation. 1

Indications:

• Glucocorticoid treatment is typically started between 4-6 years of age, when motor skills plateau or decline 8
• Should be initiated before significant functional decline 1
• The American Academy of Pediatrics recommends corticosteroids to slow decline in muscle function and prolong ambulation 1

Dosing:

• Prednisone: 0.75 mg/kg/day (daily regimen) 1
• Deflazacort: 0.9 mg/kg/day (daily regimen) 1
• Alternative: Weekend-only dosing or 10 days on/10 days off regimens 1

Duration:

• Continue throughout ambulatory phase and into non-ambulatory phase 1
• Lifelong treatment may be beneficial for respiratory and cardiac function 1

Side Effects and Monitoring:

• Weight gain and obesity (most common) 1
• Growth retardation and short stature 1
• Behavioral changes (hyperactivity, mood changes) 1
• Osteoporosis and increased fracture risk 3
• Cataracts (more common with deflazacort) 1
• Cushingoid appearance 1
• Immunosuppression and increased infection risk 1
• Monitor: weight, height, bone density, blood pressure, glucose, cataracts, behavior 1

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Management: Cardiac Care

Early introduction of cardiac medication can delay onset and/or slow progression of cardiomyopathy in DMD. 1, 3

Cardiac Monitoring:

• Baseline echocardiogram and ECG at diagnosis 1
• Regular cardiac assessments every 1-2 years during childhood, annually after age 10 1
• More frequent monitoring once cardiomyopathy detected 1

Cardiac Medications:

• ACE inhibitors (or ARBs): initiate when cardiomyopathy detected or prophylactically by age 10 1, 3
• Beta-blockers: add when left ventricular dysfunction progresses 3
• Diuretics for heart failure symptoms 1
• Consider early initiation even before cardiomyopathy is evident 3

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Management: Respiratory Support

The British Thoracic Society has endorsed evidence-based and consensus-based best practice for respiratory care of children and adults living with DMD. 1

Respiratory Monitoring:

• Baseline pulmonary function tests when cooperative (typically age 5-6) 1
• Annual spirometry and assessment of cough effectiveness 1
• Overnight oximetry/polysomnography to detect nocturnal hypoventilation 1

Respiratory Interventions:

• Non-invasive ventilation (NIV): initiate when nocturnal hypoventilation develops or FVC <50% 1
• Initially overnight, later may require 24-hour support 1
• Mechanical insufflation-exsufflation (cough assist) for secretion clearance 1
• Aggressive treatment of respiratory infections 1
• Annual influenza vaccination 1

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Management: Physiotherapy and Rehabilitation

Physiotherapy is essential for maintaining muscle strength and function, and preventing complications such as contractures and scoliosis. 3

Key Components:

• Passive stretching exercises to prevent contractures (daily) 3
• Active-assisted range of motion exercises 3
• Submaximal aerobic exercise (avoid eccentric/high-resistance exercise) 1
• Positioning and postural management 3
• Mobility aids: ankle-foot orthoses, standing frames, wheelchairs 1
• Hydrotherapy may be beneficial 3

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Management: Orthopedic Interventions

Orthopedic management addresses contractures, scoliosis, and skeletal deformities. 3

Contracture Management:

• Night splints for ankles and knees 3
• Serial casting for severe contractures 3
• Surgical release of Achilles tendons to prolong ambulation 1

Scoliosis Management:

• Spinal bracing may slow progression but does not prevent scoliosis 3
• Spinal fusion surgery when curve >20-30 degrees and FVC >30-35% 3
• Surgery improves sitting balance and may preserve respiratory function 3

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Management: Nutritional Care

Nutritional support addresses both early obesity and later malnutrition. 1

Early Phase (Ambulatory):

• Calorie restriction to prevent excessive weight gain on corticosteroids 1
• Calcium and vitamin D supplementation for bone health 3
• Balanced diet with adequate protein 1

Later Phase (Non-Ambulatory):

• Monitor for dysphagia and aspiration risk 1
• Gastrostomy tube placement if swallowing difficulties develop 1
• Maintain adequate nutrition to support respiratory function 1

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Management: Vaccination Considerations

Immunizations are important but require special considerations in corticosteroid-treated patients. 1

• All routine childhood vaccinations should be given 1
• Annual influenza vaccination is essential 1
• Pneumococcal vaccination recommended 1
• Live vaccines should be avoided if on high-dose corticosteroids (>2 mg/kg/day or >20 mg/day prednisone equivalent for >14 days) 1
• Varicella and MMR should be given before starting corticosteroids if possible 1

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Management: Psychosocial Support

Psychosocial support addresses mental health, social integration, and family coping. 2

Patient Support:

• Psychological counseling for depression and anxiety 2
• Peer support groups 2
• Assistive technology for communication and independence 2
• Transition planning to adult care 2

Family Support:

• Genetic counseling for family planning 8
• Respite care for caregivers 2
• Financial counseling and assistance 2
• Sibling support 2

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Management: School Planning

An individualized education plan should be developed. 8

Educational Accommodations:

• Assessment for learning disabilities and cognitive impairment 8, 2
• Classroom modifications (accessible facilities, extra time for tasks) 8
• Assistive technology (computers, tablets, voice recognition software) 8
• Physical therapy and occupational therapy services in school 8
• Social support and peer education 8
• Transition planning for post-secondary education or vocational training 8

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Multidisciplinary Follow-Up

Multidisciplinary follow-up with neurologist, physiotherapist, cardiologist, and respiratory specialist is necessary. 8

Core Team Members:

• Neuromuscular specialist (pediatric neurologist) 8
• Cardiologist 8
• Pulmonologist 8
• Physical therapist 8
• Occupational therapist 3
• Orthopedic surgeon 3
• Nutritionist 1
• Psychologist/psychiatrist 2
• Genetic counselor 8
• Social worker 2
• Palliative care specialist (later stages) 1

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Emerging and Novel Therapies

Exon Skipping

Exon skipping induced by antisense strategies holds great promise, with several clinical trials ongoing and proof-of-concept obtained in animal models and clinical trials. 1

Mechanism:

• Antisense oligonucleotides bind to specific exons during pre-mRNA splicing 1
• Causes skipping of targeted exon to restore reading frame 1
• Converts severe DMD phenotype to milder BMD phenotype 1

Approved Agents:

• Eteplirsen (exon 51 skipping) 2
• Golodirsen (exon 53 skipping) 2
• Viltolarsen (exon 53 skipping) 2
• Casimersen (exon 45 skipping) 2

Limitations:

• Mutation-specific: only works for specific deletions amenable to skipping 1
• Modest dystrophin restoration (typically <5-15%) 2
• Clinical benefit remains under investigation 2

Gene Therapy

Gene-delivery-based strategies exist for highly efficient delivery of functional dystrophin mini- and micro-genes to muscle fibers in vivo and muscle stem cells ex vivo. 1, 3

Mechanism:

• Adeno-associated virus (AAV) vectors deliver shortened but functional dystrophin genes (micro-dystrophin) 1
• Systemic delivery targets skeletal, cardiac, and respiratory muscles 1

Current Status:

• Multiple clinical trials ongoing 1, 3
• Challenges include immune responses to AAV and transgene 1
• Durability of expression under investigation 1

Ataluren (PTC124)

Ataluren promotes read-through of premature stop codons in nonsense mutations. 2

Mechanism:

• Allows ribosome to read through premature stop codons 2
• Enables production of full-length dystrophin protein 2

Limitations:

• Only effective for nonsense mutations (~10-15% of DMD patients) 2
• Conditional approval in some countries; efficacy data mixed 2

CRISPR-Cas9 Gene Editing

CRISPR-Cas9 technology offers potential for precise correction of dystrophin gene mutations. 1

Mechanism:

• Directly edits genomic DNA to correct mutations or restore reading frame 1
• Can permanently correct genetic defect in muscle stem cells 1

Current Status:

• Preclinical studies show promise in animal models 1
• Safety concerns regarding off-target effects being addressed 1
• Clinical trials in early planning stages 1

Stem Cell Therapy

Stem cell approaches aim to regenerate functional muscle tissue. 3, 4

Approaches:

• Myoblast transplantation 4
• Mesenchymal stem cells 4
• Induced pluripotent stem cells (iPSCs) 4

Current Status:

• Significant challenges with cell survival, immune rejection, and delivery 4
• Remains largely experimental 3, 4

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Critical Pitfalls to Avoid

Diagnostic Pitfalls:

• Do not attribute persistently elevated CK (>3,500 U/L) to exercise alone—this indicates muscle disease requiring genetic testing 8
• Do not delay genetic testing waiting for muscle biopsy—proceed directly to genetic analysis 8
• Do not assume normal muscle examination in young child (<5 years) excludes DMD 8

Management Pitfalls:

• Do not delay corticosteroid initiation—start at 4-6 years when motor skills plateau 8
• Do not discontinue corticosteroids at loss of ambulation—continue for cardiac and respiratory benefits 1
• Do not wait for symptomatic cardiomyopathy to initiate cardiac medications—consider prophylactic treatment by age 10 1, 3
• Do not overlook respiratory monitoring—initiate NIV early when nocturnal hypoventilation develops 1
• Do not forget live vaccine contraindications in patients on high-dose corticosteroids 1