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 genetic diseases of muscle characterized by progressive muscle weakness, wasting, and degeneration, with histological findings of connective tissue proliferation, variation in fiber size, and most critically, ongoing degeneration and regeneration of myofibers. 1

• These disorders result from mutations in more than 40 genes encoding proteins located at the sarcolemma, extracellular matrix, sarcomere, nuclear membrane, and glycosylation pathways 2, 3
• The dystrophic process involves replacement of functional muscle tissue with fat and connective tissue over time 4

Classification and Major Types

Duchenne Muscular Dystrophy (DMD)

DMD is the most common and severe form of muscular dystrophy in children, affecting approximately 1 in 3,000 to 1 in 5,000 live male births. 5, 4

Genetics and Molecular Pathogenesis

• Caused by mutations in the DMD gene located on the X chromosome, which codes for dystrophin protein 4
• The mutations disrupt the reading frame, resulting in nearly complete absence of functional dystrophin protein, a critical sarcolemma-cytoskeleton linker 5
• Males are predominantly affected because they possess only one X chromosome; a single mutated gene results in disease manifestation 5
• Female carriers typically remain asymptomatic due to their second, normal X chromosome, though rarely "manifesting carriers" may develop significant symptoms 4
• Approximately 30-50% of cases show inherited patterns in DMD families 5

Dystrophin-Glycoprotein Complex

• Dystrophin is a huge cytosolic protein linking intracellular F-actin filaments to members of the dystrophin-glycoprotein complex (DGC) 6
• Dystrophin deficiency results in absence or reduction of complex components that undergo degradation 6
• This disruption compromises muscle fiber integrity and repair capacity 4

Becker Muscular Dystrophy (BMD)

• Results from dystrophin gene mutations that maintain the reading frame, producing truncated but partially functional dystrophin 3
• Presents with milder phenotype and later onset compared to DMD 3

Limb-Girdle Muscular Dystrophies (LGMD)

LGMDs are clinically and genetically heterogeneous disorders with weakness and wasting predominating in pelvic and shoulder girdle muscles. 1

• Classified as LGMD1 (autosomal dominant) or LGMD2 (autosomal recessive) 1
• Caused by mutations in genes encoding sarcoglycans, dysferlin, calpain-3, and other proteins 2
• May involve myocardium with necrosis and regeneration of myofibers 1

Congenital Muscular Dystrophies (CMD)

• Present at birth or early infancy with hypotonia and weakness 2
• Caused by mutations in genes encoding extracellular matrix proteins (alpha2 laminin, collagen VI) and glycosylation pathway enzymes (fukutin, fukutin-related proteins) 2
• Recent discoveries have restricted the gap between LGMD and CMD, requiring renewed boundary definitions 2

Emery-Dreifuss Muscular Dystrophy

• Characterized by early contractures, slowly progressive muscle weakness, and cardiac conduction defects 2
• Caused by mutations in genes encoding nuclear envelope proteins (emerin, lamin A/C) 2

Facioscapulohumeral Muscular Dystrophy (FSHD)

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

Epidemiology

• DMD affects approximately 2,500 boys and men in the UK currently 4
• Incidence of DMD is approximately 1:3,000 male births globally 4
• Other muscular dystrophies collectively represent a heterogeneous group with varying prevalence 2, 3

Age of Onset and Clinical Features by Stage

DMD: Early Stage (Ages 0-5 years)

The average age of diagnosis in the UK is around 4 years, though clinical signs may be present earlier. 4

• Motor developmental delays: late walking (often after 18 months), difficulty running, jumping, climbing stairs 7
• Elevated serum creatine kinase (CK) levels, typically >10,000 U/L, which remain permanently elevated 7
• In children less than 5 years of age, a normal muscle examination cannot completely exclude DMD 7
• Calf pseudohypertrophy may be present early 7

DMD: Ambulatory Stage (Ages 5-12 years)

Skeletal muscles are first noticeably affected, with progressive muscle weakness and wasting leading to gradual decline in motor function. 4

• Gowers' sign: characteristic maneuver where child uses hands to "climb up" their own body when rising from floor, indicating proximal lower limb weakness 7
• Pseudohypertrophy of calves due to fat and connective tissue replacement 7
• Proximal muscle weakness with difficulty climbing stairs, frequent falls 7
• Lumbar lordosis and waddling gait develop 3
• Progressive loss of motor skills, with most patients stopping walking in their early teens 4

DMD: Non-Ambulatory Stage (Adolescence and Adulthood)

Loss of ambulation (LOA) typically occurs in early teens, after which respiratory and cardiac complications become prominent. 4

Respiratory Involvement

• Respiratory complications are related to inspiratory and expiratory muscle weakness, with inspiratory weakness initially causing nocturnal hypoventilation and sleep-disordered breathing 4
• Expiratory muscle weakness causes poor cough and inability to effectively manage respiratory secretions 4
• Ventilatory support frequently required—initially overnight, later potentially 24 hours/day 4
• Respiratory complications remain the second most frequent cause of death in DMD, after cardiac failure 4

Cardiac Involvement

• Progressive dilated cardiomyopathy develops in the majority of patients 4
• Cardiac involvement can impact respiratory function; respiratory failure can trigger cardiac arrhythmias or exacerbate cardiac failure 4
• Early introduction of cardiac medication can delay onset and/or slow progression of cardiomyopathy 4

Cognitive Associations

• Cognitive impairment may be present in some patients with DMD 3
• Full-scale IQ may be reduced, though significant variability exists 3

Red Flag Signs for Early Recognition

• Persistently elevated CK levels (>3,500 U/L) in young boys, especially if levels remain high after 48-72 hours of rest 7
• High CK levels should not be attributed to "only exercise effect"—in DMD, CK remains permanently high, unlike healthy individuals where exercise-induced elevation returns to normal within 24-120 hours 7
• Motor developmental delays with late walking 7
• Proximal muscle weakness with calf pseudohypertrophy 7
• Positive family history of affected male family members 7

Differential Diagnosis

The differential diagnosis of noninflammatory myopathies presenting with proximal muscle weakness and elevated muscle enzymes includes: 4

• Late-onset muscular dystrophy and limb-girdle dystrophy (dysferlinopathies) 4
• Mitochondrial myopathies 4
• Inflammatory myopathies (polymyositis, dermatomyositis) 4
• Drug-induced myopathy 4
• Endocrine myopathy (thyroid disorder, hyperparathyroidism) 4
• Metabolic and infectious myopathies 4

Diagnostic Approach

Initial Laboratory Testing

Clinical diagnosis is made after consideration of history, physical findings, and elevated serum creatine kinase levels. 4, 5

• CK concentration in DMD is usually >10,000 U/L and remains permanently high 7
• CK levels do not show temporary fluctuations associated with exercise in DMD patients 7
• Normal CRP levels indicate absence of infectious/inflammatory processes and support muscle disease diagnosis 7

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. 7

• Diagnosis is confirmed by finding an abnormality in the dystrophin gene through mutation analysis of blood leukocyte DNA 4, 5
• 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 7
• If DNA analysis is normal (as in 1/3 of patients), diagnosis should be confirmed by finding absent or abnormal dystrophin using immunohistology or protein analysis of muscle tissue 4

Electromyography (EMG)

EMG should be performed to: (1) confirm a myopathic process and (2) target a muscle for biopsy. 4

• Myopathic process characterized by polyphasic motor unit action potentials of short duration and low amplitude with increased insertional and spontaneous activity with fibrillation potentials, sharp waves, or repetitive discharges 4

Muscle Biopsy

Muscle biopsy is the gold standard for confirming diagnosis and differentiating inflammatory from noninflammatory myopathy. 4

• Typical histopathologic features include reduction or absence of dystrophin with degenerating and regenerating muscle fibers and replacement of muscle with fat or connective tissue 4
• To maximize diagnostic yield, a weak muscle should be chosen for biopsy, often guided by EMG abnormalities 4

Immunohistochemistry

• Immunohistochemistry for dystrophin, dysferlin, and other proteins helps distinguish specific muscular dystrophy types 8
• Gomori trichrome stain evaluates for ragged red fibers characteristic of mitochondrial myopathies 4

Clinical Assessment Components

• Evaluate muscle tone and strength using manual muscle testing (MRC scale) or quantitative myometry 7
• Assess range of motion using goniometry 7
• Perform standardized timed function tests 7

Screening and Prevention

Screening of Siblings

• Family screening is essential as approximately 30-50% of dilated cardiomyopathy cases in DMD families show inherited patterns 5
• Female family members should be evaluated as potential carriers 7

Prenatal Diagnosis

• Genetic counseling should be provided to families, especially potential carrier female family members 7
• Prenatal testing available for known familial mutations 3

Newborn Screening

• Early diagnosis allows for timely initiation of glucocorticoid treatment and slows disease progression 7
• Some regions implement newborn screening programs for DMD 3

Disease Progression and Natural History

With current standard of care, the median life expectancy for males with DMD is between 29 and 30 years of age. 5

• Progressive loss of muscle strength eventually results in loss of ambulation, loss of respiratory muscle strength 4
• Most patients stop walking in their early teens 4
• Respiratory decline becomes noticeable after LOA, in adolescence and into adulthood 4
• Cardiac involvement progresses to dilated cardiomyopathy in majority of patients 4

Complications

Respiratory Complications

• Respiratory failure and pneumonia result from untreated respiratory muscle weakness 4
• Nocturnal hypoventilation and sleep-disordered breathing 4
• Inability to manage respiratory secretions 4
• Respiratory complications are a major cause of morbidity and unplanned hospital admission 4

Cardiac Complications

• Progressive dilated cardiomyopathy 4
• Cardiac arrhythmias 4
• Cardiac failure 4

Orthopedic Complications

• Scoliosis develops in non-ambulatory patients 3
• Joint contractures 3
• Osteoporosis, particularly with long-term corticosteroid use 3

Prognosis and Causes of Death

Death typically occurs from respiratory insufficiency or cardiac failure. 5

• Respiratory complications remain the second most frequent cause of death in DMD, after cardiac failure 4
• Recent advances in respiratory care have improved outlook and survival 4
• Many caregivers have changed from traditional non-interventional approach to more aggressive, supportive approach 4

Quality of Life

• Maintaining respiratory health is vital to prolonging survival and quality of life in DMD 5
• Advances in supportive medicine have changed standard of care, with overall improvement in clinical course, survival, and quality of life 3
• Psychosocial support and school planning are essential components of comprehensive care 7

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Management

Pharmacologic Management: Corticosteroids

Corticosteroids are routinely recommended from a young age because they slow the rate of decline in muscle function and prolong ambulation. 4

Indications

• The American Academy of Pediatrics recommends the use of corticosteroids to slow the rate of decline in muscle function and prolong ambulation in patients with DMD 5
• Glucocorticoid treatment is typically started between 4-6 years of age, when motor skills plateau or decline 7

Mechanism and Benefits

• Corticosteroids have been shown to delay respiratory decline and help preserve ventilatory function for longer 4, 5
• The precise mechanism by which they exert therapeutic effects in DMD patients is unknown 5

Dosing and Duration

• Specific dosing protocols should be individualized based on weight and clinical response 5
• Long-term use is typically required to maintain benefits 5

Side Effects

• Osteoporosis and increased fracture risk 3
• Weight gain and cushingoid features 3
• Growth retardation 3
• Behavioral changes 3
• Increased infection risk 3

Cardiac Management

Early introduction of cardiac medication can delay the onset and/or slow progression of cardiomyopathy in DMD. 4

• The American Thoracic Society recommends that patients with DMD undergo regular cardiac assessments to monitor disease progression 5
• Cardiac evaluation with troponin, ECG, and echocardiogram should be performed regularly 8
• ACE inhibitors and beta-blockers are typically initiated when cardiomyopathy is detected 3

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. 4

Assessment and Monitoring

• The American Thoracic Society recommends that patients with DMD undergo regular respiratory assessments to monitor disease progression 5
• Pulmonary function testing with negative inspiratory force and vital capacity should be performed regularly 8
• Monitor for nocturnal hypoventilation and sleep-disordered breathing 4

Interventions

• Ventilatory support is frequently required after LOA—initially overnight but later may be needed 24 hours/day 4
• Non-invasive ventilation (NIV) should be initiated when respiratory insufficiency develops 4
• Cough assist devices help manage respiratory secretions when expiratory muscle weakness impairs cough effectiveness 4
• Emergency management protocols should be established for acute respiratory complications 4

Physiotherapy

• Regular stretching exercises to prevent contractures 3
• Range of motion exercises 7
• Positioning and mobility aids 3
• Respiratory physiotherapy to assist with secretion clearance 4

Orthopedic Interventions

• Scoliosis surgery may be required in non-ambulatory patients 3
• Management of contractures with bracing or surgical release 3
• Mobility aids and assistive devices 3

Nutritional Care

• Nutritional assessment and management to prevent obesity (particularly with corticosteroid use) or malnutrition 3
• Swallowing assessment if dysphagia develops 3
• Gastrostomy tube placement may be necessary in advanced stages 3

Vaccination Considerations

• Standard immunizations should be maintained 3
• Annual influenza vaccination is particularly important given respiratory vulnerability 3
• Pneumococcal vaccination recommended 3

Psychosocial Support

• Genetic counseling should be provided to the family, especially potential carrier female family members 7
• Psychological support for patients and families 7
• Support groups and patient advocacy organizations 3

School Planning

• An individualized education plan should be developed 7
• Accommodations for physical limitations 7
• Cognitive support if needed 3

Multidisciplinary Follow-up

Multidisciplinary follow-up with neurologist, physiotherapist, cardiologist, and respiratory specialist is necessary. 7

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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. 9

• This approach represents a promising therapy for a subset of patients whose mutations are amenable to specific exon skipping 9
• Antisense oligonucleotides restore the reading frame by skipping specific exons, allowing production of truncated but partially functional dystrophin 9
• Several exon-skipping drugs have achieved conditional approval for specific mutation subsets 3

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. 9

• AAV-based vectors show efficient systemic gene delivery to skeletal muscle directly in vivo 9
• Lentivirus-based vectors show promise of combining ex vivo gene modification strategies with cell-mediated therapies 9
• Clinical trials are at advanced stages of development 3

Ataluren (PTC124)

• Designed for patients with nonsense mutations (premature stop codons) 3
• Promotes read-through of premature stop codons to produce full-length dystrophin 3
• Has received conditional approval in some regions 3

CRISPR Gene Editing

• CRISPR-Cas9 technology offers potential for precise correction of dystrophin gene mutations 3
• Preclinical studies show promise in animal models 3
• Clinical translation is in early stages 3

Stem Cell Therapy

• Cell-based gene therapy approaches are being developed 9
• Involves ex vivo modification of muscle stem cells followed by transplantation 9
• Remains largely experimental with ongoing research 9

Current Therapeutic Landscape

The improved understanding of pathogenesis is being used for development of novel therapies, with a few personalized therapies recently achieving conditional approval in DMD and many more at advanced stages of clinical development. 3

• There is currently no effective curative treatment for DMD 4
• Conventional gene replacement strategies, RNA-based approaches, and cell-based gene therapy are being developed with main focus on DMD 9
• Genetic and cell-based therapies, particularly exon skipping and corrective gene therapy via functionally engineered dystrophin genes, hold great promise 9