What are the characteristics and management of neuromuscular movement disorders?

Neuromuscular Movement Disorders: Characteristics and Management

Neuromuscular movement disorders are genetic disorders typically caused by mutations affecting striated muscle, resulting in progressive weakness from degenerative muscle pathology that can involve both skeletal and cardiac muscle, with cardiac involvement being a significant source of morbidity and mortality. 1, 2

Types and Classification

Neuromuscular disorders (NMDs) can be broadly categorized based on their genetic basis and clinical presentation:

Major Categories of NMDs:

1. Dystrophinopathies

   • Duchenne Muscular Dystrophy (DMD)

     • Most common, affecting 1 in 3600-9300 male births
     • X-linked inheritance
     • Severe phenotype with early onset weakness
     • Loss of ambulation typically in second decade
     • Respiratory insufficiency develops in second decade
     • Glucocorticoid treatment prolongs independent ambulation by ~3 years 1

   • Becker Muscular Dystrophy (BMD)

     • Milder, more variable phenotype
     • Later onset of symptoms
     • Less predictable disease progression 1

2. Limb-Girdle Muscular Dystrophies (LGMD)

   • Autosomal dominant (LGMD1) or recessive (LGMD2) inheritance
   • Prevalence: 1 in 14,500 to 1 in 123,000
   • Progressive weakness affecting pelvic or shoulder girdle musculature
   • Variable age of onset and progression 1

3. Myofibrillar Myopathies (MFM)

   • Characterized by disruption beginning at sarcomeric Z-disk
   • Six primary genes associated (DES, MYOT, LDB3/ZASP, CRYAB, FLNC, BAG3)
   • Usually develops later in life (30-50 years)
   • Slowly progressive muscle weakness from distal to proximal 1

4. Congenital Myopathies (CM)

   • Characterized by hypotonia and weakness from birth
   • Static or slowly progressive clinical course
   • Prominent facial weakness, generalized hypotonic posture
   • Cognitive abilities typically preserved 1

Clinical Manifestations

Skeletal Muscle Involvement:

• Progressive weakness with variable distribution patterns
• Proximal muscle weakness in DMD, BMD, and many LGMDs
• Distal-to-proximal progression in MFM
• Facial weakness in congenital myopathies
• Contractures, pseudohypertrophy, and scoliosis in some forms 1

Cardiac Involvement:

Two major categories of cardiac complications:

1. Cardiomyopathy

   • Dilated cardiomyopathy most common in DMD/BMD
   • Less ventricular dilation early in disease course
   • Average age for abnormal LVEF development: 14.3 years
   • Primary cause of mortality in >20% of DMD patients
   • Cardiac symptoms often masked by limited mobility 1, 2

2. Conduction Defects and Arrhythmias

   • Common in EDMD, LGMD1B, and myotonic dystrophy
   • Risk of tachyarrhythmias increases with ventricular dysfunction
   • Can occur even with normal ejection fraction 1, 2

Respiratory Involvement:

• Restrictive lung disease due to respiratory muscle weakness
• Typically develops in second decade in DMD
• Requires ventilatory support as disease progresses 1

Diagnostic Approach

Genetic Testing:

• Crucial for definitive diagnosis due to phenotypic overlap among NMDs
• Determines inheritance patterns and genetic counseling
• Guides cardiovascular assessment and follow-up
• Essential for future mutation-specific therapies 1

Cardiac Evaluation:

• Should begin at diagnosis for conditions like DMD and BMD
• Regular monitoring as risk increases with age
• Early detection of abnormal LVEF allows for timely intervention
• Cardiac MRI with late gadolinium enhancement can detect early myocardial damage when echocardiography may miss it 1, 2

Management Principles

Multidisciplinary Care Team:

• Neurologists should collaborate with cardiologists with expertise in NMDs
• Pediatric heart failure specialists for childhood-onset conditions
• Cardiac evaluation before anesthesia or sedation 1

Cardiac Management:

• Early intervention with ACE inhibitors or ARBs recommended by age 10 in DMD
• Beta-blockers typically added after ACE inhibitors/ARBs
• Mineralocorticoid receptor antagonists to slow decline in left ventricular function
• Device therapy (ICDs) for advanced cardiomyopathy (EF <35%)
• Mechanical circulatory support and transplantation in select cases 2

Movement Disorder Management:

• Physical therapy evaluation and specialized interventions
• Management of muscle tightness and spasticity
• Anticholinergics for acute dystonic reactions if drug-induced
• Anticonvulsants for certain paroxysmal dyskinesias 3, 4, 5

Important Clinical Considerations

Cardiac Screening:

• Regular cardiac screening essential regardless of symptoms
• Patients may not report cardiac symptoms due to limited physical activity
• Standard echocardiography may miss early cardiac involvement 2

Genetic Diagnosis Impact:

• Heterogeneity in cardiovascular manifestations among NMDs:
  • DMD, BMD, FA: increased risk of cardiomyopathy and heart failure
  • EDMD, LGMD1B, DM1: elevated risk of arrhythmia and sudden death
  • BTHS, MFM: risk of both cardiomyopathy and arrhythmias
  • Some NMDs have minimal cardiac involvement 1

Surgical Considerations:

• Cardiac evaluation before anesthesia/sedation
• Procedures should take place in centers with appropriate intensive care facilities
• Cardiac monitoring by experienced anesthesiologists 1

Common Pitfalls and Caveats

1. Underdiagnosis of cardiac involvement: Cardiac symptoms may be masked by limited mobility; regular screening is essential even in asymptomatic patients 2

2. Variable progression: Poor correlation exists between genotype and phenotypes at cardiac and skeletal muscle levels; cardiac involvement often dissociated from skeletal myopathy progression 1

3. Delayed treatment: Early intervention before symptom onset has greater impact on outcomes; don't wait for symptoms to appear 1, 2

4. Incomplete evaluation: Standard echocardiography may miss early cardiac involvement; consider cardiac MRI for more sensitive detection 2

5. Overlooking carriers: Female carriers of DMD/BMD should undergo cardiac evaluation, as they can develop decreased LVEF and myocardial fibrosis 1