What is the best approach for treating the muscular component for locomotion in an adult patient with distal myopathy type 4 due to a FLNC (filamin C) gene mutation, presenting with progressive muscle weakness?

Treatment for Muscular Component of Locomotion in FLNC-Related Distal Myopathy Type 4

There is no disease-modifying pharmacological therapy available for FLNC-related myopathy; treatment focuses on physical therapy to maintain mobility and prevent contractures, combined with aggressive management of cardiac and respiratory complications that determine survival. 1, 2

Musculoskeletal Management Strategy

Physical Therapy and Mobility Preservation

• Implement regular physical therapy focused on maintaining range of motion and preventing contractures, as these are critical to preserving ambulatory function in progressive myopathies. 2
• Assess muscle strength, range of motion, and functional capacity every 4 months to track disease progression and adjust interventions. 2
• Provide orthotic devices and mobility aids (ankle-foot orthoses, canes, walkers, wheelchairs) as weakness progresses to maintain independence. 2

Exercise Prescription

• Prescribe gentle, low-resistance exercise programs to maintain muscle function without causing overwork damage. 1, 2
• Avoid high-intensity resistance training, as FLNC mutations cause structural muscle fiber abnormalities that may worsen with excessive mechanical stress. 3, 4
• Focus on aerobic activities like swimming or recumbent cycling that minimize joint stress while maintaining cardiovascular fitness. 1

Contracture Prevention

• Monitor hip, knee, and ankle joints for emerging contractures every 4-6 months, as these contribute significantly to functional deterioration. 1
• Implement daily stretching exercises targeting hip flexors, hamstrings, gastrocnemius, and ankle dorsiflexors. 1
• Consider splinting for ankle contractures if they develop despite stretching programs. 1

Critical Systemic Monitoring (Determines Mortality)

Cardiac Surveillance

• Perform annual ECG and echocardiography at minimum, as cardiac involvement occurs in FLNC-related myofibrillar myopathy and includes dilated cardiomyopathy, conduction blocks, and arrhythmias that cause sudden death. 1, 4
• Approximately one-third of patients with the p.W2710X mutation develop cardiac abnormalities including conduction blocks, tachycardia, diastolic dysfunction, and left ventricular hypertrophy. 4
• Initiate standard heart failure therapies (ACE inhibitors, beta-blockers) immediately when cardiac dysfunction is detected. 1
• Consider implantable cardioverter-defibrillator placement for patients with significant conduction abnormalities or ventricular arrhythmias. 1

Respiratory Management

• Assess respiratory function regularly, as respiratory muscle weakness develops in FLNC-related myopathy and is a major cause of morbidity. 1, 2, 4
• Perform pulmonary function testing every 6 months once respiratory symptoms emerge or forced vital capacity drops below 80% predicted. 5
• Implement non-invasive ventilation (BiPAP) when forced vital capacity falls below 50% predicted or nocturnal hypoventilation develops. 2
• Treat respiratory infections aggressively with early antibiotics, as these patients have reduced respiratory reserve. 2

Disease-Specific Considerations for FLNC Mutations

Pathophysiology Context

• FLNC mutations in the rod domain (like p.W2710X) cause protein misfolding and toxic aggregate formation, triggering myofibrillar destruction with accumulation of desmin, myotilin, and other proteins. 3, 4
• The ubiquitin-proteasome system and autophagy pathways are overwhelmed and inefficient in clearing these aggregates, leading to progressive muscle fiber damage. 3
• Distal myopathy type 4 typically presents with distal lower extremity weakness but can progress proximally over time. 6

Clinical Trajectory

• Mean age of symptom onset is 44 years (range 24-57 years) for the p.W2710X mutation, with slowly progressive weakness initially affecting lower extremities. 4
• Disease progression is variable: some patients lose ambulation within 3 years, while others maintain ambulation for decades. 7, 8
• Serum creatine kinase is typically mildly elevated (normal to 10-fold upper limit) and does not correlate with disease severity. 8, 4

Common Pitfalls to Avoid

• Do not delay cardiac evaluation: Cardiac complications can precede or occur independently of skeletal muscle severity and are a major cause of sudden death. 1, 4
• Do not prescribe high-intensity strength training: The underlying protein aggregation pathology may worsen with excessive mechanical stress on structurally compromised muscle fibers. 3
• Do not overlook respiratory decline: Respiratory muscle weakness is frequent and requires proactive monitoring rather than waiting for symptomatic dyspnea. 4
• Do not assume stable disease: Even patients with slow progression can experience accelerated decline, requiring ongoing reassessment. 7

Multidisciplinary Team Requirements

• Neuromuscular neurologist for disease monitoring and coordination. 2
• Physical therapist for mobility and contracture management. 2
• Occupational therapist for adaptive equipment and activities of daily living. 2
• Cardiologist for cardiac surveillance and management. 1, 2
• Pulmonologist for respiratory monitoring and ventilation management. 2
• Genetic counselor for family screening, as this is an autosomal dominant condition. 8, 4