What are the treatment modalities for an adult patient with distal myopathy type 4 due to FLNC (Filamin C) gene mutation, presenting with progressive muscle weakness?

Treatment Modalities for Distal Myopathy Type 4 Due to FLNC Gene Mutation

Cardiac Management: The Critical Priority

All patients with FLNC-related distal myopathy require immediate cardiac evaluation and systematic surveillance every 6 months, as cardiac complications—including atrial fibrillation (occurring in 15% of probands), stroke (affecting 7% during follow-up), and cardiomyopathy—significantly increase mortality risk and may precede skeletal muscle symptoms. 1, 2

Anticoagulation Strategy

• Initiate oral anticoagulation immediately in all patients with documented atrial fibrillation, given the substantial stroke risk (4% present with minor stroke initially, 7% develop stroke during follow-up) 2
• Apply CHA₂DS₂-VASc scoring: anticoagulate if score ≥2 in men or ≥3 in women (Class I-B recommendation), or consider anticoagulation if score is 1 in men or 2 in women (Class IIa-B) 1

Implantable Cardioverter-Defibrillator (ICD) Consideration

• Consider ICD implantation in patients with FLNC-truncating variants who have LVEF ≤35% despite optimal medical therapy for ≥3 months and life expectancy >1 year (Class IIa-C recommendation) 1
• FLNC-truncating variants carry high sudden cardiac death risk requiring comprehensive risk stratification with additional risk factors assessed every 1-2 years 1
• Cardiac conduction defects increase sudden death risk and warrant close monitoring 1

Cardiomyopathy Monitoring

• Perform multiparametric cardiac imaging (echocardiography and ECG) every 1-2 years in stable individuals with disease-causing FLNC variants 1
• Recognize that cardiomyopathy may manifest as dilated, hypertrophic, or restrictive patterns, and severe cardiomyopathy can precede skeletal muscle involvement 1, 2

Respiratory Management

Monitor respiratory function regularly at each 6-month follow-up visit, as respiratory muscle weakness complicates management, contributes to mortality, and requires early intervention to prevent cardiorespiratory failure. 1, 2

• Assess for progressive involvement of respiratory muscles, which follows the distal-to-proximal pattern affecting trunk musculature 2
• Consider non-invasive ventilation when respiratory compromise develops 3

Physical Therapy and Exercise Prescription

Exercise Parameters

• Prescribe submaximal and aerobic exercise over excessive resistive exercise for patients capable of voluntary movement 3
• Implement gentle strengthening within physiological limits: 3 sets of 8-10 repetitions at 50-70% of 1 repetition maximum (1RM) 3
• Incorporate rest periods between sets to prevent excessive fatigue and avoid overwork weakness 3

Critical Exercise Precautions

• Avoid excessive resistive and eccentric exercise, as these can worsen muscle damage through protein misfolding and aggregate formation that characterizes FLNC-related myofibrillar myopathy. 3, 4
• Monitor cardiorespiratory response during activity, especially in supine position 3
• Watch for signs of overwork weakness, which can lead to further deterioration 3

Functional Training Approach

• Focus on functional activities rather than isolated exercises, incorporating self-care skills, mobility training, and adaptive equipment use 3
• Implement early mobilization with active or passive exercise combined with structured physiotherapy to prevent further muscle loss 3

Monitoring and Assessment Protocol

Neuromuscular Surveillance

• Establish regular follow-up every 6 months with neuromuscular specialists 2
• Perform manual muscle testing using the MRC scale every 4-6 months to quantify strength changes 3
• Conduct timed functional tests (10-meter walk, time to rise from chair, 6-minute walk test) every 4-6 months 3
• Assess range of motion to identify emerging contractures 3

Disease Progression Monitoring

• Document the characteristic distal-to-proximal progression pattern: lower extremities → upper extremities → trunk → facial and respiratory muscles 2
• Evaluate for peripheral neuropathy, which occurs in 15-30% of patients 2

Assistive Technology and Adaptive Equipment

• Provide appropriate assistive technology with proper training for home, educational, and work environments 3
• Consider mobility aids (manual or electric wheelchairs) when ambulation becomes significantly impaired 3
• Implement orthotic intervention to prevent contractures and deformity 3

Genetic Counseling and Family Screening

• Offer genetic counseling to all affected patients and at-risk family members, given the autosomal dominant inheritance pattern 2
• Perform cascade genetic testing in first-degree relatives with pre- and post-test counseling (Class I-B recommendation) 1
• Conduct multiparametric cardiac evaluation including ECG and imaging in all first-degree relatives who test positive for the disease-causing FLNC variant 1

Common Pitfalls to Avoid

• Never delay cardiac evaluation, as cardiac complications are the primary mortality driver and may manifest before significant skeletal muscle weakness 1, 2
• Do not prescribe high-intensity resistive training, as this exacerbates the underlying protein aggregation pathology characteristic of FLNC mutations in the rod domain 4
• Avoid underestimating respiratory involvement, which requires systematic monitoring and early intervention 1, 2
• Do not overlook stroke prevention in patients with atrial fibrillation, given the 7% stroke risk during follow-up 2

Pathophysiology-Informed Management

The underlying disease mechanism involves protein misfolding triggered by pathogenic FLNC mutations (particularly in the rod domain), leading to aggregation of mutant filamin C protein and subsequent involvement of desmin, myotilin, and other proteins 4. The affected muscle fibers show increased expression of chaperones and proteins involved in proteasomal degradation and autophagy, but with diminished efficiency of both the ubiquitin-proteasome system and autophagy 4. This impaired protein clearance capacity informs the rationale for avoiding exercise that generates additional protein damage 4.