What is the diagnosis and management approach for an individual with suspected distal myopathy type 4 due to FLNC (filamin C) gene mutation, presenting with symptoms of distal muscle weakness and a known family history?

Distal Myopathy Type 4 Due to FLNC Gene Mutation

Overview and Genetic Basis

FLNC-related distal myopathy represents a distinct clinical entity within the spectrum of filaminopathies, characterized by distal-predominant muscle weakness caused by mutations in the filamin C gene, which plays an essential role in attaching the sarcomere to the plasma membrane. 1

• FLNC mutations account for approximately 50% of myofibrillar myopathy cases when considering the six traditionally associated genes 1
• The condition is most commonly inherited in an autosomal dominant manner 1, 2
• Almost 20 genes including FLNC have been associated with autosomal dominant distal myopathy 2

Clinical Presentation

Skeletal Muscle Manifestations

The typical presentation involves late-onset (30-50 years of age) slowly progressive muscle weakness beginning distally in the lower extremities, with eventual proximal and upper extremity involvement. 1

• Distal leg weakness is the hallmark initial symptom, presenting with gait impairment in the third decade 3
• Disease progression follows a distal-to-proximal pattern: lower extremities → upper extremities → trunk → facial and respiratory muscles 1
• Hand muscle involvement develops as the disease advances 3
• Peripheral neuropathy may be an associated feature in 15-30% of patients 1

Important Clinical Caveat

The mutation location within FLNC determines the phenotype: actin-binding domain mutations cause distal myopathy with non-specific myopathic features, while rod domain mutations cause proximal myofibrillar myopathy with protein aggregates. 4

• The p.A193T mutation in the actin-binding domain can paradoxically cause predominantly proximal rather than distal weakness 5
• Mutations in the N-terminal actin-binding domain (such as c.A664G:p.M222V) present with predominant leg involvement and myofibrillar aggregates 3

Cardiac Complications

Cardiac involvement is a critical feature requiring systematic surveillance, as FLNC variants carry significant risk for atrial fibrillation and stroke. 1

• Atrial fibrillation occurs in 8% of all FLNC patients (15% of probands, 4% of mutation carriers) 1
• 4% of probands initially present with minor stroke; 7% of probands suffer stroke during follow-up 1
• Cardiomyopathy may manifest as dilated, hypertrophic, or restrictive patterns 1
• Severe cardiomyopathy can precede skeletal muscle involvement, particularly in childhood-onset cases 1

Arrhythmic Complications

Cardiac conduction defects increase the risk of sudden cardiac death and require aggressive monitoring. 1

• Sinus node dysfunction may develop 1
• Atrioventricular block of varying degrees occurs 1
• Both supraventricular and ventricular tachycardias are documented 1
• Heart failure and sudden death are recognized complications 1

Diagnostic Approach

Clinical Evaluation

Suspect FLNC-related distal myopathy in patients presenting with distal lower extremity weakness beginning in the third to fifth decade, particularly with a family history suggesting autosomal dominant inheritance. 1, 3

• Document the pattern of weakness progression (distal to proximal) 1
• Assess for respiratory muscle weakness, which complicates evaluation and management 1
• Evaluate for cardiac symptoms including palpitations, syncope, or stroke 1

Genetic Testing Strategy

Perform targeted gene panel testing for myofibrillar myopathies using next-generation sequencing (NGS) to identify FLNC mutations. 3

• Sequence the entire FLNC gene, paying particular attention to the actin-binding domain (exons 2-8) and rod domain 3, 4
• The founder variant c.8129G>A (p.Trp2710*) is particularly common in Hong Kong Chinese populations 6
• Haplotype analysis can confirm founder effects in specific ethnic populations 6

Muscle Biopsy Findings

Muscle biopsy reveals myofibrillar disruption beginning at the sarcomeric Z-disk, with abnormal accumulation of myofibrillar degradation products. 1

• Actin-binding domain mutations may show non-specific myopathic features without typical myofibrillar myopathy changes 5, 4
• Rod domain mutations produce focal destructive lesions with polymorphous aggregates containing desmin, myotilin, and other proteins 4
• Amorphous material or granulofilamentous masses are detected in approximately 50% of cases 6
• Mitochondrial abnormalities are noted in two-thirds of biopsies 6

Cardiac Screening

All FLNC mutation carriers require comprehensive cardiac evaluation at diagnosis and regular surveillance. 1

• Perform extended Holter monitoring to detect paroxysmal atrial fibrillation 1
• Echocardiography to assess for cardiomyopathy (dilated, hypertrophic, or restrictive patterns) 1
• Cardiac MRI to evaluate for myocardial fibrosis 1
• ECG to detect conduction abnormalities 1

Management Strategy

Multidisciplinary Surveillance

Establish regular follow-up every 6 months with neuromuscular specialists, incorporating cardiac monitoring at each visit. 1

• Strength testing, range of motion assessment, and timed function tests 7, 8
• Activities of daily living evaluations 7, 8
• Specialized physical and occupational therapy evaluations every 4 months 7, 8

Cardiac Management

Initiate anticoagulation for stroke prevention in all patients with documented atrial fibrillation, given the 7% stroke risk in probands. 1

• Direct oral anticoagulants are appropriate for atrial fibrillation management 1
• Beta-blockers for rate control in atrial fibrillation with fast ventricular response 1
• Consider ICD placement for patients with significant ventricular arrhythmias or severe cardiomyopathy 1
• Upgrade to biventricular pacing (CRT-D) if left ventricular ejection fraction deteriorates significantly 1

Respiratory Management

Monitor respiratory function regularly, as respiratory muscle weakness complicates management and contributes to mortality. 1, 6

• Four of 34 patients in one cohort died of pneumonia and/or respiratory failure 6
• Pulmonary function testing should be performed at regular intervals 1

Genetic Counseling

Provide genetic counseling to all family members, as the condition is highly penetrant with autosomal dominant inheritance. 6

• The late-onset nature and slowly progressive course mean early diagnosis benefits the entire family 6
• Test at-risk family members, particularly given the founder effect in certain populations 6
• Discuss family planning and prenatal diagnosis options 8

Prognosis and Disease Course

FLNC-related distal myopathy follows a slowly progressive course over decades, with variable penetrance and significant risk of cardiorespiratory complications. 6

• The condition is highly penetrant in families carrying pathogenic variants 6
• Cardiac complications including stroke and sudden death represent major sources of morbidity and mortality 1
• Respiratory failure is a recognized cause of death 6
• Specific therapies such as chaperone-based or antisense oligonucleotide strategies are under development for this particular type of myopathy 6

Key Clinical Pitfalls

Do not exclude FLNC-related myopathy based on absence of typical myofibrillar changes on muscle biopsy, as actin-binding domain mutations may show only non-specific myopathic features. 5

Do not overlook cardiac screening in asymptomatic mutation carriers, as 4% of probands present initially with stroke. 1

Muscle imaging plays an important role in distinguishing different filamin-C myopathy types and should be incorporated into the diagnostic workup. 5