FLNC-related myopathy: a description of 27 patients from 21 unrelated families

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Genetically confirmed FLNC-related myofibrillar myopathy (n=27). Intervention: Pathogenic FLNC genetic variants. Primary outcome: Cardiac involvement (cardiomyopathies, conduction, and rhythm disorders).

Q: What does this research mean for the field?

FLNC-related myopathy most frequently presents as an adult-onset proximal myopathy with frequent cardiac involvement, a characteristic MRI pattern affecting posterior thigh and paravertebral muscles, and no clear genotype–phenotype correlation. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

Manh‐Louis Nguyen; Beatrice Labella; Teresinha Evangelista; Nathalie Streichenberger; Gisèle Bonne; Pascale Richard; Karim Wahbi; Philippe Petiot; Béatrice Lannes; Pascal Laforêt; Aleksandra Nadaj‐Pakleza; Marie‐Laure Martin‐Négrier; Yann Péréon; J.-B. Noury; Céline Tard; Edoardo Malfatti; Guilhem Solé; Fanny Duval; Elisabeth Ollagnon; Mathilde Renaud; Thierry Maisonobe; Isabelle P. Nelson; Rabah Ben Yaou; Norma B. Romero; Corinne Métay; Marion Masingue; Sarah Léonard-Louis; Rocío‐Nur Villar‐Quiles; Anthony Béhin; Tanya Stojkovic

doi:10.21203/rs.3.rs-11079249/v1

Key result

FLNC-related myopathy features cardiac involvement in ~48% of patients alongside proximal weakness.

n=27

Why the study?

FLNC-related myopathy is a subtype of myofibrillar myopathy encompassing a broad clinical spectrum from limb-girdle and distal myopathies to isolated cardiomyopathy.

Key Points

To describe the clinical, radiological, histopathological, and genetic characteristics of patients diagnosed with FLNC-related myofibrillar myopathy.
Retrospectively evaluated 27 patients (13 men, 14 women) harboring genetically confirmed FLNC variants across 21 unrelated families.
Characterized phenotypic presentation, muscle magnetic resonance imaging or CT scans (n=17), muscle biopsy histology (n=13), and FLNC gene sequencing variants.
Mean age at symptom onset was 40 ± 14 years and mean age at diagnosis was 54 ± 17 years, presenting with proximal weakness only in 48% (13/27), proximal and distal weakness in 33% (9/27), distal only in 11% (3/27), and axial weakness in 59% (16/27).
Cardiac involvement was present in 48% (13/27) with hypertrophic or dilated cardiomyopathy, including conduction and rhythm disorders requiring an implantable cardioverter defibrillator in 2 patients.
Muscle imaging identified fatty replacement predominantly in the posterior thigh (47%) and paravertebral muscles (35%), while genetic analysis found heterozygous missense variants in 81% (22/27) without clear genotype–phenotype correlations.

Study Design

Type

Cohort (n=27)

Multicenter

Yes

Structured PICO

P

Population

27 patients (mean age at diagnosis 54 years, 51.9% female) from 21 families with genetically confirmed FLNC-related myopathy evaluated across 10 French reference centers.

O

Outcome

Clinical, electrophysiological, muscle imaging, histopathological, and genetic phenotype characterization of FLNC-related myopathy, including skeletal muscle weakness patterns, cardiac involvement (cardiomyopathies, conduction and rhythm disorders), and respiratory involvement.

This multicenter cohort study demonstrates that FLNC-related myopathy most commonly presents as adult-onset proximal muscle weakness with a high prevalence (48%) of cardiac involvement—including hypertrophic and dilated cardiomyopathies and arrhythmias—highlighting the need for systematic cardiac evaluation across all FLNC variant types regardless of genotype.

Limitations

Retrospective observational study design
Missing data for several clinical, imaging, and biopsy variables across the cohort
Descriptive nature with no inferential statistical analyses performed
No definitive mutation hot-spot or clear genotype-phenotype correlation could be established
Retrospective data collection from medical records
Missing data for several clinical, biological, imaging, and biopsy variables across the cohort
Descriptive nature of the study with no inferential statistical analyses performed

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Implication

FLNC-related myopathy frequently involves the heart; extends phenotypic spectrum but leaves open optimal screening strategies.

Abstract

Myofibrillar myopathies are inherited neuromuscular disorders characterized by protein aggregation and myofibrillar disorganization. FLNC -related myopathy, a subtype of MFM, encompasses a broad clinical spectrum ranging from limb-girdle and distal myopathies to isolated cardiomyopathy. We retrospectively collected a cohort of 27 patients with genetically confirmed FLNC- related myopathy. Mean age at first symptoms and diagnosis was 40 ± 14 and 54 ± 17 years, respectively. Among the 27 patients, 13 (48%) had proximal muscle weakness only, 3 (11%) had distal muscle weakness only, 9 (33%) had both proximal and distal weakness, and 2 (8%) had no limb weakness. Axial weakness was identified in 16 patients (59%), facial weakness in 4 patients (15%), cardiac involvement such as cardiomyopathies (hypertrophic or dilated) in 13 patients (48%), and conduction and rhythm disorders requiring an implantable cardioverter defibrillator in 2 patients. Mean value of forced vital capacity was 85 ± 28% and 3 patients with sleep apnea syndrome required nocturnal CPAP. Muscle magnetic resonance imaging showed fatty replacement mainly in thigh muscles affecting the posterior compartment, pelvic girdle, and paravertebral muscles. Mean creatine kinase value was 502 ± 436 U/L. Muscle biopsy showed muscle fiber size variability, intracytoplasmic protein aggregates, internalized nuclei, rimmed vacuoles and type 1 muscle fiber predominance. FLNC gene analysis identified heterozygous missense and nonsense variants in 22 (81%) and 3 (11%) patients respectively, and a complex deletion insertion variant in 2 patients (7%). This study reports one of the largest multicenter cohorts of FLNC -related myopathy, confirming that the disease most frequently presents as an adult-onset proximal myopathy with frequent cardiac involvement. We also identified a relatively consistent MRI pattern mainly involving the posterior thigh and paravertebral muscles. Despite the predominance of missense FLNC variants, substantial clinical and pathological heterogeneity was observed, with no clear genotype–phenotype correlation.

Discussion

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Cite This Study

Nguyen et al. (2026) conducted a cohort in Genetically confirmed FLNC-related myofibrillar myopathy (n=27). Pathogenic FLNC genetic variants was evaluated on Cardiac involvement (cardiomyopathies, conduction, and rhythm disorders). FLNC-related myopathy presented with proximal muscle weakness in 48% of patients and cardiac involvement (cardiomyopathies or arrhythmias) in 48% of patients.

synapsesocial.com/papers/6ae682a3e432e7a5c4ef35c4 https://doi.org/10.21203/rs.3.rs-11079249/v1

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FLNC-related myopathy: a description of 27 patients from 21 unrelated families

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

FLNC-related myopathy: a description of 27 patients from 21 unrelated families

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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