Dados do Trabalho

Título

Clinical and molecular spectrum of myofibrillar and distal myopathies.

Resumo

Introduction: Distal myopathies (DMs) are a group of muscle diseases featuring a predominance of weakness in the distal extremities, while myofibrillar myopathies (MFMs) are skeletal and cardiac muscle diseases with Z-disk protein aggregates and myofibril disarray. Both conditions may present with predominant distal weakness and demonstrate a vacuolar histology, confounding clinical classification.

Objectives: To characterize patients with DMs and MFMs, comparing both groups and classifying their genetic subtypes.

Methods: This observational study identified patients at a tertiary neuromuscular center with MFM and DM diagnoses. Patients underwent a next-generation sequencing panel, followed by whole-exome sequencing.

Results: We included 54 patients from 42 families: 34 patients (23 families) with MFMs, and 20 patients (19 families) with DMs. Among the MFM families, variants in DES were the main cause (n=8), followed by TTN (n=4), FHL1 (n=3), FLNC (n=2), BAG3 (n=2), MYOT (n=1) and HNRNPA2B1 (n=1). Among the DM families, DYSF (n=6) and GNE (n=4) were the most frequent disease-causative genes, followed by MYH7 (n=2), NEB (n=2), TTN (n=1), ANO5 (n=1), RYR1 (n=1), and DNM2 (n=1). The severity of motor impairment occurred in a similar proportion between distal myopathy and myofibrillar myopathy, being more pronounced in patients with variants in the BAG3, FHL1, MYH7 and GNE. Myofibrillar myopathies had a higher proportion and severity of cardiorespiratory impairment. DES myopathy was related to more frequent cardiopathy. BAG3 myopathy was an early and severe subgroup with axial contractures, cardiac and respiratory impairment. Child FHL1 patients presented with inflammatory histology, and adult female presented a scapuloperoneal phenotype. Miyoshi phenotype was seen in dysferlinopathy and anoctaminopathy. GNE myopathy, in turn, presented with involvement of the anterior leg muscles. Some genes related to congenital myopathies were also causes of DMs (TTN, RYR1, DNM2) and were confounded with hereditary neuropathy during the first years of disease, although we only noted concomitant peripheral nerve involvement in patients with BAG3 myopathy.

Conclusion: DMs and MFMs comprise heterogeneous groups, but their phenotypic characteristics allow relative categorization into subgroups. Recognizing these myopathies is important due to their potential severity, early cardiac complications, and respiratory failure, which can lead to preventable death.

Palavras Chave

Myofibrillar myopathy, distal myopathy, vacuolar myopathy, desminopathy.