Dados do Trabalho

Título

Phenotype-genotype correlation in desminopathy: variant location in DES gene determines the severity of phenotype and the morphology of intracytoplasmic aggregates

Resumo

Introduction: Desmin (DES) is the main intermediate filament in the muscle, arranged in a tridimensional structure that connects myofibrils to each other as well as to the nuclei, the sarcolemma and organelles. Pathogenic variants in DES cause desminopathy, a disorder affecting skeletal muscles and the heart. It is characterized by a spectrum of phenotypes and arrangements of intracytoplasmic aggregates.
Objectives: We aimed to analyze the clinical features and the morphology and distribution of desmin aggregates in the skeletal muscle biopsies of patients with desminopathy, and to correlate these findings with genetic characteristics.
Methods: This is a retrospective study that included patients with molecularly confirmed desminopathy from two national referral centers (Brazil and Spain).
Results: Thirty patients from 20 unrelated families were included. The mean age of disease onset was 25 years old. Cardiopathy was present in 86.7% of them, and in 14 patients, the cardiac symptoms preceded musculoskeletal weakness. From 21 available biopsies, two distinct patterns of desmin aggregates were identified: subsarcolemmal well-demarcated aggregates (in eight patients) and aggregates with diffuse and poorly delimited borders (in 13 patients). Pathogenic variants in the 1B segment and the tail domain presented cardiopathy and the proximal distribution of weakness at the onset of symptoms more frequently when compared with patients with variants in other segments of the desmin. All patients with mutations in the 1B segment presented the well-demarcated desmin aggregate pattern, and no patients with variants in other segments showed this histological arrangement.
Conclusion: We suggest a phenotype-genotype correlation that associates the presence of variants in the 1B segment and the tail protein domain with a more prominent cardiac presentation and a proximal-onset weakness distribution. Additionally, we found a morphotype-genotype correlation, with variants in the 1B segment causing well-demarcated subsarcolemmal desmin aggregate formation. These findings may be useful for identifying more severe patients, thus optimizing clinical care in this subgroup.

Palavras Chave

Desminopathy; myofibrillar myopathy; desmin-related myopathy; desmin.