The Location of Disease-Causing DES Variants Determines the Severity of Phenotype and the Morphology of Sarcoplasmic Aggregates
Por:
Silva, AMS, Rodrigo, P, Moreno, CAM, Mendonca, RD, Estephan, ED, Camelo, CG, Campos, ED, Dias, AT, Nascimento, AM, Kulikowski, LD, Oliveira, ASB, Reed, UC, Goldfarb, LG, Olive, M, Zanoteli, E
Publicada:
16 ago 2022
Ahead of Print:
1 jul 2022
Resumen:
Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.
Filiaciones:
Silva, AMS:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Rodrigo, P:
IDIBELL Hosp Univ Bellvitge, Dept Pathol, Neuropathol Unit, Barcelona, Spain
IDIBELL Hosp Univ Bellvitge, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Hosp Univ, Basurto, Spain
Moreno, CAM:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Mendonca, RD:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Estephan, ED:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Camelo, CG:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Campos, ED:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Dias, AT:
Univ Sao Paulo FMUSP, Fac Med, Dept Pathol, Sao Paulo, Brazil
Nascimento, AM:
Univ Sao Paulo FMUSP, Fac Med, Dept Pathol, Sao Paulo, Brazil
Kulikowski, LD:
Univ Sao Paulo FMUSP, Fac Med, Dept Pathol, Sao Paulo, Brazil
Oliveira, ASB:
Univ Fed Sao Paulo UNIFESP, Dept Neurol & Neurosurg, Div Neuromuscular Dis, Sao Paulo, SP, Brazil
Reed, UC:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
Goldfarb, LG:
Queens Univ, Kingston Gen Hosp, Dept Pathol & Mol Med, Kingston, ON, Canada
Olive, M:
IDIBELL Hosp Univ Bellvitge, Dept Pathol, Neuropathol Unit, Barcelona, Spain
IDIBELL Hosp Univ Bellvitge, Dept Neurol, Neuromuscular Unit, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Zanoteli, E:
Univ Sao Paulo FMUSP, Fac Med, Dept Neurol, Av Dr Eneas Carvalho Aguiar 255,5 Andar,Sala 5084, BR-05403900 Sao Paulo, SP, Brazil
|