RESUMO
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.
Assuntos
Cardiomiopatias , Cardiomiopatias/genética , Cardiomiopatias/patologia , Desmina/genética , Humanos , Músculo Esquelético/patologia , Mutação/genética , Fenótipo , Estudos RetrospectivosRESUMO
We present a synthesis of clinical, neuropatholgical, and biological details of the National Institutes of Health series of 300 experimentally transmitted cases of spongiform encephalopathy from among more than 1,000 cases of various neurological disorder inoculated into nonhuman primates during the past 30 years. The series comprises of 278 subjects with Creutzfeldt-Jakob disease, of whom 234 had sporadic, 36 familial, and 8 iatrogenic disease; 18 patients with kuru; and 4 patients with Gerstmann-Straussler-Scheinker syndrome. Sporadic Creutzfeldt-Jakob disease, numerically by far the most important representative, showed an average age at onset of 60 years, with the frequent early appearance of cerebellar and visual/oculomotor signs, and a broad spectrum of clinical features during the subsequent course of illness, which was usually fatal in less than 6 months. Characteristic spongiform neuropathology was present in all but 2 subjects. Microscopically visible kuru-type amyloid plaques were found in 5 percent of patients with Creutzfeldt-Jakob disease. 75 percent of those with kuru, and 100 percent of those with Gerstmann-Straussler-Scheinker syndrome; brain biopsy was diagnostic in 95 percent of cases later confirmed at autopsy, and proteinase-resistant amyloid protein was identified in Western blots of brain extracts from 88 percent of tested subjects. Experimental transmission rates were highest for iatrogenic Creutzfeldt-Jakob disease (100 percent), kuru (95 percent), and sporadic Creutzfeldt-Jakob disease (90 percent), and considerably lower for most familiar forms of disease (68 percent). Incubation periods as well as the durations and character of illness showed great variability, even in animals receiving the same inoculum, mirroring the spectrum of clinical profiles seen in human disease. Infectivity reached average levels of nearly 10(to the 5th power) median lethal doses/gm of brain tissue, but was only irregularly present (and at much lower levels) in tissues outside the brain, and, except for cerebrospinal fluid, was never detected in bodily secretions or excretions (AU)