目的:肌原纤维性肌病(MFM)和远端肌病(DM)的诊断过程特别复杂,因为有大量的致病基因,仍然存在分子上不确定的疾病实体,以及两个类别之间的重叠特征。这项研究旨在表征受MFM和DM影响的大量患者,并确定这些疾病最重要的诊断和预后方面。
方法:这项回顾性多中心国家研究包括肌病病理诊断为MFM或临床诊断为DM的患者。人口统计,遗传,临床,匿名患者的组织病理学数据来自意大利肌学协会网络的神经肌肉中心.
结果:有关132例MFM患者的数据(平均年龄57.0±15.8岁,49%女性)和298例DM患者(平均年龄50.7±15.9岁,40%的女性)来自20个神经肌肉中心。69例患者符合两组的标准(远端肌病与肌原纤维病理,DM-MP)。在63%的患者中实现了分子确认。52%的MFM患者在任一DES中携带致病变异(n=30),MYOT(n=20),或DNAJB6(n=18),也是DM-MP中最常见的致病基因,而GNE(n=44)和MYH7(n=23)是DM中最常携带致病变异的基因。发病的平均年龄从MYH7和DYSF致病变异患者的<25岁到肌病患者的59岁不等。据报道,29%的MFM患者和16%的DM患者有心脏受累,DES和MYH7变异与心肌病的发展显着相关。呼吸损害在患有TTN和DES变异的患者中更为普遍,在其他疾病如GNE肌病和异常疾病中很少见。相反,它们是相关的,连同DNAJB6相关和PLIN4相关的肌病,在疾病过程中有失去行走的风险。
结论:意大利MFM和DM患者队列概括了两组之间的表型异质性和部分重叠。然而,与所遇到的表型变异性形成相对对比,只有5个基因占大多数的分子诊断。特定的遗传实体与发生心肺并发症或失去下床活动的风险显着增加有关。具有相关的预后意义。
OBJECTIVE: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases.
METHODS: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network.
RESULTS: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course.
CONCLUSIONS: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.