Background

Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts, and the relationship between phenotypes and genotypes is only partially understood.

Methods

This is a retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological, and molecular characterization of 104 patients with CM is reported.

Results

The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild-grade endomysial fibrosis (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with “specific” histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65 of 104 patients (62%), with RYR1 (24/104) and TTN (8/104) being the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in one of three patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%.

Conclusions

This study provides an updated picture of the clinical, histopathological, and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy specimens are significantly associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.

中文翻译：

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基于大型儿科队列的先天性肌病的表型和基因型

背景

先天性肌病 (CM) 是一组临床和遗传异质性的遗传性肌肉疾病。遗传和组织学亚型的分布仅在少数队列中得到解决，表型和基因型之间的关系仅部分了解。

方法

这是在单个中心进行的回顾性横断面数据收集研究。报告了 104 名 CM 患者的临床、组织病理学和分子特征。

结果

最常见的组织病理学亚型是核心肌病 (42%)。与仅有轻度肌内膜纤维化的患者相比，重度肌内膜纤维化患者更常无法行走（56% vs 16%）。在严重脂肪替代的患者中，无法行走也更为普遍（44% 对 19%）。在具有“特定”组织学发现的那些患者中，更频繁地确定遗传病因（74% 对 62%）。104 名患者中有 65 名 (62%) 获得明确的分子诊断，其中RYR1 (24/104) 和TTN(8/104) 是最常见的致病基因。新生儿发病率为 56%。独立行走的成功率为 74%。迟到的患者更可能依赖轮椅。三名患者中的一名需要呼吸支持。15% 的患者需要放置胃造口术。3% 的患者出现心脏受累，43% 的患者出现脊柱侧弯，6% 的患者出现智力障碍。

结论

这项研究提供了 CM 的临床、组织病理学和分子景观的最新图景。独立于致病基因，肌肉活检标本中的纤维化和脂肪替代与临床严重程度显着相关。TTN中的突变导致比以前认为的更高比例的病例。