Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene
Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene
复制标题
DOI：
10.1212/01.wnl.0000188870.37076.f2
复制
发表时间：
2005-12-27
期刊：
影响因子：
9.9
通讯作者：
Muntoni, F
中科院分区：
文献类型：
--
作者：
Jungbluth, H;Zhou, H;Muntoni, F
背景资料：微小核肌病（多微小核疾病[MmD]）是一种先天性肌病，其特征为肌肉活检显示多灶性区域氧化活性丧失。MmD在临床上是异质性的，不同的表型与硒蛋白N（SEPN 1）或骨骼肌兰尼碱受体（RYR 1）基因的隐性突变相关，也与中央核心疾病和恶性高热有关。外眼肌麻痹是MmD患者亚组的另一个发现。目的：对多发性骨髓瘤（MmD）伴眼外肌麻痹家系进行临床和遗传学检查。方法：作者调查了来自5个无血缘关系家庭的11名患病者。进行了临床、组织病理学和影像学研究，并进行了RYR1单体型分析和突变分析。结果：所有患者在纵切面上均有多个纤维芯累及整个纤维直径。肩胛带的虚弱和消瘦、脊柱侧凸、中度呼吸障碍和进食困难是突出的。与SEPN1相关的肌病相反，在肌肉MRI上比目鱼肌比腓肠肌受到更严重的影响。单倍型分析表明，与RYR1基因位点的连锁信息的家庭和突变筛查发现四个新的RYR1突变在三个无关的家庭，此外，功能性单倍不足被发现在一个等位基因的两个隐性病例。结论：这些发现扩大了骨骼肌兰尼碱受体（RYR1）基因突变相关的表型谱。在恶性高热中通常受影响的结构域的隐性突变似乎在伴有眼外肌麻痹的多微核心疾病中特别普遍，并且可能表明与涉及中央核心疾病的病理机制不同。
Background: Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N ( SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD. Objective: To clinically and genetically examine families with MmD and external ophthalmoplegia. Methods: The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out. Results: All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases. Conclusion: These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor ( RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different patho-mechanism from that involved in central core disease.