From the Neuromuscular Center (C.S., C.B., L.B., B.P., F.G., S.V., B.F.G., G.S., E.P.), Department of Neurosciences, and Departments of Cardiac, Thoracic and Vascular Sciences (M.P., C.C.), Biomedical Sciences (G.M., S.C.E.T.), and Medicine (R.S.), Section of Radiology, University of Padova, Italy; Dubowitz Neuromuscular Centre (Developmental Neuroscience Programme) (F.C.), UCL Great Ormond Street Institute of Child Health, University College London, UK; Neuromuscular and Rare Disease Unit (I.C., M.M.), Department of Neuroscience, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan; Department of Biomedical and Neuromotor Sciences (G.C., V.P.), University of Bologna; and CNR Institute of Neuroscience (S.C.E.T.), Padova, Italy.
Neurology. 2018 Oct 23;91(17):e1629-e1641. doi: 10.1212/WNL.0000000000006387. Epub 2018 Sep 26.
To identify and characterize patients with calsequestrin 1 ()-related myopathy.
Patients selected according to histopathologic features underwent genetic screening. mutated patients were clinically evaluated and underwent muscle MRI. Vacuole morphology and vacuolated fiber type were characterized.
Twenty-two -mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation. Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern. Three patients presented subclinical cardiac abnormalities. Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins. The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates.
We report the clinical and molecular details of the largest cohort of -mutated patients. A possible heart involvement is presented, further expanding the phenotype of the disease. One mutation is common due to a founder effect, but other mutations are possible. Because of a paucity of symptoms, it is likely that mutations may remain undiagnosed if a muscle biopsy is not performed.
鉴定并描述肌质网钙结合蛋白 1（）相关肌病患者。
根据组织病理学特征选择患者进行基因筛查。突变患者接受临床评估并进行肌肉 MRI 检查。对空泡形态和空泡纤维类型进行特征描述。
共鉴定出 22 名突变患者（12 个家系），其中 21 名患者携带先前描述的热点突变（p.Asp244Gly），1 名患者携带 p.Gly103Asp 突变。患者通常在 60 岁左右出现运动不耐受和肌肉疼痛，随后发展为轻度至中度、进展缓慢的近端肌无力，伴有股四头肌萎缩和肩胛骨翼状突出。肌肉 MRI（n = 11）显示出反复的纤维脂肪替代模式。3 名患者出现亚临床心脏异常。p.Asp244Gly 突变患者的肌肉组织病理学显示 II 型纤维有空泡，在苏木精-伊红、Gomori 和烟酰胺腺嘌呤二核苷酸（NADH）四唑还原酶染色中呈现空泡状，但肌质网蛋白呈强阳性。p.Gly103Asp 突变的肌肉组织病理学不同，也显示 NADH 阳性堆积，符合管状聚集。
我们报告了最大一组突变患者的临床和分子细节。可能存在心脏受累，进一步扩展了疾病的表型。由于存在一个热点突变，因此可能存在一个由创始人效应引起的常见突变，但也可能存在其他突变。由于症状相对较少，如果不进行肌肉活检，可能会导致一些突变患者无法得到诊断。
