Cheema Ikreet, Goodwin Jacob, Liewluck Teerin, Bucelli Robert Charles, Pestronk Alan, Milone Margherita
Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
Department of Neurology, Washington University, St. Louis, MO, USA.
Orphanet J Rare Dis. 2025 Jun 22;20(1):317. doi: 10.1186/s13023-025-03850-w.
Dysferlin (DYSF) has a crucial role in sarcolemmal repair. While DYSF mutations commonly manifest as limb-girdle muscular dystrophy (LGMDR2) or distal Miyoshi myopathy, atypical manifestations, such as asymptomatic hyperCKemia and pseudometabolic myopathy, are rarely reported. We describe clinical, serologic, radiologic, genetic, and muscle pathology findings of three patients with rare dysferlinopathy phenotypes and long-term follow up in one of them. We also review the literature pertinent to uncommon forms of dysferlinopathy presenting with hyperCKemia and pseudometabolic phenotype.
Patient 1 is a 51-year-old female with exercise-induced myalgia predominantly affecting calf muscles for 7 years. She had a 22-year history of asymptomatic hyperCKemia (CK 812-2,223 U/L). Neurologic exam showed mild calf enlargement without weakness. CT of the lower limb revealed fatty infiltration of distal peroneal and calf muscles. Genetic testing showed two DYSF variants, c.2163-2A > G (pathogenic) and c.866C > G, p.Ser289Cys (VUS), unknown if heteroallelic. Muscle biopsy demonstrated nuclei internalization and absent dysferlin immunoreactivity. Patient 2 is a 20-year-old male, football player, with an episode of exercise-induced myalgia followed by asymptomatic persistent hyperCKemia (729-2,645 U/L). He had normal strength but mild calf muscle atrophy. Muscle MRI demonstrated subtle T2 hyperintensity in the posterior leg compartment musculature. He has two heteroallelic DYSF variants, c.6008G > A, p.Gly2003Asp (pathogenic) and c.854C > T, p.Thr285Met (VUS). Muscle biopsy showed no myopathic changes but reduced dysferlin immunoreactivity. Patient 3 is a 58-year-old female with incidentally detected asymptomatic hyperCKemia (CK: 249-2,096 U/L) for 2 years. She had normal strength and normal lower limb muscle MRI. She carries two heteroallelic DYSF variants, c.2517del, p.Met840Trpfs*108 (pathogenic) and c.6058C > T, p.Arg2020Cys (VUS). Muscle biopsy showed minimal myopathic changes and attenuated dysferlin immunoreactivity. Reduced dysferlin expression was confirmed by western blot in patients 2 and 3. Needle EMG was normal in all patients.
Dysferlinopathy should be considered in the differential diagnosis of metabolic myopathies and asymptomatic hyperCKemia. Patient 1's long history of hyperCKemia without weakness over two decades suggests that CK elevation in dysferlinopathy does not necessarily predict development of weakness. Additionally, the lack of dystrophic changes on muscle biopsy of patients with asymptomatic or minimally symptomatic hyperCKemia should not discourage the search for dysferlin deficiency in muscle, particularly in the setting of DYSF variants.
肌膜修复蛋白（DYSF）在肌膜修复中起关键作用。虽然DYSF突变通常表现为肢带型肌营养不良症（LGMDR2）或远端型宫下肌病，但非典型表现，如无症状性高肌酸激酶血症和假性代谢性肌病，鲜有报道。我们描述了3例具有罕见肌膜修复蛋白病表型患者的临床、血清学、放射学、遗传学和肌肉病理学检查结果，并对其中1例进行了长期随访。我们还回顾了与表现为高肌酸激酶血症和假性代谢表型的不常见形式的肌膜修复蛋白病相关的文献。
患者1为51岁女性，有运动诱发的肌痛，主要累及小腿肌肉达7年。她有22年无症状性高肌酸激酶血症病史（肌酸激酶812 - 2223 U/L）。神经系统检查显示小腿轻度增粗但无肌无力。下肢CT显示腓骨远端和小腿肌肉脂肪浸润。基因检测显示两个DYSF变异，c.2163 - 2A＞G（致病性）和c.866C＞G，p.Ser289Cys（意义未明变异），是否为杂合等位基因未知。肌肉活检显示细胞核内移且肌膜修复蛋白免疫反应性缺失。患者2为20岁男性，足球运动员，有一次运动诱发的肌痛发作，随后出现无症状性持续性高肌酸激酶血症（729 - 2645 U/L）。他肌力正常，但小腿肌肉轻度萎缩。肌肉MRI显示小腿后侧肌群有轻微T2高信号。他有两个杂合等位基因DYSF变异，c.6008G＞A，p.Gly2003Asp（致病性）和c.854C＞T，p.Thr285Met（意义未明变异）。肌肉活检未显示肌病改变，但肌膜修复蛋白免疫反应性降低。患者3为58岁女性，偶然发现无症状性高肌酸激酶血症（肌酸激酶：249 - 2096 U/L）达2年。她肌力正常，下肢肌肉MRI正常。她携带两个杂合等位基因DYSF变异，c.2517del，p.Met840Trpfs*108（致病性）和c.6058C＞T，p.Arg2020Cys（意义未明变异）。肌肉活检显示轻微肌病改变且肌膜修复蛋白免疫反应性减弱。患者2和3经蛋白质免疫印迹法证实肌膜修复蛋白表达降低。所有患者针电极肌电图均正常。
在代谢性肌病和无症状性高肌酸激酶血症的鉴别诊断中应考虑肌膜修复蛋白病。患者1二十多年来有高肌酸激酶血症病史但无肌无力，提示肌膜修复蛋白病中的肌酸激酶升高不一定预示肌无力的发生。此外，无症状或症状轻微的高肌酸激酶血症患者肌肉活检缺乏营养不良性改变，不应妨碍在肌肉中寻找肌膜修复蛋白缺乏，特别是在存在DYSF变异的情况下。
