Expanding the phenotype and genotype spectra of PLIN4-associated myopathy with rimmed ubiquitin-positive autophagic vacuolation
Expanding the phenotype and genotype spectra of PLIN4-associated myopathy with rimmed ubiquitin-positive autophagic vacuolation
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边缘泛素阳性自噬空泡扩大 PLIN4 相关肌病的表型和基因型谱
DOI：
10.1007/s00401-022-02422-7
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发表时间：
2022-05-02
影响因子：
12.7
通讯作者：
Wang, Ning
中科院分区：
文献类型：
--
作者：
Yang, Kang;Zeng, Yi-Heng;Wang, Ning
最近，Ruggieri等人[2]报告了一种常染色体显性肌病伴边缘泛素阳性自噬空泡化（MRUPAV），其在PLIN 4中具有编码99-mer重复扩增，其临床特征为远端肌肉无力，病理特征为边缘泛素阳性自噬空泡化[2]。在这里，我们报告说，在我们的神经病学中心的肌病患者中，我们发现两个家族表现出明显的近端肌无力，最终发现这些家族在PLIN 4的外显子3中有重复扩增。值得注意的是，在一个家庭，重复扩张的数量高于以前的报告，从这个家庭的患者有较早的发病和相对更严重的肌病比以前报告的情况。表1（补充）列出了这些患者的详细临床特征。在家族1中，F1-III 3从58岁开始出现近端肌无力，主要发生在下肢。其他受影响的家庭成员报告从45-65岁开始缓慢进展的近端下肢无力。血清肌酸激酶（CK）水平正常或轻度升高;肌电图（EMG）显示肌病变化和肌强直放电;一些患者（F1-III 4、F1-III 5和F1-III 6）无症状，但在EMG中显示肌病变化。在家族2中，F2-III 4从25岁开始出现下肢近端肌无力，随后上肢近端肌肉受累，远端肌肉也部分受累。他在39岁时失去了行动能力，只能依靠轮椅。他家族中的其他受影响的人报告说，他们从20多岁开始肌肉无力。F2-III 4和F2-III 6的CK水平轻度升高，EMG显示肌病改变。我们的患者没有出现延髓症状或呼吸系统异常。两个家族中的患者主要表现为进行性近端无力;这与MRUPAV患者的既往报告不同，MRUPAV患者的既往报告主要表现为进行性远端无力[1，2]。因此，我们两个家族的发病症状和肌肉受累模式与之前报道的MRUPAV患者不同。与家族1和既往报告病例相比，家族2患者的发病年龄更早（家族2为25-26岁，家族1为45-65岁），近端肢体无力更严重，疾病进展更快。在家族1中，肌肉成像显示轻度至重度脂肪替代，小腿肌肉比大腿肌肉受累更多。在F2-III 6中，在发病后3年（26岁）仅大腿和小腿有轻度脂肪浸润。包括苏木精和伊红以及改良Gomori三色染色在内的组织病理学检查显示不同程度的肌病改变，其特征为纤维大小变异、肌内膜纤维化和镶边空泡（图1g-n），这些体征与先前报告的病例相似。油红O和高碘酸-希夫染色正常（图1 o和p）。一些纤维显示出缺乏NADH-四唑还原酶活性的小病灶区域（图1 q）。细胞色素c氧化酶/琥珀酸脱氢酶（考克斯/SDH）双染偶见考克斯缺陷纤维呈蓝色（图1 r）。电子显微镜显示空泡充满膜体、部分降解的细胞器和无定形或颗粒状物质，这些物质通常覆盖细胞外空间（补充图1）。杨康和曾一恒对这项工作同样做出了贡献。
Recently, Ruggieri et al. [2] reported an autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) with a coding 99-mer repeat-expansion in PLIN4, which was characterized clinically by weakness in distal muscles and pathologically by rimmed ubiquitinpositive autophagic vacuolation [2]. Here, we report that among myopathy patients at our neurology center, we found two families exhibiting marked proximal muscle weakness, ultimately finding that these families have repeat expansions in exon 3 of PLIN4. Notably, in one family, the number of repeat-expansions was higher than previous reports, and patients from this family had earlier onset and relatively more severe myopathy than previously reported cases. Table 1 (Supplementary) presents detailed clinical characteristics of these patients. In Family 1, F1-III3 had proximal muscle weakness, predominantly in lower limbs, from age 58. Other affected family members reported slowly progressing proximal lower limb weakness beginning at age 45–65. Serum creatine kinase (CK) levels were normal or mildly elevated; electromyography (EMG) showed myopathic changes and myotonic discharges; some patients (F1-III4, F1-III5, and F1-III6) were asymptomatic but showed myopathic changes in their EMG. In Family 2, F2-III4 developed proximal muscle weakness in lower limbs from age 25, followed by muscle involvement in the proximal upper limb, and the distal muscles were also partially involved. He lost his mobility at age 39 and relied on a wheelchair. Other affected individuals in his family reported muscle weakness beginning in their twenties. The CK levels of F2-III4 and F2-III6 were mildly elevated and EMG showed myopathic changes. None of our patients had bulbar symptoms or respiratory abnormalities. Patients in both families were mainly characterized by progressive proximal weakness; this is distinct from previous reports of MRUPAV patients, which were mainly characterized by progressive distal weakness [1, 2]. Therefore, both the onset symptoms and pattern of muscle involvement in our two families were distinct from the MRUPAV patients reported previously. Patients in Family 2 had earlier age at onset (25–26 in Family 2 vs 45–65 in Family 1), more severe proximal limb weakness, and faster disease progression than patients in Family 1 and the previous reported cases. In Family 1, muscle imaging showed mild to severe fatty replacement, and calf muscles were more involved than thigh muscles. In F2-III6, there was only mild fatty infiltration of the thighs and calves at 3 years after onset (at 26 years). Histopathology including haematoxylin and eosin and modified Gomori trichrome staining showed myopathic changes to various degrees, characterized by fiber size variation, endomysial fibrosis, and rimmed vacuoles (Fig. 1g–n), signs similar to the previously reported cases. Oil Red O and periodic acid–Schiff staining were normal (Fig. 1o and p). Some fibers showed small focal areas devoid of NADH-tetrazolium reductase activity (Fig. 1q). Cytochrome c oxidase/succinate dehydrogenase (COX/SDH) double-staining occasionally showed COX deficient fibers which appeared blue (Fig. 1r). Electron microscopy revealed vacuoles filled with membranous bodies, partially degraded organelles, and amorphous or granular material, which often abutted the extracellular space (Supplementary Fig. 1). Kang Yang and Yi-Heng Zeng contributed equally to this work.