Oculopharyngodistal myopathy caused by CGG repeat expansion in 5'untranslated region of LRP12 gene: four cases report

doi:10.3969/j.issn.1672-6731.2023.09.005

Abstract

Abstract:

Objective: To report the clinical and pathological features of 4 patients with oculopharyngodistal myopathy type 1 (OPDM1) caused by CGG repeat expansion in the 5'untranslated region (5'UTR) of LRP12 gene. Methods and Results: This study included 4 patients with OPDM1 who were admitted to Peking University First Hospital from January 2008 to August 2023. All 4 patients presented with weakness of eyes closed, dysarthria, dysphagia, facial muscle weakness and muscle weakness mainly involving distal muscles. None of 4 patients had restricted eye movements. Two of the patients had ptosis (Case 1 and Case 2). Serum creatine kinase (CK) levels were mildly to moderately elevated (190-1211 U/L) in 4 patients. Three patients (Case 1, Case 2 and Case 3) underwent lower extremity muscle MRI which showed varying degrees of fatty infiltration, with the soleus and tibialis anterior muscles being worst affected. Skeletal muscle biopsies in all 4 patients showed rimmed vacuoles with muscular dystrophy - like pathological changes. Immunofluorescence staining revealed p62 - positive and ubiquitin - positive intranuclear inclusions in all 4 patients. Genetic testing revealed that all 4 patients carried CGG repeat expansion in the 5'UTR of the LRP12 gene. Conclusions: Most OPDM1 patients start with weakness in the distal extremities of both limbs and dysarthria. The involvement of muscles in the lower extremities is asymmetrical, and the involvement of tissues and organs other than muscles is not obvious. The remaining clinical phenotype and pathological features are consistent with other subtypes of OPDM.

Key words: Neuromuscular diseases, Trinucleotide repeat expansion, Pathology

摘要：

目的: 回顾分析LRP12基因5’非翻译区(5’UTR)CGG异常重复扩增变异致眼咽远端型肌病(OPDM)1型患者临床经过，总结其临床和组织病理学特征。方法与结果: 纳入对象均为2008年1月至2023年8月在北京大学第一医院就诊并经基因检测确诊的OPDM1型患者，临床表现为以闭目无力、构音障碍、吞咽困难、面肌无力和四肢远端肌肉受累为主的肌无力特征，无眼球固定，其中2例伴上睑下垂；病程中血清肌酸激酶轻至中度升高(190~1211 U/L)；3例患者下肢肌肉MRI呈不同程度脂肪化，以比目鱼肌和胫骨前肌受累明显。骨骼肌组织活检可见镶边空泡伴肌营养不良样改变；免疫荧光染色可见p62自噬蛋白和泛素蛋白阳性的核内包涵体形成。基因检测4例患者均携带LRP12基因5’UTR区CGG异常重复扩增变异，最终根据基因检测结果确诊为OPDM1型。结论: OPDM1型患者多以双下肢远端无力和构音障碍发病，下肢肌肉受累不对称，肌肉以外组织器官较少受累，其临床表型和病理特征与其他眼咽远端型肌病亚型具有一致性。

关键词: 神经肌肉疾病, 三核苷酸重复扩增, 病理学

Jia-xi YU, Meng YU, Wei ZHANG, Yun YUAN, Jian-wen DENG, Zhao-xia WANG. Oculopharyngodistal myopathy caused by CGG repeat expansion in 5'untranslated region of LRP12 gene: four cases report[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2023, 23(9): 798-806.

于佳希, 俞萌, 张巍, 袁云, 邓健文, 王朝霞. LRP12基因5’非翻译区CGG异常重复扩增变异致眼咽远端型肌病四例[J]. 中国现代神经疾病杂志, 2023, 23(9): 798-806.

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URL: http://journal11.magtechjournal.com/cjcnn/EN/10.3969/j.issn.1672-6731.2023.09.005

http://journal11.magtechjournal.com/cjcnn/EN/Y2023/V23/I9/798

Figures/Tables 5

Figure 1 Pedigree chart of one OPDM1 family with CGG repeat expansion in 5'untranslated region of LRP12 gene.

Figure 2 Muscle MRI findings of OPDM1 Muscle MRI of OPDM1 patients showed fatty infiltration of lower limb muscles, with the distal muscles more severely affected than the proximal muscles. Axial T₂-FLAIR of both lower limbs of Case 1 and Case 2 showed different degrees of fatty replacement in thigh and calf muscles. In thigh lateralis, intermedius, biceps femoris longhead, semimembranus and adductor maximus, while the rectus femoris, gracilis and semitendinosus were relatively preserved. The soleus, gastrocnemius and anterior tibialis muscles of the lower leg were severely affected by fatty replacement, while the posterior tibialis muscles were relatively preserved. Axial T₂-FLAIR in both lower extremities of Case 3 showed light to moderate fatty replacement in the vastus intermedius, tibialis anterior, and extensor digital longus, as well as in the left soleus and right peroneus longus. Axial T₂-FLAIR of both thigh of Case 1 (Panel 2a). Axial T₂-FLAIR of both calf of Case 1 (Panel 2b). Axial T₂-FLAIR of both thigh of Case 2 (Panel 2c). Axial T₂-FLAIR of both calf of Case 2 (Panel 2d). Axial T₂-FLAIR of both thigh of Case 3 (Panel 2e). Axial T₂-FLAIR of both calf of Case 3 (Panel 2f).

Figure 3 Muscle pathological changes of OPDM1 patients Median power magnified The muscle tissue of Case 1 showed the formation of rimmed vacuoles in the angular atrophy muscle fibers (arrow indicates, Panel 3a). HE staining The muscle tissue of Case 1 showed the formation of rimmed vacuoles in the angular atrophy muscle fibers (arrow indicates, Panel 3b). MGT staining The muscle tissue of Case 2 was reconstructed by hyperplasia of connective tissue, presenting end - stage pathological changes (Panel 3c). HE staining The muscle tissue of Case 2 was reconstructed by hyperplasia of connective tissue, presenting end - stage pathological changes (Panel 3d). MGT staining The muscle tissue of Case 3 showed the formation of rimmed vacuoles in the angular atrophy muscle fibers (arrow indicates, Panel 3e). HE staining The muscle tissue of Case 3 showed the formation of rimmed vacuoles in the angular atrophy muscle fibers (arrow indicates, Panel 3f). MGT staining The muscle tissue of Case 3 showed no COX-negative muscle fibers (Panel 3g). COX staining The muscle tissue of Case 3 showed the group distribution scale of type Ⅰ and type Ⅱ muscle fibers (Panel 3h). ATP4.4 staining

Figure 4 Immunofluorescence results of patients with LRP12 gene mutation. p62 (red fluorescence indiate) and ubiquitin (green fluorescence indiate) positive intranuclear inclusion bodies formation in muscle samples of 4 OPDM1 patients (arrows indicate).

Figure 5 Compared with normal control, RP-PCR analysis in the 5'UTR of LRP12 gene showed a "saw-tooth tail" pattern of the repeat exapnsion more than 200 bp in OPDM1 patients.

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