晚发型糖原贮积病Ⅱ型临床、肌肉组织病理学及分子生物学特征分析

doi:10.3969/j.issn.1672-6731.2021.06.007

摘要/Abstract

摘要：

目的总结晚发型糖原贮积病Ⅱ型（GSDⅡ）的临床表现、肌肉组织病理学和分子生物学特征。方法与结果 选择2013年1月至2020年1月在郑州大学第五附属医院诊断与治疗的5例晚发型GSDⅡ型患者，临床主要表现为抬头无力、四肢近端肌无力、肌张力降低、不耐受疲劳和呼吸困难，酸性α葡糖苷酶（GAA）活性均明显降低。5例患者肌肉组织HE染色显示多数肌纤维内可见大小不一、数量不等、形态不规则的空泡样变性；改良Gomori三色染色可见空泡内有大量蓝紫色颗粒沉积；高碘酸-雪夫染色显示4例空泡内糖原成分增多，1例空泡内糖原成分流失。GAA基因检测显示，5例患者共检出9个变异位点，4例为复合杂合突变，分别来源于父亲和母亲，分别为c.1320_1322delGAT（p.Met440del）缺失突变、c.2331G > C（p.Thr777Thr）同义突变、c.2237G > A（p.Trp746*）无义突变、c.877G > A（p.Gly293Arg）错义突变、c.2238G > C（p.Trp746Cys）错义突变、c.784G > A（p.Glu262Lys）错义突变、c.2014C > T（p.Arg672Trp）错义突变和c.2332-2A > G剪切突变；1例为c.1432G > A（p.Gly478Arg）纯合突变，来源于母亲。其中，c.2331G > C、c.1432G > A和c.2332-2A > G系国内外首次报道。结论晚发型GSDⅡ型患者临床表现主要为四肢近端肌无力和呼吸困难，血清GAA酶活性明显下降，肌肉组织病理学具有特征性，GAA基因变异主要为复合杂合突变，其中，c.2331G > C、c.1432G > A和c.2332-2A > G为新发变异，扩展了GAA基因变异谱。

关键词: 糖原贮积病Ⅱ型, 晚发性障碍, &alpha, 葡糖苷酶类, 病理学, 分子生物学, 基因, 突变

Abstract:

Objective To summarize the clinical, muscle pathology and molecular biological features of late-onset glycogen storage disease type Ⅱ (GSDⅡ). Methods and Results Five patients with late-onset GSD Ⅱ diagnosed and treated in The Fifth Affiliated Hospital of Zhengzhou University from January 2013 to January 2020 were selected. The main clinical manifestations of 5 patients were weakness of raising the head, weakness of the proximal extremities, decreased muscle tone, fatigue intolerance, and dyspnea. The activity of acid α-glucosidase (GAA) was significantly reduced. HE staining of muscular tissues in 5 patients showed vacuole-like changes of different sizes, different numbers, and irregular shapes in most muscle fibers. Modified Gomori trichrome (MGT) staining showed a large number of blue and purple particles deposited in the vacuole. Periodic acid-Schiff (PAS) staining showed the glycogen content in the vacuoles were increased in 4 cases, and the glycogen content in the vacuoles were lost in one case. GAA gene testing showed that 9 mutations were detected in 5 patients, and 4 cases were compound heterozygous mutations, which were derived from father and mother respectively. The c.1320_1322delGAT (p.Met440del) was a deletion mutation, c.2331G > C (p.Thr777Thr) was a synonymous mutation, c.2237G > A (p.Trp746*) was a nonsense mutation, c.877G > A (p.Gly293Arg) was a missense mutation, c.2238G > C (p. Trp746Cys) was a missense mutation, c.784G > A (p.Glu262Lys) was a missense mutation, c.2014C > T (p. Arg672Trp) was a missense mutation, and c. 2332-2A > G was a splicing mutation. One case was homozygous mutation of c. 1432G > A (p. Gly478Arg), which originated from the mother. Among them, c. 2331G > C, c. 1432G > A and c. 2332-2A > G were reported for the first time at home and abroad. Conclusions The clinical manifestations of late-onset GSD Ⅱ are weakness of proximal limbs and dyspnea. The activity of GAA in peripheral serum is decreased significantly. Muscle tissue pathology is characteristic. GAA gene mutations are mainly compound heterozygous mutation, c.2331G > C, c.1432G > A and c.2332-2A > G are new mutations, which extended the mutation spectrum of GAA gene.

Key words: Glycogen storage disease type Ⅱ, Late onset disorders, alpha-Glucosidases, Pathology, Molecular biology, Genes, Mutation

吴世陶, 刘方, 石伟伟, 张敏, 刘恒方. 晚发型糖原贮积病Ⅱ型临床、肌肉组织病理学及分子生物学特征分析[J]. 中国现代神经疾病杂志, 2021, 21(6): 466-472.

WU Shi-tao, LIU Fang, SHI Wei-wei, ZHANG Min, LIU Heng-fang. Clinical, muscle pathology and molecular biological features of late-onset glycogen storage disease typeⅡ[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2021, 21(6): 466-472.

https://journal11.magtechjournal.com/cjcnn/CN/Y2021/V21/I6/466

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2 晚发型糖原贮积病Ⅱ型临床、肌肉组织病理学及分子生物学特征分析

Clinical, muscle pathology and molecular biological features of late-onset glycogen storage disease typeⅡ

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2 晚发型糖原贮积病Ⅱ型临床、肌肉组织病理学及分子生物学特征分析

Clinical, muscle pathology and molecular biological features of late-onset glycogen storage disease typeⅡ

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