An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
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DOI：
10.1111/nan.12580
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发表时间：
2019-10-24
影响因子：
5
通讯作者：
Schaenzer, A.
中科院分区：
文献类型：
--
作者：
Kulessa, M.;Weyer-Menkhoff, I;Schaenzer, A.
庞贝氏症是由α 1，4-葡萄糖苷酶（GAA）基因的致病性突变引起的，在晚发型庞贝氏症（LOPD）患者中，基因型-表型相关性是不可预测的。骨骼肌病理包括糖原积累和不同程度的自噬改变。肌肉形态学与临床特征和遗传背景的相关性可能有助于对GAA表型变异的理解。方法对53例LOPD患者在酶替代治疗前的肌活检进行分析。在树脂切片上，分析糖原累积、纤维化、自噬空泡和肌肉损伤程度（形态学评分），并将结果与临床结果进行比较。在22例LOPD活检的冷冻切片上分析了其他自噬标志物微管相关蛋白1A/1B-轻链3、p62和Bcl 2相关的嗜酸性蛋白3。结果肌病理表现出高度的变异性，在大多数患者中，中度糖原积聚和低形态评分。高形态学评分与纤维化和自噬增加相关，突出了自噬在骨骼肌损伤严重阶段的作用。形态学评分与患者活检时的年龄、病程、残留GAA酶活性或肌酸激酶水平无关。在37例LOPD患者中，遗传分析确定了最常见的突变，c. 32- 13 T>G，占95%，最常见的是与c.525 delT组合（19%）。不同GAA基因型与肌肉形态类型间无显著相关性。结论LOPD患者的肌肉形态表现出高度的变异性，在大多数情况下，中度病理。病理学的增加与更多的纤维化和自噬有关。
Aims Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. Methods Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. Results The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. Conclusions Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.