Thurberg Beth L, Lynch Maloney Colleen, Vaccaro Charles, Afonso Kendra, Tsai Anne Chun-Hui, Bossen Edward, Kishnani Priya S, O'Callaghan Michael
Department of Pathology, Genzyme Corporation, Framingham, MA 01701-9322, USA.
Lab Invest. 2006 Dec;86(12):1208-20. doi: 10.1038/labinvest.3700484. Epub 2006 Oct 30.
In Pompe disease, a genetic deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates abnormally in the lysosomes of skeletal, cardiac and smooth muscle, and contributes to clinically progressive and debilitating muscle weakness. The present study involved 8 infantile-onset Pompe patients, treated weekly with 10 mg/kg of recombinant human acid alpha-glucosidase (rhGAA). Muscle biopsies were obtained at baseline, 12 and 52 weeks post-treatment to establish an indicator of efficacy. Several histologic strategies were employed to characterize changes in pre- and post-treatment samples, including high-resolution light microscopy and digital histomorphometry, electron microscopy, capillary density and fiber type analysis, and confocal microscopy for satellite cell activation analysis. Histomorphometric analysis was performed on muscle samples to assess glycogen depletion in response to enzyme replacement therapy (ERT). The extent of glycogen clearance varied widely among these patient samples, and correlated well with clinical outcome. Low glycogen levels, mild ultrastructural damage, a high proportion of type I fibers, and young age at baseline were all features associated with good histologic response. There was no correlation between capillary density and glycogen clearance, and activated satellite cell levels were shown to be higher in post-treatment biopsies with poor histologic responses. This histopathologic study of infantile Pompe disease provides detailed insight into the cellular progression of the disease and its response to therapy while highlighting a number of methodologies which may be employed to assess regression or progression of the associated pathology. As enzyme replacement therapy becomes more prevalent for the treatment of lysosomal storage diseases, such evaluation of post-treatment pathology will likely become a more common occurrence in the daily practice of pathologists.
在庞贝病中，由于溶酶体酸性α-葡萄糖苷酶存在基因缺陷，糖原在骨骼肌、心肌和平滑肌的溶酶体中异常蓄积，导致临床上进行性且使人衰弱的肌无力。本研究纳入了8例婴儿型庞贝病患者，每周接受10 mg/kg重组人酸性α-葡萄糖苷酶（rhGAA）治疗。在基线、治疗后12周和52周时获取肌肉活检样本以确定疗效指标。采用了多种组织学方法来表征治疗前后样本的变化，包括高分辨率光学显微镜检查和数字组织形态计量学、电子显微镜检查、毛细血管密度和纤维类型分析，以及用于卫星细胞激活分析的共聚焦显微镜检查。对肌肉样本进行组织形态计量学分析，以评估酶替代疗法（ERT）对糖原消耗的影响。这些患者样本中糖原清除的程度差异很大，且与临床结果密切相关。低糖原水平、轻度超微结构损伤、高比例的I型纤维以及基线时年龄较小均是与良好组织学反应相关的特征。毛细血管密度与糖原清除之间无相关性，且组织学反应较差的治疗后活检样本中激活的卫星细胞水平较高。这项关于婴儿型庞贝病的组织病理学研究详细深入地了解了该疾病的细胞进展及其对治疗的反应，同时突出了一些可用于评估相关病理学消退或进展的方法。随着酶替代疗法在溶酶体贮积病治疗中变得更加普遍，这种对治疗后病理学的评估在病理学家的日常实践中可能会变得更加常见。
