Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
Department of Pediatrics and Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
J Neuropathol Exp Neurol. 2023 Mar 20;82(4):345-362. doi: 10.1093/jnen/nlad012.
The survival of infantile-onset Pompe disease (IOPD) patients has improved dramatically since the introduction of enzyme replacement therapy (ERT) with a1glucosidase alfa. However, long-term IOPD survivors on ERT demonstrate motor deficits indicating that current therapy cannot completely prevent disease progression in skeletal muscle. We hypothesized that in IOPD, skeletal muscle endomysial stroma and capillaries would show consistent changes that could impede the movement of infused ERT from blood to muscle fibers. We retrospectively examined 9 skeletal muscle biopsies from 6 treated IOPD patients using light and electron microscopy. We found consistent ultrastructural endomysial stromal and capillary changes. The endomysial interstitium was expanded by lysosomal material, glycosomes/glycogen, cellular debris, and organelles, some exocytosed by viable muscle fibers and some released on fiber lysis. Endomysial scavenger cells phagocytosed this material. Mature fibrillary collagen was seen in the endomysium, and both muscle fibers and endomysial capillaries showed basal laminar reduplication and/or expansion. Capillary endothelial cells showed hypertrophy and degeneration, with narrowing of the vascular lumen. Ultrastructurally defined stromal and vascular changes likely constitute obstacles to movement of infused ERT from capillary lumen to muscle fiber sarcolemma, contributing to the incomplete efficacy of infused ERT in skeletal muscle. Our observations can inform approaches to overcoming these barriers to therapy.
婴儿型庞贝病（IOPD）患者的生存率自使用 a1 葡萄糖苷酶 alfa 进行酶替代疗法（ERT）以来有了显著提高。然而，长期接受 ERT 治疗的 IOPD 幸存者表现出运动功能障碍，这表明目前的治疗方法不能完全阻止骨骼肌疾病的进展。我们假设在 IOPD 中，骨骼肌的肌内膜基质和毛细血管会出现一致的变化，从而阻碍 ERT 从血液向肌肉纤维的输注。我们回顾性地使用光镜和电镜检查了 6 名接受治疗的 IOPD 患者的 9 个骨骼肌活检。我们发现了一致的超微结构肌内膜基质和毛细血管变化。肌内膜间质被溶酶体物质、糖体/糖原、细胞碎片和细胞器扩张，一些由有活力的肌纤维胞吐，一些在纤维溶解时释放。肌内膜吞噬细胞吞噬了这些物质。在肌内膜中可见成熟的纤维状胶原，肌纤维和肌内膜毛细血管均显示基底层的重复和/或扩张。毛细血管内皮细胞表现出肥大和退化，血管腔变窄。超微结构定义的基质和血管变化可能构成了 ERT 从毛细血管腔向肌纤维肌膜输注的运动障碍，导致 ERT 在骨骼肌中的疗效不完全。我们的观察结果可以为克服这些治疗障碍的方法提供信息。
