Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children Hospital, Azienda Ospedaliero-Universitaria Consorziale, Bari, Italy.
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
Endocr Metab Immune Disord Drug Targets. 2022;22(14):1425-1432. doi: 10.2174/1871530322666220520121839.
Mucopolysaccharidosis-1H (Hurler syndrome, MPS-1H) is the most severe form of a lysosomal storage disorder (LSD) caused by variants in IDUA, encoding alpha- L-iduronidase (IDUA). MPS-1H is also associated with various degrees of skeletal defects due to the accumulation of partially degraded glycosaminoglycans (GAGs) in the lysosomes of connective tissue cells. The efficacy of hematopoietic stem cell transplantation (HSCT) and enzymatic replacement therapy (ERT) on MPS-1H skeletal manifestations is still considered unsatisfactory.
We report the case of a young girl, who manifested significant changes in bone remodeling markers and osteoclastogenesis potential after HSCT combined with ERT. She received ERT and underwent two HSCTs. The skeletal alterations at the time of diagnosis showed a trend toward improvement of both mobility and radiological features after HSCT. We observed the highest levels of Receptor activator of nuclear factor-kappa-Β ligand (RANKL) and RANK/osteoprotegerin (OPG) ratio at diagnosis and during ERT, consistently with spontaneous osteoclastogenesis. Conversely, after the successful HSCT with ongoing ERT, the highest levels of osteocalcin were observed and all markers of bone formation and resorption improved.
The combination therapy of ERT and HSCT was effective in reducing osteoclast activity and increasing osteoblast activity, and these changes were according to the child's bone phenotype, IDUA activity, and Glycosaminoglycan (GAG) trends. These results represent one of the few pieces of human evidence in this context.
黏多糖贮积症-1H（Hurler 综合征，MPS-1H）是由 IDUA 变异引起的溶酶体贮积症（LSD）中最严重的形式，该基因编码α-L-艾杜糖苷酸酶（IDUA）。MPS-1H 还伴有各种程度的骨骼缺陷，这是由于连接组织细胞溶酶体中部分降解的糖胺聚糖（GAG）的积累所致。造血干细胞移植（HSCT）和酶替代疗法（ERT）对 MPS-1H 骨骼表现的疗效仍不理想。
我们报告了一名年轻女孩的病例，她在接受 HSCT 联合 ERT 治疗后，骨重塑标志物和破骨细胞生成潜能发生了显著变化。她接受了 ERT 并接受了两次 HSCT。诊断时的骨骼改变在 HSCT 后表现出在运动和影像学特征方面均有改善的趋势。我们观察到在诊断时和 ERT 期间，核因子κB 受体激活剂（RANKL）和 RANK/骨保护素（OPG）比值最高，这与自发的破骨细胞生成一致。相反，在成功接受 HSCT 并持续进行 ERT 后，观察到最高水平的骨钙素，所有骨形成和吸收标志物均得到改善。
ERT 和 HSCT 的联合治疗可有效降低破骨细胞活性并增加成骨细胞活性，这些变化与患儿的骨骼表型、IDUA 活性和糖胺聚糖（GAG）趋势有关。这些结果代表了该领域中为数不多的人类证据之一。
