Division of Metabolic Disorders, Pediatric Subspecialty Faculty, CHOC Children's, Orange, CA 92868, USA.
Mol Genet Metab. 2009 Dec;98(4):406-11. doi: 10.1016/j.ymgme.2009.07.015. Epub 2009 Aug 5.
The mucopolysaccharidoses (MPSs) are a family of lysosomal storage disorders caused by impaired glycosaminoglycan degradation. Characteristic brain imaging abnormalities are seen in MPS patients. This study aims to determine the effects of hematopoietic stem cell transplantation (HSCT) and/or intravenous enzyme replacement therapy (ERT) on these abnormalities.
A retrospective chart and brain imaging study review was conducted of MPS types I and II patients with brain magnetic resonance imaging (MRI) performed at, and following, initiation of treatment. White matter abnormalities, dilated perivascular spaces, corpus callosal abnormalities, and ventriculomegaly were scored by three independent neuroradiologists blinded to cognitive status, date of treatment initiation, and type(s) of treatment.
Five patients were identified: three patients with MPS I and two with MPS II. Duration of follow-up ranged from 13 to 51 months. One patient had severe MPS I (genotype W402X/35del12) and received ERT followed by HSCT. The remaining patients had ERT only. The other two MPS I patients were cognitively normal siblings (genotype P533R/P533R) with an intermediate phenotype. One MPS II patient had moderate cognitive impairment without regression (genotype 979insAGCA); the other (genotype R8X) had normal cognition. There was very little inter-observer variation in MRI scoring. The greatest abnormalities for each patient were found at initial MRI. All patients, including the ERT-only patients, demonstrated improved or unchanged MRI scores following treatment. Severity of white matter abnormalities or dilated perivascular spaces did not correlate with cognitive impairment; as such, extensive pre-treatment MRI abnormalities were noted in the older, cognitively normal MPS I sibling. In comparison, his younger sibling had only mild MRI abnormalities at the same age, after receiving 4 years of ERT.
This study represents one of the first to document the CNS effects of ERT in MPS patients utilizing serial brain MR imaging studies, and raises several important observations. Brain MRI abnormalities typically become more pronounced with age; initiation of ERT or HSCT reversed or stabilized this trend in the MPS patients studied. In addition, earlier initiation of treatment resulted in decreased severity of imaging abnormalities. Possible mechanisms for these observations include improved cerebrospinal fluid dynamics, reduced central nervous system glycosaminoglycan storage via efflux through the blood-brain barrier (BBB), repair of damaged BBB, reduction in CNS inflammation, or ERT permeability through the BBB.
黏多糖贮积症（MPS）是一组由糖胺聚糖降解受损引起的溶酶体贮积症。MPS 患者存在特征性的脑影像学异常。本研究旨在确定造血干细胞移植（HSCT）和/或静脉内酶替代疗法（ERT）对这些异常的影响。
对接受脑磁共振成像（MRI）检查的 MPS Ⅰ型和Ⅱ型患者进行回顾性病历和脑影像学研究，检查内容包括治疗开始前和开始后的 MRI 检查。三位独立的神经放射科医生对脑白质异常、血管周围间隙扩张、胼胝体异常和脑室扩大进行评分，评分时对认知状态、治疗开始日期和治疗类型均不知情。
共确定了 5 名患者：3 名 MPS Ⅰ型患者和 2 名 MPS Ⅱ型患者。随访时间为 13 至 51 个月。1 名 MPS Ⅰ型患者（基因型 W402X/35del12）接受 ERT 治疗后接受 HSCT。其余患者仅接受 ERT 治疗。另外 2 名 MPS Ⅰ型患者是认知正常的同胞（基因型 P533R/P533R），具有中间表型。1 名 MPS Ⅱ型患者（基因型 979insAGCA）认知功能正常但存在退化；另一名患者（基因型 R8X）认知功能正常。MRI 评分的观察者间差异非常小。每位患者的初始 MRI 检查结果最异常。所有患者，包括仅接受 ERT 治疗的患者，在治疗后 MRI 评分均有改善或无变化。脑白质异常或血管周围间隙扩张的严重程度与认知障碍无关；因此，在认知正常的年长 MPS Ⅰ型同胞中发现了广泛的治疗前 MRI 异常。相比之下，他的弟弟在接受 4 年 ERT 治疗后，在相同年龄时仅出现轻度 MRI 异常。
本研究利用连续脑 MRI 研究首次记录了 ERT 在 MPS 患者中的 CNS 影响，并提出了几个重要的观察结果。脑 MRI 异常通常随着年龄的增长而变得更加明显；在本研究中接受 ERT 或 HSCT 的 MPS 患者中，该趋势得到逆转或稳定。此外，早期开始治疗可降低影像学异常的严重程度。这些观察结果可能的机制包括改善脑脊液动力学、通过血脑屏障（BBB）流出减少中枢神经系统糖胺聚糖储存、修复受损的 BBB、减少中枢神经系统炎症或 ERT 通过 BBB 的通透性。
