Sanfilippo syndrome or mucopolysaccharidosis type III (MPS III) is a childhood metabolic disorder marked by neuropathology arising due to impaired heparan sulphate (HS) catabolism. Consequently, partially degraded HS accumulates in the lysosomes of affected cells and is excreted in the urine. The measurement of HS in urine has long been considered a biomarker of Sanfilippo syndrome although it is largely non-specific. Using blood, urine and CSF collected from a cohort of Sanfilippo patients we investigated the utility of primary and secondary biomarkers to inform on disease activity. These included enzyme activity, specific oligosaccharides with non-reducing end residues reflective of the enzyme deficiency, and gangliosides. The diagnostic oligosaccharides - a HS disaccharide and tetrasaccharide - were elevated in the urine, plasma and CSF of all MPS IIIA and IIIB patients, respectively. There was no correlation between the concentrations in any of the matrices suggesting they reflect specific tissues and not overall disease burden. Enzyme activity did not inform on disease severity, with no measurable activity in CSF and activity approaching normal in MPS IIIA plasma. The concentration of gangliosides, GM2 and GM3, were significantly higher in the CSF of all MPS III subjects when compared to controls and correlated with the age of onset of first symptoms. Given that these gangliosides reflect delayed brain development they may be useful measures of disease burden, within the limitations of the clinical surrogates. Observation of these biochemical measurements in MPS III patients enrolled in clinical trials may determine whether they represent true pharmacodynamics biomarkers.

中文翻译：

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评估Sanfilippo综合征的生物标志物。

Sanfilippo综合征或III型粘多糖贮积病（MPS III）是一种儿童代谢紊乱，其特征是由于硫酸乙酰肝素（HS）分解代谢受损而引起的神经病理学。因此，部分降解的HS会积聚在受影响细胞的溶酶体中，并在尿液中排泄。尿中HS的测定长期以来一直被认为是Sanfilippo综合征的生物标志物，尽管它基本上是非特异性的。使用从Sanfilippo患者队列中收集的血液，尿液和CSF，我们调查了主要和次要生物标志物在疾病活动中的作用。这些包括酶活性，具有非还原性末端残基的特定寡糖和反映神经节苷脂的减少的神经节苷脂。诊断性低聚糖（HS双糖和四糖）在尿液中升高，所有MPS IIIA和IIIB患者的血浆和脑脊液。任何基质中的浓度之间均无相关性，表明它们反映的是特定组织，而不是总体疾病负担。酶的活性不能决定疾病的严重程度，CSF中没有可测量的活性，MPS IIIA血浆中的活性接近正常。与对照组相比，所有MPS III受试者的脑脊液中神经节苷脂GM2和GM3的浓度均显着较高，并且与第一症状发作的年龄相关。鉴于这些神经节苷脂反映了大脑发育的延迟，在临床替代品的范围内，它们可能是疾病负担的有用措施。