Mathis Déborah, Prost Jean-Christophe, Maeder Gabriela, Arackal Liya, Zhang Haoyue, Kurth Sandra, Freiburghaus Katrin, Nuoffer Jean-Marc
University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern Bern Switzerland.
Biochemical Genetics Laboratory Duke University Health System Durham North Carolina USA.
JIMD Rep. 2024 Feb 8;65(2):116-123. doi: 10.1002/jmd2.12412. eCollection 2024 Mar.
Mucopolysaccharidoses (MPS) screening is tedious and still performed by analysis of total glycosaminoglycans (GAG) using 1,9-dimethylmethylene blue (DMB) photometric assay, although false positive and negative tests have been reported. Analysis of differentiated GAGs have been pursued classically by gel electrophoresis or more recently by quantitative LC-MS assays. Secondary elevations of GAGs have been reported in urinary tract infections (UTI). In this manuscript, we describe the diagnostic accuracy of urinary GAG measurements by LC-MS for MPS typing in 68 untreated MPS and mucolipidosis (ML) patients, 183 controls and 153 UTI samples. We report age-dependent reference values and cut-offs for chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS) and keratan sulfate (KS) and specific GAG ratios. The use of HS/DS ratio in combination to GAG concentrations normalized to creatinine improves the diagnostic accuracy in MPS type I, II, VI and VII. In total 15 samples classified to the wrong MPS type could be correctly assigned using HS/DS ratio. Increased KS/HS ratio in addition to increased KS improves discrimination of MPS type IV by excluding false positives. Some samples of UTI patients showed elevation of specific GAGs, mainly CS, KS and KS/HS ratio and could be misclassified as MPS type IV. Finally, DMB photometric assay performed in MPS and ML samples reveal four false negative tests (sensitivity of 94%). In conclusion, specific GAG ratios in complement to quantitative GAG values obtained by LC-MS enhance discrimination of MPS types. Exclusion of patients with UTI improve diagnostic accuracy in MPS IV but not in other types.
黏多糖贮积症（MPS）筛查很繁琐，目前仍通过使用1,9 - 二甲基亚甲基蓝（DMB）光度法分析总糖胺聚糖（GAG）来进行，尽管已有假阳性和假阴性检测的报道。经典的方法是通过凝胶电泳分析不同的GAG，最近则采用定量液相色谱 - 质谱（LC - MS）分析。已有报道称尿路感染（UTI）时GAG会出现继发性升高。在本论文中，我们描述了通过LC - MS测量尿液GAG对68例未经治疗的MPS和黏脂贮积症（ML）患者、183例对照以及153份UTI样本进行MPS分型的诊断准确性。我们报告了硫酸软骨素（CS）、硫酸皮肤素（DS）、硫酸乙酰肝素（HS）和硫酸角质素（KS）的年龄依赖性参考值和临界值以及特定的GAG比值。将HS/DS比值与肌酐标准化后的GAG浓度相结合，可提高MPS I型、II型、VI型和VII型的诊断准确性。使用HS/DS比值总共可将15个被误分到错误MPS类型的样本正确归类。除了KS升高外，KS/HS比值升高可通过排除假阳性来提高MPS IV型的鉴别能力。一些UTI患者的样本显示特定GAG升高，主要是CS、KS和KS/HS比值，可能会被误分类为MPS IV型。最后，在MPS和ML样本中进行的DMB光度法显示有4例假阴性检测结果（灵敏度为94%）。总之，特定的GAG比值与通过LC - MS获得的定量GAG值相辅相成，可增强对MPS类型的鉴别能力。排除UTI患者可提高MPS IV型的诊断准确性，但对其他类型无效。
