Montavon Brittany, Winter Linda E, Gan Qi, Arasteh Amirhossein, Montaño Adriana M
Department of Pediatrics, School of Medicine, Saint Louis University, St. Louis, MO, United States.
School of Medicine, Saint Louis University, St. Louis, MO, United States.
Front Cardiovasc Med. 2022 May 10;9:829111. doi: 10.3389/fcvm.2022.829111. eCollection 2022.
Cardiovascular disease (CVD) in Mucopolysaccharidosis Type IVA (Morquio A), signified by valvular disease and cardiac hypertrophy, is the second leading cause of death and remains untouched by current therapies. Enzyme replacement therapy (ERT) is the gold-standard treatment for MPS disorders including Morquio A. Early administration of ERT improves outcomes of patients from childhood to adulthood while posing new challenges including prognosis of CVD and ERT's negligible effect on cardiovascular health. Thus, having accurate biomarkers for CVD could be critical. Here we show that cathepsin S (CTSS) and elastin (ELN) can be used as biomarkers of extracellular matrix remodeling in Morquio A disease. We found in a cohort of 54 treatment naïve Morquio A patients and 74 normal controls that CTSS shows promising attributes as a biomarker in young Morquio A children. On the other hand, ELN shows promising attributes as a biomarker in adolescent and adult Morquio A. Plasma/urine keratan sulfate (KS), and urinary glycosaminoglycan (GAG) levels were significantly higher in Morquio A patients ( < 0.001) which decreased with age of patients. CTSS levels did not correlate with patients' phenotypic severity but differed significantly between patients (median range 5.45-8.52 ng/mL) and normal controls (median range 9.61-15.9 ng/mL; < 0.001). We also studied α -2-macroglobulin (A2M), C-reactive protein (CRP), and circulating vascular cell adhesion molecule-1 (sVCAM-1) in a subset of samples to understand the relation between ECM biomarkers and the severity of CVD in Morquio A patients. Our experiments revealed that CRP and sVCAM-1 levels were lower in Morquio A patients compared to normal controls. We also observed a strong inverse correlation between urine/plasma KS and CRP ( = 0.013 and = 0.022, respectively) in Morquio A patients as well as a moderate correlation between sVCAM-1 and CTSS in Morquio A patients at all ages ( = 0.03). As the first study to date investigating CTSS and ELN levels in Morquio A patients and in the normal population, our results establish a starting point for more elaborate studies in larger populations to understand how CTSS and ELN levels correlate with Morquio A severity.
IVA型黏多糖贮积症（Morquio A综合征）中的心血管疾病（CVD）以瓣膜病和心脏肥大为特征，是第二大死亡原因，目前的治疗方法对此束手无策。酶替代疗法（ERT）是包括Morquio A综合征在内的黏多糖贮积症的金标准治疗方法。早期给予ERT可改善患者从儿童到成人的预后，但也带来了新的挑战，包括CVD的预后以及ERT对心血管健康的影响微乎其微。因此，拥有准确的CVD生物标志物可能至关重要。在此，我们表明组织蛋白酶S（CTSS）和弹性蛋白（ELN）可作为Morquio A病细胞外基质重塑的生物标志物。我们在一组54例未经治疗的Morquio A患者和74例正常对照中发现，CTSS在年幼的Morquio A儿童中显示出作为生物标志物的良好特性。另一方面，ELN在青少年和成年Morquio A患者中显示出作为生物标志物的良好特性。Morquio A患者的血浆/尿硫酸角质素（KS）和尿糖胺聚糖（GAG）水平显著更高（<0.001），且随患者年龄增长而降低。CTSS水平与患者的表型严重程度无关，但在患者（中位数范围5.45 - 8.52 ng/mL）和正常对照（中位数范围9.61 - 15.9 ng/mL；<0.001）之间存在显著差异。我们还在一部分样本中研究了α - 2 -巨球蛋白（A2M）、C反应蛋白（CRP）和循环血管细胞黏附分子-1（sVCAM - 1），以了解Morquio A患者中细胞外基质生物标志物与CVD严重程度之间的关系。我们的实验表明，与正常对照相比，Morquio A患者的CRP和sVCAM - 1水平较低。我们还观察到，Morquio A患者的尿/血浆KS与CRP之间存在强烈的负相关（分别为= 0.013和= 0.
