Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.
Clin Biochem. 2023 Nov;121-122:110659. doi: 10.1016/j.clinbiochem.2023.110659. Epub 2023 Oct 4.
Fragile-X syndrome(FXS) is a neurological disease caused by abnormal repeats in the 5'untranslated region of the FMR1 gene leading to a defective fragile-X-messenger-ribonucleoprotein-1 (FMRP). Although relatively common in children, it is usually under-diagnosed especially in developing countries where genetic screening is not routinely practiced. So far, FXS lacks a laboratory biomarker that can be used for screening, severity scoring or therapeutic monitoring of potential new treatments.
110 subjects were recruited; 80 male children with suspected FXS and 30 matched healthy children. We evaluated the clinical utility of serum matrix metalloproteinase-9(MMP9) and amyloid-beta protein precursor(APP) as potential biomarkers for FXS.
Out of 80 suspected children, 14 had full mutation, 8 had the premutation and 58 children had normal genotypes. No statistically-significant difference was detected between children with different genotypes concerning age of onset(P = 0.658), main clinical presentation(P = 0.388), clinical severity-score(P = 0.799), patient's disease-course(P = 0.719) and intellectual disability(P = 0.351). Both MMP9 and APP showed a statistically significant difference when comparing different genotype subgroups(P = 0.019 and < 0.001, respectively). Clinically, MMP9 levels were highest in children presenting with language defects, while APP was highest in children with neurodevelopmental delay. In receiver operating curve analysis, comparing full and premutation with the normal genotype group, MMP9 has an area-under-the-curve of 0.701(95 % CI 0.557-0.845), while APP was marginally better at 0.763(95 % CI 0.620-0.906). When combined together, elevated MMP9 or APP had excellent sensitivity > 95 % for picking-up FXS cases in the clinical setting.
Screening for circulating biomarkers in the absence of FXS genetic diagnosis is justified. Our study is the first to evaluate both MMP9 and APP in FXS suspected children in a clinical setting and to assess their correlation with disease presentation and severity.
脆性 X 综合征（FXS）是一种由 FMR1 基因 5'非翻译区异常重复引起的神经疾病，导致脆弱 X 信使核糖核蛋白 1（FMRP）缺陷。尽管在儿童中相对常见，但在发展中国家，特别是在没有常规进行遗传筛查的国家，通常诊断不足。到目前为止，FXS 缺乏可用于筛查、严重程度评分或治疗监测潜在新治疗方法的实验室生物标志物。
招募了 110 名受试者；80 名疑似 FXS 的男性儿童和 30 名匹配的健康儿童。我们评估了血清基质金属蛋白酶 9（MMP9）和淀粉样前体蛋白（APP）作为 FXS 潜在生物标志物的临床实用性。
在 80 名疑似儿童中，有 14 名患有完全突变，8 名患有前突变，58 名儿童具有正常基因型。不同基因型的儿童在发病年龄（P=0.658）、主要临床表现（P=0.388）、临床严重程度评分（P=0.799）、患者病程（P=0.719）和智力障碍（P=0.351）方面无统计学差异。MMP9 和 APP 在比较不同基因型亚组时均显示出统计学差异（P=0.019 和 <0.001）。临床观察显示，语言缺陷儿童的 MMP9 水平最高，而神经发育迟缓儿童的 APP 水平最高。在接受者操作特征曲线分析中，与正常基因型组相比，MMP9 在全突变和前突变组的曲线下面积为 0.701（95%CI 0.557-0.845），而 APP 略好于 0.763（95%CI 0.620-0.906）。当两者结合时，升高的 MMP9 或 APP 具有优异的敏感性，可在临床环境中检出超过 95%的 FXS 病例。
在没有 FXS 基因诊断的情况下，筛查循环生物标志物是合理的。我们的研究首次在临床环境中评估了 MMP9 和 APP 在疑似 FXS 儿童中的应用，并评估了它们与疾病表现和严重程度的相关性。
