Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots
Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots
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DOI：
10.1016/j.ymgme.2018.08.007
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发表时间：
2019-02-01
影响因子：
3.8
通讯作者：
Ory, Daniel S.
中科院分区：
文献类型：
--
作者：
Jiang, Xuntian;Sidhu, Rohini;Ory, Daniel S.
背景：尼曼-匹克病Cl型（NPC 1）是一种罕见的神经退行性胆固醇储存障碍。由于该病的罕见性和非特异性早期症状，诊断延迟> 5年是常见的。为了提高诊断和促进早期干预，我们以前开发了一种新生儿筛查检测新确定的血浆胆汁酸生物标志物的基础上。由于新生儿筛查已经使用来自已经诊断的NPC 1患者的干血斑（DBS）进行了验证，因此一个未回答的问题是该筛查是否能够在出生时检测出NPC 1患者。为了解决这一关键问题，我们为居住在加州、纽约、密歇根州将残留的DBS保存在生物储存库中。对于每个DBS，我们从NPC 1患者和携带者同一天出生的同一家医院的患者中获得了两个相邻对照DBS。3 β，5 α，6 β-三羟基胆烷酸（胆汁酸A）和三羟基胆烷酸甘氨酸结合物使用液相色谱-串联质谱法测量DBS中的胆汁酸（B（LC-MS/MS）分析。胆汁酸B是一种特异性更强的生物标志物，开发了经充分验证的DBS测定法，在8/15例NPC 1患者中检测到，在2/15例患者中升高至临界值以上（储存时间最短的两个样品）。分别在储存时间< 10.5年、13-20年和> 20年的2/2、6/10和0/7份NPC 1样本中检测到胆汁酸B，表明甘氨酸缀合物在DBS中可检测到，但与胆汁酸A（前体三羟基胆烷酸）相比，其长期稳定性可能降低，胆汁酸A在15/15名NPC 1受试者中升高，结论：这些结果表明使用胆汁酸生物标志物筛查NPC 1疾病的新生儿是可行的。
Background: Niemann-Pick disease type Cl (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of > 5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth.Methods: To address this critical question, we obtained the newborn DBS for already diagnosed NPC1 subjects (n = 15) and carriers (n = 3) residing in California, New York, and Michigan states that archive residual DBS in biorepositories. For each of the DBS, we obtained two neighbor controls DBS from patients born on the same day and in the same hospital as the NPC1 patients and carriers. 3 beta,5 alpha,6 beta-trihydroxycholanic acid (bile acid A) and trihydroxycholanic acid glycine conjugate (bile acid B) were measured in the DBS using a liquid chromatography -tandem mass spectrometry (LC-MS/MS) assay.Results: Bile acid B, the more specific biomarker for which the fully validated DBS assay was developed, was detected in 8/15 NPC1 patients, and elevated above the cut-off in 2/15 patients (the two samples with the shortest storage time). Bile acid B was detected in 2/2, 6/10, and 0/7 NPC1 samples that have been stored for < 10.5 years, 13-20 years, and > 20 years, respectively, indicating that the glycine conjugate is detectable in DBS but may have reduced long-term stability compared with bile acid A, the precursor trihydroxycholanic acid, which was elevated in 15/15 NPC1 subjects, but not in carriers and controls.Conclusions: These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers.