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Mol Genet Metab. 2019 Feb;126(2):183-187. doi: 10.1016/j.ymgme.2018.08.007. Epub 2018 Aug 24.

Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots.

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Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
New York State Dept. of Health, Wadsworth Center, Albany, NY 12201, USA.
Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD 20892, USA.
Rush University Medical Center, Chicago, IL 60612, USA.
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:



Niemann-Pick disease type C1 (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.


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. 3β,5α,6β-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.


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.


These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers.


Bile acid; Biomarker; Newborn screening; Niemann-pick C disease

[Available on 2020-02-01]

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