Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites

Yamato Muto; Mitsuyoshi Suzuki; Hajime Takei; Nobutomo Saito; Jun Mori; Satoru Sugimoto; Kazuo Imagawa; Ryusuke Nambu; Saori Oguri; Tomoyo Itonaga; Kenji Ihara; Hisamitsu Hayashi; Kei Murayama; Genta Kakiyama; Hiroshi Nittono; Toshiaki Shimizu

doi:10.1016/j.ymgme.2023.107703

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites

Mol Genet Metab. 2023 Sep-Oct;140(1-2):107703. doi: 10.1016/j.ymgme.2023.107703. Epub 2023 Sep 28.

Authors

Affiliations

¹ Department of Pediatrics, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
² Department of Pediatrics, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: [email protected].
³ Junshin Clinic Bile Acid Institute, 2-1-24 Haramachi, Meguro-ku, Tokyo 152-0011, Japan.
⁴ Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-hondori, Miyakojima-ku, Osaka 534-0021, Japan.
⁵ Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
⁶ Department of Child Health, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁷ Division of Gastroenterology & Hepatology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama-city 330-8777, Japan.
⁸ Department of Pediatrics, Oita University Faculty of Medicine, 1-1 Oji-shinmachi, Oita 870-0819, Japan.
⁹ Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
¹⁰ Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
¹¹ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, 1101 E. Marshall St., Richmond, VA 23298, USA; Central Virginia VA Healthcare System, 1201 Broad Rock Blvd., Richmond, VA 23249, USA.

PMID: 37802748
DOI: 10.1016/j.ymgme.2023.107703

Abstract

Objective: To examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis.

Methods: Patients with 3β-hydroxy-ΔSuchy et al. (2021)⁵-C₂₇-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)⁴-steroid 5β-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run).

Results: In healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3β,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3β-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5β-cholestanoic acid for PBD1A (78%); and tauro 3β,7β-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen.

Conclusions: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

Keywords: Bile acid; Liquid chromatography-tandem mass spectrometry; Liver; Neonatal cholestasis; Newborn screening.

MeSH terms

Bile Acids and Salts
Humans
Infant, Newborn
Liver Diseases*
Neonatal Screening
Steroids
Sulfates
Zellweger Syndrome*

Substances

Bile Acids and Salts
Steroids
Sulfates