Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Mazzacuva, Francesca; Mills, Philippa; Mills, Kevin; Camuzeaux, Stéphane; Gissen, Paul; Nicoli, Elena‐Raluca; Wassif, Christopher A.; Vruchte, Daniëlle te; Porter, Forbes D.; Maekawa, Masamitsu; Mano, Nariyasu; Iida, Takashi; Platt, Frances M.; Clayton, Peter T.

doi:10.1002/1873-3468.12196

Cited by 84 publications

(111 citation statements)

References 32 publications

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“…Sulfate or glycine conjugation of general drug metabolism appears to be very ef cient at birth 27,28 , while the maturation of sulfation to UDCA was not likely to be earlier than N-acethylglucosaminidation. The UGT3A1 de ciency is reported to be about 10% in the study of the Niemann Pick Type C biomarker analyzing 3 -sulfooxy-7 -N-acethylglucosaminyl-5 -cholen-24-oic acid 29 , and similarly in this study, 2 of 21 samples showed no UDCAs-7NAG.…”

Section: Discussionsupporting

confidence: 81%

Transition of Urinary Ursodeoxycholic Acid 7β-N-acetylglucosaminide and 3α-sulfate from Neonates to Adolescents Using LC/ESI-MS/MS Analysis

:筆頭著者

Murai

Kurosawa

et al. 2017

Showa Univ J Med Sci

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: This study evaluated the urinary metabolism of ursodeoxycholic acid UDCA by measuring 7 -N-acetylglucosaminide and 3 -sulfate composition in neonates to adolescents using liquid chromatography electrospray ionization tandem mass spectrometry LC/ESI-MS/MS . We obtained urine from 13 babies, corrected gestational age CGA 37-70 weeks, receiving UDCA to treat cholestasis due to total parenteral nutrition TPN and 8 patients, aged from 9 months to 15 years, who were treated with oral UDCA administration. The ratios of each UDCA conjugate to total UDCA were as follows : at CGA 37-42 weeks : nonamidated and glycine-or taurine-amidated ursodeoxycholic acid UDCAs : 44.0 8.0% mean SD , UDCAs 3 -sulfate UDCAs-3S : 37.8 10.1%, UDCAs 7 -N-acetylglucosaminide UDCAs-7NAG : 18.1 14.9% ; at 9 months-3years : UDCAs : 15.7 23.2%, UDCAs-3S : 37.2 8.8%, UDCAs-7NAG : 47.0 22.1%. The ratios of UDCAs-3S and UDCAs-7NAG increased gradually between the ages of 5 and 15 years, as follows : UDCAs, 2.2 1.3% ; UDCAs-3S, 51.2 22.9% ; and, UDCAs-7NAG, 46.6 22.6%. The ratio of 3-sulfooxy-7-N-acetylglucosaminylUDCAs UDCAs-3S-7NAG lowered by 0.2% per each age group. Urinary UDCAs-7NAG was not detectable in 2 of 21 patients, who were thus considered to have 7 -hydroxy bile acid N-acetylglucosaminyl transferase UGT3A1 deficiency. The enzyme activity of N-acetylglucosaminyl transferase to UDCAs was at the same degree as sulfotransferase to UDCAs in early neonates, but reached the adult values by 3-5 years.

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Section: Discussionsupporting

confidence: 81%

Transition of Urinary Ursodeoxycholic Acid 7β-N-acetylglucosaminide and 3α-sulfate from Neonates to Adolescents Using LC/ESI-MS/MS Analysis

:筆頭著者

Murai

Kurosawa

et al. 2017

Showa Univ J Med Sci

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“…Analysis of cholanoic acids (normal bile acids) and their taurine and glycine conjugates was performed by targeted UPLC-MS/MS essentially as described previously (23), with modifications to include the analysis of the cholestanoic acids (C27 bile acids) THCA and [27,27,27-D 3 ]-THCA, purchased from Herman Ten Brink of the VU Medical Centre, Amsterdam, The Netherlands. UPLC retention times and mass spectrometry transitions for the C27 bile acids are shown in Table S3.…”

Section: Methodsmentioning

confidence: 99%

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Vilarinho

Sarı

Mazzacuva

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2. Immunohistochemistry confirmed the absence of ACOX2 expression in the patient’s liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

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“…3β-Sulfooxy-7β-hydroxy-5-cholen-24-oic acid is the precursor of SNAG-Δ 5 -CA. UDP glycosyltransferase (UGT) 3A1 catalyzes the transfer of Nacetylglucosamine from UDP N-acetylglucosamine to the 7β-hydroxy group on ursodeoxycholic acid, [17][18][19] and Mazzacuva et al 20) reported that the same enzyme catalyzes the transfer of N-acetylglucosamine onto 3β,7β-dihydroxy-5-cholenoic acid. Moreover, the same authors showed that the inactivation of UGT3A1 by genetic mutation suppress the production of 3β-hydroxy-7β-N-acetylglucosaminyl-5-cholenoic acid in NPC patients.…”

Section: Resultsmentioning

confidence: 99%

Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann–Pick Disease Type C as Novel Candidate Diagnostic Markers

et al. 2016

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In the urine of a Niemann-Pick disease type C (NPC) patient, we have identi ed three characteristic intense peaks that have not been observed in the urine of a 3β-hydroxysteroid-Δ 5 -C 27 -steroid dehydrogenase de ciency patient or a healthy infant and adult. Based on accurate masses of the protonated molecules, we focused on two of them as candidate NPC diagnostic markers. Two synthesized authentic preparations agreed with the two compounds found in NPC patient urine in regard to both chromatographic behavior and accurate masses of the deprotonated molecules. Moreover, the isotopic patterns of the deprotonated molecules, twin peaks unique to the sulfur-containing compounds appearing in their second isotope positions, and accurate masses of product ions observed at m/z 97 also agreed between the target compounds and authentic preparations. We identi ed the two compounds as the sulfated cholesterol metabolites as 3β-sulfooxy-7β-hydroxy-5-cholen-24-oic acid and 3β-sulfooxy-7-oxo-5-cholen-24-oic acid.ese two compounds represent more promising candidate diagnostic markers for NPC diagnosis than three other candidates that are multiple conjugates of cholesterol metabolites, 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine and taurine conjugates, although we have reported an analytical method for determining the urinary levels of these compounds using liquid chromatography/electrospray ionization tandem mass spectrometry, because of their lack of N-acetylglucosamine conjugation.

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Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Cited by 84 publications

References 32 publications

Transition of Urinary Ursodeoxycholic Acid 7β-N-acetylglucosaminide and 3α-sulfate from Neonates to Adolescents Using LC/ESI-MS/MS Analysis

Transition of Urinary Ursodeoxycholic Acid 7β-N-acetylglucosaminide and 3α-sulfate from Neonates to Adolescents Using LC/ESI-MS/MS Analysis

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann–Pick Disease Type C as Novel Candidate Diagnostic Markers

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