Neonatal Cholestatic Liver Disease in an Asian Patient With a Homozygous Mutation in the Oxysterol 7α‐hydroxylase Gene

Ueki, Isao; Kimura, Akihiko; Nishiyori, Atsushi; Chen, Huey‐Ling; Takei, Hiroyuki; Nittono, Hiroshi; Kurosawa, Takao

doi:10.1097/mpg.0b013e31815a9911

Cited by 63 publications

(52 citation statements)

References 18 publications

(24 reference statements)

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“…In the initial bile acid analysis, we detected large amounts of 3␤-hydroxy-⌬ 5 -bile acids such as ⌬ 5 -3␤-ol in serum and urine from patient 2, a finding also reported in oxysterol 7␣-hydroxylase deficiency (8,9). We speculate that the main pathway of bile acid synthesis was the acidic pathway, based on the results of initial bile acid analysis in serum and urine.…”

Section: Discussionmentioning

confidence: 72%

“…This led us to suspect oxysterol 7␣-hydroxylase deficiency (8,9), but we could not detect a mutation of the CYP7B1 gene. In the second urinary bile acid analysis during UDCA treatment, we detected large proportions of 3␤-hydroxy-⌬ 5 -bile acids such as ⌬ 5 -3␤-ol and ⌬ 5 -3␤,7␣,12␣-triol, when UDCA was excluded from calculations (Table 1).…”

Section: Patientmentioning

confidence: 99%

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Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

et al. 2010

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ABSTRACT:We report definitive diagnosis and effective chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum ␥-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3␤-hydroxy-⌬ 5 bile acids were detected by gas chromatography-mass spectrometry. HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patients and their parents identified four novel mutations of the HSD3B7 gene in the patients. One had a homozygous mutation, 314delA; the other had compound heterozygous mutations: V132F, T149I, and 973_974insCCTGC. Interestingly, the second patient's mother had V132F and T149I mutations in one allele. Excessive 3␤-hydroxy-⌬ 5 -bile acids such as 3␤,7␣-dihydroxy-and 3␤,7␣,12␣-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3␤-hydroxy-5-cholenoic acid. Liver dysfunction in both patients decreased with ursodeoxycholic acid treatment, but unusual bile acids were still detected. Normalization of the patients' liver function and improvement of bile acid profiles occurred with CDCA treatment. Thus, we found mutations in the HSD3B7 gene accounting for autosomal recessive neonatal cholestasis caused by 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage. (Pediatr Res 68: 258-263, 2010) D eficiency of 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/ isomerase (3␤-HSD) was first described by Clayton et al. in 1987 (1). This inborn error of bile acid synthesis is very rare and shows autosomal recessive inheritance. The main findings in 3␤-HSD deficiency are low or normal concentrations of total bile acid and normal activity of ␥-glutamyltransferase (GGT) in serum, as well as absence of pruritus despite conjugated hyperbilirubinemia, elevated alanine aminotransferase (ALT), and fatty stools. In the synthesis of bile acids from cholesterol, 3␤-HSD catalyzes the second of a series of reactions leading to excretion of 3␤,7␣-dihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣-diol) and 3␤,7␣,12␣-trihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣,12␣-triol) in the urine. In the first reported patient, complete absence of 3␤-HSD activity was found by Buchmann et al. in 1990 (2) based on the study of cultured fibroblasts. In 2000, Schwarz et al. (3) reported that the same patient had a homozygous mutation representing a 2-bp deletion in exon 6 of the 3␤-HSD gene (HSD3B7) on chromosome 16p11.2-12. The human HSD3B7 gene contains six coding exons and encodes 369 amino acids; so far, 13 distinct mutations causing 3␤-HSD deficiency have been reported (4,5).Here, we report genetic analyses of two Japanese patients with 3␤-HSD deficiency: one previously reported patient (6,7) was diagnosed with 3␤-HSD deficiency by bile acid analysis and the ot...

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Section: Discussionmentioning

confidence: 72%

Section: Patientmentioning

confidence: 99%

Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

et al. 2010

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“…This oxysterol is metabolized by CYP39A1 ( 5 ) and is not a substrate for CYP7B1 ( 12 ). More recently, another fatal neonatal case with a mutation in the CYP7B1 gene and development of cholestasis was described ( 13 ). The oxysterol levels in this patients were not reported.…”

Section: Resultsmentioning

confidence: 99%

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

Schüle

Siddique

Deng

et al. 2010

Journal of Lipid Research

102

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“…The mean plasma concentrations of 7 ␣ C4, 7 ␣ 12 ␣ C4, and 5 ␣ -cholestanol measured in CTX-affected adults were, respectively, 183-, 3862-, and 24-fold the mean concentrations in unaffected adults, with no The acidic BA pathway initiated by cholesterol 27-hydroxylation (lower pathway in Fig. 1 ) has been proposed to be the major BA synthesis pathway in neonates, as deficiency in the oxysterol 7 ␣ -hydroxylase enzyme (CYP7B1) can cause severe liver disease in infancy (36)(37)(38). Our data and the recent observation that CYP7B1 mutations also cause a form of hereditary spastic paraplegia with disease onset outside of the newborn period ( 39 ) suggest that when the acidic pathway is blocked, neonates are able to synthesize BA via the neutral pathway.…”

Section: Quantifi Cation Of Endogenous Ketosterols As a Blood Test Fomentioning

confidence: 99%

A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns

DeBarber

Luo

Star-Weinstock³

et al. 2014

Journal of Lipid Research

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Neonatal Cholestatic Liver Disease in an Asian Patient With a Homozygous Mutation in the Oxysterol 7α‐hydroxylase Gene

Cited by 63 publications

References 18 publications

Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis

A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns

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