Two neonatal cholestasis patients with mutations in the SRD5B1 (AKR1D1) gene: diagnosis and bile acid profiles during chenodeoxycholic acid treatment
Abstract
BACKGROUND AND AIMS: In two Japanese infants with neonatal cholestasis, 3-oxo-Δ(4)-steroid 5β-reductase deficiency was diagnosed based on mutations of the SRD5B1 gene. Unusual bile acids such as elevated 3-oxo-Δ(4) bile acids were detected in their serum and urine by gas chromatography-mass spectrometry. We studied effects of oral chenodeoxycholic acid treatment. PATIENTS AND METHODS: SRD5B1 gene analysis used peripheral lymphocyte genomic DNA. Diagnosis and treatment of these two patients were investigated retrospectively and prospectively investigated. RESULTS: With respect to SRD5B1, one patient was heterozygous (R266Q, a novel mutation) while the other was a compound heterozygote (G223E/R261C). Chenodeoxycholic acid treatment was effective in improving liver function and decreasing unusual bile acids such as 7α-hydroxy- and 7α,12α-dihydroxy-3-oxo-4-cholen-24-oic acids in serum and urine. CONCLUSION: Primary bile acid treatment using chenodeoxycholic acid was effective for these patients treated in early infancy before the late stage of chronic cholestatic liver dysfunction.
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The deficiency is exacerbated by inability to form sufficient bile acids to feedback-inhibit CYP7A1, leading to further elevation of allo-bile acids.
“This deficiency is exacerbated by the inability to from sufficient bile acids to feed-back and inhibit the rate determining step in the pathway, 7α-hydroxylase (CYP7A1), and thus the formation of allo-bile acids will be further elevated [95–99].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [99]
Inherited AKR1D1 mutations cause bile-acid deficiency in infants characterized by reduced bile acid formation and accumulation of hepatotoxic Δ4-3-keto and 5α-reduced allo-bile acids.
“Inherited mutations in AKR1D1 have been studied in patients with bile-acid deficiency that develops in infants and is characterized by reduced formation of bile acids and accumulation of Δ4-3-keto and 5α-reduced (allo-bile acids) which are hepatotoxic.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [99]
Seven point mutations are known in patients with 5β-reductase deficiency: Leu106Phe, Pro133Arg, Gly223Glu, Pro198Leu, Asp241Val, Arg261Cys, and Arg266Glu.
“seven point mutations have been identified in patients with 5β-reductase deficiency: Leu106Phe, Pro133Arg, Gly223Glu, Pro198Leu, Asp241Val, Arg261Cys and Arg266Glu [95–97, 99, 100].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [99]
SNPs in AKR1C1, AKR1C2, and AKR1C4 have been studied at the protein level, and Phe46Tyr has been associated with disease.
“So far SNPs in AKR1C1, AKR1C2 and AKR1C4 have been studied at the protein level and Phe46Tyr has been associated with disease [95–97, 99, 103, 104].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [99]
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Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism
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- Authors
- Seki, Y., Mizuochi, T., Kimura, A., Takahashi, T., Ohtake, A., Hayashi, S., Morimura, T., Ohno, Y., Hoshina, T., Ihara, K., Takei, H., Nittono, H., Kurosawa, T., Homma, K., Hasegawa, T., & Matsuishi, T.
- Affiliations
- Kurume University (JP)
- Saitama Medical University (JP)
- Department of Pediatric Surgery, Faculty of Medicine Saitama Medical University Saitama Japan
- Kyushu University (JP)
- Institution of Bile Acid, Junshin Clinic Tokyo Japan
- Health Sciences University of Hokkaido (JP)
- Keio University Hospital (JP)
- Keio University (JP)
- Corresponding author
- Kimura, Akihiko
- ORCID
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2012-11-16
- Volume
- 36
- Issue
- 3
- Pages
- 565-573
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W2084182282
- Cited by
- 26
- References
- 28
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 8 · 2022: 2 · 2021: 2 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 1
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22591144, 22791008, 25461568)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- neonatal cholestasis, AKR1D1, chenodeoxycholic acid, bile acid profile, novel mutations, compound heterozygosity
- MeSH terms
- Bile Acids and Salts, Chenodeoxycholic Acid, Cholestasis, Female, Gastrointestinal Agents, Humans, Infant, Newborn, Infant, Newborn, Diseases, Liver, Male, Mutation, Oxidoreductases, Asian People
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