Liver disease in infancy caused by oxysterol 7α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid
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A child of consanguineous parents of Pakistani origin developed jaundice at 5 weeks and then, at 3 months, irritability, a prolonged prothrombin time, a low albumin, and episodes of hypoglycaemia. Investigation showed an elevated alanine aminotransferase with a normal γ-glutamyl-transpeptidase. Analysis of urine by electrospray ionisation tandem mass spectrometry (ESI-MS/MS) showed that the major peaks were m/z 480 (taurine-conjugated 3β-hydroxy-5-cholenoic acid) and m/z 453 (sulphated 3β-hydroxy-5-cholenoic acid). Analysis of plasma by gas chromatography-mass spectrometry (GC-MS) showed increased concentrations of 3β-hydroxy-5-cholenoic acid, 3β-hydroxy-5-cholestenoic acid and 27-hydroxycholesterol, indicating oxysterol 7α-hydroxylase deficiency. The patient was homozygous for a mutation (c.1249C>T) in CYP7B1 that alters a highly conserved residue in oxysterol 7α-hydroxylase (p.R417C) - previously reported in a family with hereditary spastic paraplegia type 5. On treatment with ursodeoxycholic acid (UDCA), his condition was worsening, but on chenodeoxycholic acid (CDCA), 15 mg/kg/d, he improved rapidly. A biopsy (after 2 weeks on CDCA), showed a giant cell hepatitis, an evolving micronodular cirrhosis, and steatosis. The improvement in liver function on CDCA was associated with a drop in the plasma concentrations and urinary excretions of the 3β-hydroxy-Δ5 bile acids which are considered hepatotoxic. At age 5 years (on CDCA, 6 mg/kg/d), he was thriving with normal liver function. Neurological development was normal apart from a tendency to trip. Examination revealed pes cavus but no upper motor neuron signs. The findings in this case suggest that CDCA can reduce the activity of cholesterol 27-hydroxylase - the first step in the acidic pathway for bile acid synthesis.
The authors thank the family members for their participation. PTC and PBM were funded by Great Ormond Street Children’s Charity. PG is funded by a Wellcome Trust Senior Fellowship. Work in Swansea was supported by BBSRC. Work in Bordeaux was supported by the Agence Nationale de la Recherche (ANR) (Project 2010BLAN112601/LIGENAX), the Association Française contre les Myopathies (AFM) (14879/MNM2 2012), the Conseil Régional d’Aquitaine (CRA) (2011-0151/LIGENAX), The Association Strumpell-Lorrain (ASL) (2011–0135), and the Pôle de compétitivité Prod’Innov.
Dongling Dai, Philippa Mills, Emma Footitt, Paul Gissen, Patricia McClean, Jens Stahlschmidt, Isabelle Coupry, Julie Lavie, Fanny Mochel, Cyril Goizet, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Karin Schwarz, Peter Crick, Yuqin Wang, William Griffiths and Peter Clayton declare that they are not paid personally, or for research, by any company involved in the manufacture, distribution or marketing of CDCA for medicinal use, nor do they hold shares in any such company. Cyril Goizet makes the following declaration: The work under consideration was financially supported by Agence Nationale de la Recherche (ANR) (Project 2010BLAN112601/LIGENAX), the Association Française contre les Myopathies (AFM) (14879/MNM2 2012), the Conseil Régional d’Aquitaine (CRA) (2011-0151/LIGENAX), The Association Strumpell-Lorrain (ASL) (2011–0135), and the Pôle de compétitivité Prod’Innov. This support was addressed to Pr Cyril Goizet. Pr Cyril Goizet received consulting fees from Raptor, Genzyme, Actelion and Shire. Pr Cyril Goizet received financial support for research activities from TKT5S, Shire, Genzyme, Association Française contre les myopathies (AFM), Association contre les maladies mitochondriales (AMMi), Association Strumpell-Lorrain (ASL), Connaitre les Syndromes Cérébelleux (CSC), Conseil régional d’Aquitaine (CRA), Agence Nationale pour la Recherche (ANR), Programme Hospitalier de Recherche Clinique (PHRC), and Registry of the European Huntington Disease Network (EHDN). Inscriptions and travels for congresses of Dr Cyril Goizet were funded by Shire, Genzyme, Actelion, Takeda. William Griiffiths, Peter Crick and Yuqun Wang declare that the development of the analytical methods used in Swansea for the analysis of cholesterol metabolites was funded by a grant from the UIK Research Council, BBSRC (grant no BB/I001735/1). Peter Clayton receives a salary from Great Ormond Street Hospital Children’s Charity and declares the following relevant financial activities outside the submitted work: Grant from Actelion for investigator led project on diagnosis and monitoring of Niemann-Pick C, fees for teaching on courses from Orphan Europe/Recordati Foundation for Rare Diseases, fees for lectures / consultancy from Merck Corp USA, Actelion, shares in Waters, Abbott, Abbvie.
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