title: Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid.
abstract: 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 7 α-hydroxylase deficiency. The patient was homozygous for a mutation (c.1249C>T) in CYP7B1 that alters a highly conserved residue in oxysterol 7 α-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.
authors.forename: Dongling
authors.initials: D
authors.lastname: Dai
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Emma
authors.initials: E
authors.lastname: Footitt
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Patricia
authors.initials: P
authors.lastname: McClean
authors.forename: Jens
authors.initials: J
authors.lastname: Stahlschmidt
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Mizuochi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nittono
authors.forename: Karin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crick
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D001647:Bile Acids and Salts / Q000097:blood / Q000652:urine; D002635:Chenodeoxycholic Acid / Q000627:therapeutic use*; D003241:Consanguinity; D000072474:Cytochrome P450 Family 7; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000188:drug therapy / Q000235:genetics; D013250:Steroid Hydroxylases / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human