J Clin Invest 1998 Nov 1;102(9):1690-703

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease

Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL, Lathe R, Thompson HR,
Weslie Tyson R, Sokol RJ, Russell DW
Clinical Mass Spectrometry Center, Department of Pediatrics, Children's Hospital
Medical Center, Cincinnati, Ohio 45229, USA. setck0@chmcc.org

Abstract
We describe a metabolic defect in bile acid synthesis involving a deficiency in
7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol
7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis.
The defect, identified in a 10-wk-old boy presenting with severe cholestasis,
cirrhosis, and liver synthetic failure, was established by fast atom bombardment
ionization-mass spectrometry, which revealed elevated urinary bile acid
excretion, a mass spectrum with intense ions at m/z 453 and m/z 510
corresponding to sulfate and glycosulfate conjugates of unsaturated
monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas
chromatography-mass spectrometric analysis confirmed the major products of
hepatic synthesis to be 3beta-hydroxy-5-cholenoic and
3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum
bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The
biochemical findings were consistent with a deficiency in 7alpha-hydroxylation,
leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids.
Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the
patient. Gene analysis revealed a cytosine to thymidine transition mutation in
exon 5 that converts an arginine codon at position 388 to a stop codon. The
truncated protein was inactive when expressed in 293 cells. These findings
indicate the quantitative importance of the acidic pathway in early life in
humans and define a further inborn error in bile acid synthesis as a metabolic
cause of severe cholestatic liver disease