Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy.
OBJECTIVE
Inborn errors of bile acid metabolism may present as neonatal cholestasis and fat-soluble vitamin malabsorption or as late onset chronic liver disease. Our aim was to fully characterize a defect in bile acid synthesis in a 2-week-old African-American girl presenting with coagulopathy, vitamin D and E deficiencies, and mild cholestasis and in her sibling, whose liver had been used for orthotopic liver transplantation (OLT).


METHODS
Bile acids were measured by mass spectrometry in urine, bile, serum, and feces of the patient and in urine from the unrelated recipient.


RESULTS
Liver biopsy specimens showed neonatal hepatitis with giant cell transformation and hepatocyte necrosis; peroxisomes were reduced in number. High concentrations of (25R)3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid in the urine, bile, and serum established a pattern similar to that of Zellweger syndrome and identical to the Alligator mississippiensis. Serum phytanic acid was normal, whereas pristanic acid was markedly elevated. Biochemical, MRI, and neurologic findings were inconsistent with a generalized defect of peroxisomal function and were unique. Analysis of the urine from the recipient of the deceased sibling's liver confirmed the same bile acid synthetic defect. A deficiency in 2-methylacyl-CoA racemase, which is essential for conversion of (25R)THCA to its 25S-isomer, the substrate to initiate peroxisomal beta-oxidation to primary bile acids, was confirmed by DNA analysis revealing a missense mutation (S52P) in the gene encoding this enzyme. Long-term treatment with cholic acid normalized liver enzymes and prevented progression of symptoms.


CONCLUSIONS
This genetic defect further highlights bile acid synthetic defects as a cause of neonatal cholestasis.
Setchell
Kenneth D R
KD
Division of Clinical Mass Spectrometry, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Kenneth_setchell@chmcc.org
Heubi
James E
JE
Bove
Kevin E
KE
O'Connell
Nancy C
NC
Brewsaugh
Tracy
T
Steinberg
Steven J
SJ
Moser
Ann
A
Squires
Robert H
RH
D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis / Q000096:biosynthesis* / Q000627:therapeutic use / Q000652:urine; D015415:Biomarkers / Q000032:analysis; D001769:Blood / Q000378:metabolism; D002777:Cholestanols / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007231:Infant, Newborn; D008107:Liver Diseases / Q000209:etiology* / Q000601:surgery; D016031:Liver Transplantation; D008661:Metabolism, Inborn Errors / Q000150:complications* / Q000188:drug therapy; D009154:Mutation / Q000502:physiology; D020675:Peroxisomes / Q000201:enzymology; D019998:Racemases and Epimerases / Q000235:genetics; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014556:Urine / Q000737:chemistry
D001647:Bile Acids and Salts; D015415:Biomarkers; D002777:Cholestanols; C022069:3,7,12-trihydroxycholestan-26-oic acid; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase