BILE-ACID PROFILES IN PEROXISOMAL 3-OXOACYL-COENZYME-A THIOLASE DEFICIENCY

Fast atom bombardment mass spectrometry and gas chromatography-mass spectrometry were used to analyze bile acids in the body fluids of an infant (L.C.) whose liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase. The profiles were compared with those of six patients with undetectable peroxisomes (Zellweger syndrome) and two siblings (N.B. and I.B.) whose defect of peroxisomal β-oxidation could not be localized by morphological studies of peroxisomes or by immunoblotting of peroxisomal β-oxidation proteins. 3α,7α,12α-Trihydroxy-5β-cholestan-26-oic acid (THCA) was present in bile and plasma of all patients. However, bile from L.C., N.B. and I.B. contained unconjugated varanic acid (3α,7α,12α,24-tetrahydroxy-5β-cholestan-26-oic acid) as the major C27 bile acid, whereas bile from Zellweger patients contained only small amounts of varanic acid. In the bile from L.C. two isomers of varanic acid were present; in the bile from N.B. and I.B. a single isomer predominated. L.C.,N.B., and I.B. all produced bile containing small amounts of (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-en-26-oic acid ((24E]-Δ24-THCA), its [24Z]- isomer, 3α,7α,12α-trihydroxy-5β-cholest-23-en-26-oic acid and 3α,7α,12α-trihydroxy-27-nor-5β-cholestan-24-one. The results provide evidence for peroxisomal pathways for cholic acid synthesis in man via THCA, Δ24-THCA and varanic acid and show that bile acid analyses can be used to diagnose peroxisomal thiolase deficiency.