Bile acid‐CoA ligase deficiency—a new inborn error of bile acid metabolism

Abstract

Born at 27 weeks gestation, a child of consanguineous parents of Pakistani origin required prolonged parenteral nutrition. She developed jaundice, with extensive fibrosis and architectural distortion at liver biopsy; jaundice resolved with supportive care. Serum γ-glutamyl transpeptidase values were within normal ranges. The bile acids in her plasma and urine were >85% unconjugated (non-amidated). Two genes encoding bile-acid amidation enzymes were sequenced. No mutations were found in BAAT, encoding bile acid-CoA : aminoacid N-acyl transferase. The patient was homozygous for the missense mutation c.1012C > T in SLC27A5, predicted to alter a highly conserved amino-acid residue (p.H338Y) in bile acid-CoA ligase (BACL). She also was homozygous for the missense mutation c.1772A > G in ABCB11, predicted to alter a highly conserved amino-acid residue (p.N591S) in bile salt export pump (BSEP). BACL is essential for reconjugation of bile acids deconjugated by gut bacteria, and BSEP is essential for hepatocyte-canaliculus export of conjugated bile acids. A female sibling born at term had the same bile-acid phenotype and SLC27A5 genotype, without clinical liver disease. She was heterozygous for the c.1772A > G ABCB11 mutation. This is the first report of a mutation in SLC27A5. The amidation defect may have contributed to cholestatic liver disease in the setting of prematurity, parenteral nutrition, and homozygosity for an ABCB11 mutation.

Genetic Defects in Bile Acid Conjugation Cause Fat-Soluble Vitamin Deficiency

“…ESI-MS can also be used to make this diagnosis 19 , as was recently reported for a patient with defective amidation due to a bile acid-CoA ligase deficiency 20 . The striking feature of the mass spectra of the urine, bile and serum of patients with defective amidation is the complete absence of ions corresponding to glycine- and taurineconjugated bile acids, and the presence of a dominant ion at m/z 407 representing unconjugated cholic acid; this conclusion was confirmed by GC-MS analysis.…”

“…Recently, the first confirmed defect associated with a mutation in SLC27A5 was reported 20 . The patient, of Pakistani origin and born to consanguineous parents, presented with cholestasis, elevated serum bilirubin and transaminases, normal serum γ-GT concentrations and low serum fat-soluble vitamins - a similar presentation to that of the patients with BAAT deficiency described here.…”

“…UDCA therapy was been reportedly beneficial in a single patient with defective bile acid amidation caused by a mutation in SLC27A5 20 . However, oral administration of primary conjugated bile acids should provide a better and rational therapeutic approach to correcting the fat-soluble vitamin malabsorption in patients with amidation defects 23 .…”

11β-Hydroxysteroid dehydrogenase-1 is involved in bile acid homeostasis by modulating fatty acid transport protein-5 in the liver of mice

“…Mice deficient in Fatp5 , albeit having normal total BA concentrations in gall bladder bile, feces, liver, serum, and urine, show a dramatically increased percentage of unconjugated BAs in bile, suggesting that Fatp5 -deficiency leads to a defect in BA conjugation [41]. Moreover, an accumulation of unconjugated BAs (>85%) in plasma and urine of neonatal humans with homozygous missense mutations in Fatp5 (Slc27a5) has been reported [42]. Thus, the decreased Fatp5 expression in mouse models of 11β-HSD1-deficiency may explain the elevated circulating concentrations of unconjugated BAs.…”

Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury

“…Amidation increases bile acid aqueous solubility and enhances their digestive function in the gut. Defective bile acid amidation, such as in pediatric patients lacking functional bile acid-CoA synthase (BACS) or bile acid-CoA:amino acid N-acetyltransferase (BAAT), caused fat-soluble vitamin deficiency, growth retardation, and cholangiopathy (8,9,41). Therefore, coordinated regulation of bile acid synthesis and taurine synthesis by bile acids may ensure that sufficient taurine is available when de novo bile acid synthesis is induced.…”