Bile Acid Synthesis Defect, Congenital, 2

A number sign (#) is used with this entry because of evidence that this form of congenital defect in bile acid synthesis with delta(4)-3-oxosteroid 5-beta-reductase deficiency, referred to here as CBAS2, is caused by homozygous or compound heterozygous mutation in the AKR1D1 gene (604741) on chromosome 7q33.

For a general description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see 607765.

Clinical Features

Setchell et al. (1988) reported monozygotic male twins who presented at birth with cholestatic jaundice due to severe intrahepatic cholestasis. A previously born sib had died at the age of 4 months of hepatic failure following an identical course. Using fast atom bombardment ionization-mass spectrometry, the authors found increased urinary excretion and predominance of taurine-conjugated unsaturated hydroxy-oxo-bile acids. The biochemical findings indicated a defect in bile acid synthesis involving the delta(4)-3-oxosteroid 5-beta-reductase enzyme which converts delta(4)-3-oxo-C27 bile acid intermediates into the corresponding 3-alpha-hydroxy-5-beta(H) structures. The inheritance suggested an autosomal recessive disorder. On follow-up studies of the patients reported by Setchell et al. (1988), Daugherty et al. (1993) found defective primary bile acid synthesis and markedly increased levels of atypical oxo and allo bile acids in urine and serum. Liver biopsy showed hepatocellular cholestasis and giant-cell transformation which resolved in parallel with clinical and biochemical recovery during oral bile acid administration. In the twins, 5 years old at the time of report, portal fibrosis stabilized at a mild level. Follow-up biopsy in another brother at 8 months was normal, and he was doing well at 3 years of age. Daugherty et al. (1993) identified 8 additional patients by urine screening; all were boys.

Shneider et al. (1994) and Siafakas et al. (1997) reported a total of 5 infants with delta(4)-3-oxosteroid 5-beta-reductase deficiency who also had neonatal hemochromatosis (231100).

Kimura et al. (1998) studied a 5-month-old Japanese boy with severe neonatal cholestasis associated with hypertyrosinemia. A liver sample was examined by immunoblot analysis using monoclonal antibodies against 5-beta-reductase. Although an indistinct band of 5-beta-reductase was seen in the analysis, it remained uncertain as to whether this represented a primary or inherited 5-beta-reductase deficiency. It may have been a secondary deficiency due to severe liver damage, even though 3-oxo-delta(4) bile acids constituted more than 70% of the total urinary bile acids.

Clayton et al. (1996) and Lemonde et al. (2003) reported a Sardinian girl who presented at age 3 weeks with hyperbilirubinemia, elevated liver enzymes, and prolonged prothrombin time consistent with cholestasis. She also had steatorrhea, failure to thrive, and rickets. Liver biopsy showed extensive giant cell transformation and steatosis. Gamma-GGT (see 612346) was normal. By age 9 years, she was doing well on bile replacement therapy with chenodeoxycholic acid and cholic acid.

Lemonde et al. (2003) described 2 additional unrelated patients with neonatal cholestatic jaundice. Both patients were born of consanguineous parents. Other clinical features included coagulopathy, giant cell hepatitis, and almost complete absence of chenodeoxycholic and cholic acids. Both patients developed liver failure necessitating liver transplantation.

Molecular Genetics

In 3 unrelated patients with progressive familial intrahepatic cholestasis due to delta(4)-3-oxosteroid 5-beta-reductase deficiency, Lemonde et al. (2003) identified 3 different homozygous mutations in the AKR1D1 gene (604741.0001-604741.0003). Urinary profile of all 3 patients showed almost complete absence of chenodeoxycholic and cholic acids. One of the patients had been reported by Clayton et al. (1996).

Exclusion Studies

In an infant with clinical and biochemical features of 5-beta-reductase deficiency, including urinary bile salts with a 3-oxo-delta(4) content greater than 94%, Sumazaki et al. (1997) excluded a pathogenic mutation in the AKR1D1 gene.

Genotype/Phenotype Correlations

Drury et al. (2010) noted that a patient with a homozygous truncating mutation in the ARK1D1 gene (604741.0002; Lemonde et al., 2003) had a more severe phenotype necessitating liver transplantation compared to 2 sibs with compound heterozygous missense mutations resulting in some residual protein function (605741.0004 and 604741.0005; Gonzales et al., 2004) who responded well to oral cholic acid supplementation and did not need liver transplantation.