Congenital bile acid synthesis defect, type 1

Other Names: CBAS1; 3-alpha beta-hydroxy-delta-5-c27-steroid oxidoreductase, deficiency of; 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency; Congenital bile acid synthesis defect type 1; BASD1

Congenital bile acid synthesis defect type 1 is a disorder characterized by cholestasis, a condition that impairs the production and release of a digestive fluid called bile from liver cells. Bile is used during digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D, E, and K. People with congenital bile acid synthesis defect type 1 cannot produce (synthesize) bile acids, which are a component of bile that stimulate bile flow and help it absorb fats and fat-soluble vitamins. As a result, an abnormal form of bile is produced. If left untreated, congenital bile acid synthesis defect type 1 often leads to cirrhosis and death in childhood.

Epidemiology

The prevalence of congenital bile acid synthesis defect type 1 is unknown; however, it is the most common of all the congenital defects of bile acid synthesis. Together, these conditions are thought to have a prevalence of 1 to 9 per million people.

Cause

Mutations in the HSD3B7 gene cause congenital bile acid synthesis defect type 1. The HSD3B7 gene provides instructions for making an enzyme called 3 beta-hydroxysteroid dehydrogenase type 7 (3β-HSD7). This enzyme is found in liver cells that produce bile acids. Bile acids are produced from cholesterol in a multi-step process. The 3β-HSD7 enzyme is responsible for the second step in that process, which converts 7alpha(α)-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one.

HSD3B7 gene mutations result in a 3β-HSD7 enzyme with little or no function. Without enough functional 3β-HSD7 enzyme, the conversion of 7α-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one is impaired. The 7α-hydroxycholesterol instead gets converted into abnormal bile acid compounds that cannot be transported out of the liver into the intestine, where the bile acids are needed to digest fats. As a result, cholesterol and other fats build up in the liver and fat-soluble vitamins are not absorbed, which contribute to the signs and symptoms of congenital bile acid synthesis defect type 1.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The signs and symptoms of congenital bile acid synthesis defect type 1 often develop during the first weeks of life, but they can begin anytime from infancy into adulthood. Affected infants often have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. Excess fat in the feces (steatorrhea) is an additional feature of congenital bile acid synthesis defect type 1. As the condition progresses, affected individuals can develop liver abnormalities including an enlarged liver (hepatomegaly), inflammation, or chronic liver disease (cirrhosis). The spleen may also become enlarged (splenomegaly). The inability to absorb certain fat-soluble vitamins (vitamin D in particular) can result in softening and weakening of the bones (rickets) in some individuals.

Diagnosis

Diagnostic methods Diagnosis is based on detection of sulfate and glycosulfate conjugates of 3-beta-hydroxy-delta-5 bile acids, which are the signature metabolites of this bile acid defect, on liquid secondary ionization mass spectrometry (LSIMS) analysis of urine. Gas chromatography - mass spectrometry (GC-MS) or electroscopy and tandem mass spectrometry may also be used.

Differential diagnosis

Differential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency of ZZ phenotype, Alagille syndrome, biliary atresia, cystic fibrosis, and metabolic diseases (tyrosinemia type I, galactosemia, hereditary fructose intolerance) (see these terms), diseases that present with fat and fat soluble vitamin malabsorption, including other liver diseases, and intestinal disease, or diseases that present with growth failure.

Antenatal diagnosis

Antenatal diagnosis can be made on embryonic tissue obtained when there has been a previously identified sibling. Urine LSIMS in a suspect infant can confirm the diagnosis in the first neonatal days.

Treatment

Treatment is based on oral administration of cholic acid which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease, even in cases with hepatic fibrosis and cirrhosis. Cholic acid therapy stimulates bile flow and suppresses synthesis of atypical bile acids and production of toxic intermediates via the bile acid pathway linked to the pathogenesis of disease. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• cholic acid (Brand name: Cholbam)Treatment of bile acid synthesis disorders due to single enzyme defects and as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption.

Prognosis

With early treatment the long-term prognosis is excellent.

NIH genetic and rare disease info

• NIH info on Congenital bile acid synthesis defect, type 1

Congenital bile acid synthesis defect, type 1 is a rare disease.

Congenital bile acid synthesis defect, type 1 Resources
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