Congenital Bile Acid Synthesis Defect, Type 1

What are the other Names for this Condition? (Also known as/Synonyms)

• 3-Beta-Hydroxy-Delta-5-C27-Steroid Oxidoreductase Deficiency Disorder
• BAS Defect Type 1 (BASD1)
• Deficiency of 3-Alpha Beta-Hydroxy-Delta-5-C27-Steroid Oxidoreductase

What is Congenital Bile Acid Synthesis Defect, Type 1? (Definition/Background Information)

• Congenital Bile Acid Synthesis Defect Type 1 (CBAS1 or BAS Defect Type 1) is the most common anomaly of bile acid synthesis, characterized by variable manifestations of progressive cholestatic liver disease, and fat malabsorption
• The clinical presentation is heterogeneous, however most patients present with features of neonatal cholestasis. Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. In most cases, pruritus is absent
• The clinical course of early-onset disease is heterogeneous with some patients resolving jaundice and being identified later in life, or with more fulminant disease that results in death or requires liver transplantation at an early age
• The disorder may also present as late-onset chronic cholestasis. In such patients, liver disease is not always evident and patients may have fat-soluble vitamin malabsorption with rickets, corrected by vitamin supplementation, and/or other complications including bleeding diathesis (hematochezia or intracranial bleeding), neuroaxonal dystrophy and night blindness
• Serum liver enzymes are initially often normal but later show increases with progression of liver disease to fibrosis. Children and adolescents may also present with extensive fibrosis and/or cirrhosis
• With early treatment of Congenital Bile Acid Synthesis Defect Type 1 the long-term prognosis is excellent

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Congenital Bile Acid Synthesis Defect, Type 1? (Age and Sex Distribution)

• The prevalence of Congenital Bile Acid Synthesis Defect, Type 1 is unknown but may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

• Congenital Bile Acid Synthesis Defect, Type 1 is a rare congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Congenital Bile Acid Synthesis Defect, Type 1? (Predisposing Factors)

• A positive family history may be an important risk factor, since Congenital Bile Acid Synthesis Defect, Type 1 can be inherited
• Currently, no other risk factors have been clearly identified for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Congenital Bile Acid Synthesis Defect, Type 1? (Etiology)

• Congenital Bile Acid Synthesis Defect, Type 1 is caused by a mutation in the gene encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase (HSD3B7, 16p12-p11.2)
• Transmission is autosomal recessive

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Congenital Bile Acid Synthesis Defect, Type 1?

The signs and symptoms of Congenital Bile Acid Synthesis Defect, Type 1 may include:

Very frequently present symptoms in 80-99% of the cases:

• Biliary tract abnormality
• Elevated hepatic transaminases
• Failure to thrive
• Hepatomegaly
• Jaundice
• Malabsorption
• Neonatal cholestatic liver disease

Frequently present symptoms in 30-79% of the cases:

• Abnormality of coagulation
• Gastrointestinal hemorrhage
• Splenomegaly

Occasionally present symptoms in 5-29% of the cases:

• Cirrhosis
• Nyctalopia
• Osteoporosis
• Peripheral neuropathy
• Pruritus

In addition to the above, the following signs and symptoms may be present:

• Abnormality of the coagulation cascade
• Acholic stools
• Diarrhea
• Giant cell hepatitis
• Hyperbilirubinemia
• Hypocholesterolemia
• Intrahepatic cholestasis
• Steatorrhea

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Congenital Bile Acid Synthesis Defect, Type 1 Diagnosed?

The diagnosis of Congenital Bile Acid Synthesis Defect, Type 1 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 (on urine samples)
• Liver function tests (to check for elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT)
• Liver histology (shows inflammation, giant cells, evidence of cholestasis, and variable degrees of liver fibrosis)
• Antenatal diagnosis on embryonic tissue (obtained when there has been a previously identified sibling)
• Urine LSIMS in a suspect infant to confirm the diagnosis in the first neonatal days

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Congenital Bile Acid Synthesis Defect, Type 1?

The complications of Congenital Bile Acid Synthesis Defect, Type 1 may include:

• Inadequate weight gain in infants
• Unintended weight loss in older individuals due to intestinal malabsorption
• Severe jaundice
• Liver cirrhosis; fibrosis of liver
• Liver failure
• Intracranial bleeding

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Congenital Bile Acid Synthesis Defect, Type 1 Treated?

• The treatment for Congenital Bile Acid Synthesis Defect, Type 1 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

(Source: Congenital Bile Acid Synthesis Defect, Type 1; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Congenital Bile Acid Synthesis Defect, Type 1 be Prevented?

Congenital Bile Acid Synthesis Defect, Type 1 may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Congenital Bile Acid Synthesis Defect, Type 1? (Outcomes/Resolutions)

• The prognosis of Congenital Bile Acid Synthesis Defect, Type 1 is dependent upon the severity of the signs and symptoms and associated complications, if any
• With a timely diagnosis and prompt treatment, the prognosis is excellent
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Congenital Bile Acid Synthesis Defect, Type 1:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/