congenital bile acid synthesis defect 5

Congenital Bile Acid Synthesis Defect 5 (CBAS5) Overview

Congenital bile acid synthesis defect 5, also known as CBAS5, is a rare autosomal recessive disorder caused by pathogenic variants in the ABCD3 gene [4]. This condition is characterized by hepatosplenomegaly, hepatic fibrosis, progressive liver failure, and accumulation of peroxisomal C27-bile acid intermediates in plasma [3].

Clinical Features

The clinical features of CBAS5 include:

• Hepatosplenomegaly (enlargement of the liver and spleen)
• Hepatic fibrosis (scarring of the liver tissue)
• Progressive liver failure
• Accumulation of peroxisomal C27-bile acid intermediates in plasma

Inheritance Pattern

CBAS5 is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition [9].

Important Note

If left untreated, CBAS5 can lead to cirrhosis and death in childhood. However, with proper treatment, individuals with this condition can have a favorable outcome in adulthood [1].

Common Signs and Symptoms

The main symptom of most (but not all) Congenital Bile Acid Synthesis Defect 5 (CBAS5) is interruption or suppression of the flow of bile from the liver, leading to cholestasis. This can cause a range of symptoms, including:

• Jaundice: Yellowing of the skin and eyes [2]
• Pruritis: Itching sensation due to bile buildup in the skin [3]
• White-colored stool: Due to lack of bile pigmentation [2]
• Dark brown urine: As a result of bilirubin buildup [2]

In addition, affected infants may experience:

• Failure to gain weight and grow at the expected rate (failure to thrive) [4][5]
• Hepatomegaly: Enlargement of the liver [6]
• Fat and fat-soluble vitamin malabsorption: Due to impaired bile production [6]

If left untreated, symptoms can progress to include:

• An enlarged liver (hepatomegaly)
• An enlarged spleen (splenomegaly)
• Diarrhoea
• Clay-colored stools
• Fat in the stools [9]

Diagnostic Tests for Congenital Bile Acid Synthesis Defect 5

Congenital bile acid synthesis defect 5 (CBASD5) is a rare genetic disorder that affects the production of bile acids in the liver. Diagnostic tests are essential to confirm the diagnosis and rule out other conditions.

• Sequence analysis: This test involves analyzing the entire coding region of the ABCD3 gene, which is associated with CBASD5. Sequence analysis can detect mutations or deletions in the gene that cause the condition (Source: [4], [11]).
• Next-Generation Sequencing (NGS): NGS is a comprehensive genetic testing approach that can identify mutations in multiple genes, including ABCD3. This test is often used as a reflex test after initial screening tests (Source: [2], [6]).
• Deletion/Duplication Analysis: This test specifically looks for deletions or duplications of the ABCD3 gene, which are associated with CBASD5 (Source: [5], [10]).

Other Relevant Information

• The impaired production and release of bile acids in CBASD5 can lead to cholestasis, a condition characterized by the buildup of bile in the liver. Liver function tests may show elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT (Source: [8]).
• Early diagnosis is crucial to avoid the progression to end-stage liver disease or liver transplantation (Source: [14]).

References

[2] Our molecular genetics lab offers next-generation gene sequencing for bile acid synthesis defects (1, 2 & 3). Learn more about this genetic panel. [4] Clinical Genetic Test offered by Intergen for conditions (1): Congenital bile acid synthesis defect 5; Testing genes (1): ABCD3 (1p21.3); [5] Genetic tests related with Bile Acid Synthesis Defect, Congenital, 5; 1, ABCD3 Deletion/duplication analysis · Congenital bile acid synthesis defect 5; 2, ABCD3 [6] Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based ... [8] In most cases, pruritus is absent. Liver function tests present elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT. [10] Abnormality of the digestive system (HP:0025031) [11] Clinical Genetic Test offered by Intergen for conditions (1): Congenital bile acid synthesis defect 5; Testing genes (1): ABCD3 (1p21.3); [14] normal primary bile acids. Early diagnosis is important to avoid the progression to end-stage liver disease, or liver transplantation. Primary bile acid therapy with oral cholic acid was recently approved by the FDA for the treatment of bile acid synthetic disorders.

Treatment Options for Congenital Bile Acid Synthesis Defect 5

Congenital bile acid synthesis defects are rare genetic disorders characterized by defects in the creation (synthesis) of bile acids. One such defect is type 5, which affects the production of bile acids.

• Ursodeoxycholic acid replacement therapy: According to a study published in [3], ursodeoxycholic acid replacement therapy has been shown to be an effective treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency. While the specific effectiveness of this treatment for type 5 defect is not mentioned, it may still be considered as a potential option.
• Cholic acid replacement therapy: Another study published in [6] suggests that oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects. This treatment approach may also be applicable to congenital bile acid synthesis defect 5, although specific studies on this topic are not available.
• Cholic acid: According to [9], cholic acid has been approved as a drug for the treatment of bile acid synthesis disorders due to single enzyme defects. It is possible that cholic acid may also be effective in treating congenital bile acid synthesis defect 5, although further research is needed to confirm this.

Other Treatment Considerations

• Dietary restriction: In addition to pharmacological treatments, dietary restrictions may also play a role in managing congenital bile acid synthesis defect 5. According to [7], dietary restriction of phytanic and pristanic acids may be necessary to prevent progression of the disease.
• Bile acid replacement therapy: As mentioned earlier, bile acid replacement therapy with cholic acid has been shown to be effective in treating primary bile acid synthesis defects. This treatment approach may also be applicable to congenital bile acid synthesis defect 5.

Conclusion

While specific studies on the treatment of congenital bile acid synthesis defect 5 are not available, various treatment options may still be considered based on related research. These include ursodeoxycholic acid replacement therapy, cholic acid replacement therapy, and dietary restriction. Further research is needed to confirm the effectiveness of these treatments for type 5 defect.

References:

[3] by W Mo · 2022 — Ursodeoxycholic acid replacement therapy is an effective and affordable treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α- ...

[6] by E Gonzales · 2018 · Cited by 51 — Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe ...

[7] Transmission is autosomal recessive. Treatment is based on primary bile acid therapy with cholic acid. Dietary restriction of phytanic and pristanic acids is ...

[9] May 3, 2021 — In most cases, patients respond to treatment with missing bile acid replacement therapy. In particular, cholic acid has been approved as a drug ...

The differential diagnosis for congenital bile acid synthesis defect 5 involves considering various conditions that present similar symptoms and characteristics.

According to the available information, diseases that have a similar and fairly overlapping phenotype to that of congenital defects in bile acid synthesis should be considered in the differential diagnosis [4]. This includes progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which can also lead to liver disease.

In addition, other conditions such as galactosemia or rare inborn errors of bile acids synthesis may also need to be ruled out through a timely diagnosis and specific treatment [12].

It's worth noting that the clinical presentations of congenital bile acid synthesis defects can be similar to those of other causes of neonatal liver failure, neonatal cholestasis, and chronic liver disease. Therefore, a high index of suspicion is required to prevent the diagnosis being overlooked [15].