Congenital defects of bile acid synthesis

Panel testing recommended at Breda Genetics for this condition:

Congenital bile acid synthesis defect (ABCD3, ACOX2, AKR1D1, AMACR, CYP7B1, HSD3B7)


Congenital defects of bile acid synthesis (BASD) are a group of rare metabolic disorders due to a primary defect in the production of bile acids and are part of the class of progressive liver diseases. Bile acids are substances produced by the liver, starting from cholesterol, which play a key role in digestion and absorption of fats and fat-soluble vitamins. In association with the accumulation of intermediate metabolites and cholesterol, their lack of production can damage various organs. Clinically, BASDs generally manifest with intrahepatic cholestasis and malabsorption of fat and fat-soluble vitamins. However, they are characterized by phenotypic heterogeneity (age of onset, symptoms, severity…). Often, patients with these pathologies respond to replacement therapies with the missing bile acid.

Detailed clinical description

BASDs are progressive liver diseases characterized by intrahepatic cholestasis and malabsorption of fat and fat-soluble vitamins. They manifest with jaundice, poor growth and malnutrition. The onset is generally neonatal/infantile, but some milder forms can be identified later, in adulthood. Hepatomegaly with or without splenomegaly and moderate steatorrhea may also be present. Itching is usually absent.

The inability to assimilate vitamins can give rise to numerous consequences such as rickets (fragile bones), vision problems, developmental delay and secondary coagulopathies. Neurological signs such as axonal dystrophy may also rarely be present.

Without treatment, liver damage progresses variably over time. Patients can experience liver inflammation, fibrosis, and cirrhosis. In the most severe cases, patients may develop liver failure and require liver transplantation.

Biochemical tests for liver function show an increase in liver enzymes (transaminases, AST and ALT) and in conjugated bilirubin, in the presence of normal gamma-GT values ​​and normal or low serum total bile acid levels.

The diagnosis of BASD is based on the analysis of the urine bile acids profile obtained through mass spectrometry and on the identification of pathogenic mutations in the associated genes.

In most cases, patients respond to treatment with missing bile acid replacement therapy. In particular, cholic acid has been approved as a drug for the treatment of pediatric and adult patients suffering from a congenital defect in the synthesis of bile acids. This treatment is able to reduce biochemical abnormalities and prevent disease progression. It has also been shown that early treatment has an excellent long-term prognosis.


The prevalence of each of the currently known forms of BASD is unknown; however, it is estimated that overall, BASDs have a prevalence of about 1-9/1,000,000.

Molecular genetics

BASDs are inherited in an autosomal recessive way and manifest genetic heterogeneity. The genes involved encode enzymes that take part in the process of bile acid synthesis. Most patients have mutations in HSD3B7 and AKR1D1 genes that cause congenital defect of bile acid synthesis 1 and congenital defect of bile acid synthesis 2, respectively. More rarely, ACOX2, AMACR, CYP7B1 may also be mutated, respectively causing the congenital defect of bile acid synthesis of type 6, type 4 and type 3. Finally, there is evidence that mutations in ABCD3 cause the congenital defect of type 5 bile acid synthesis, but only one family has been described in the literature and phenotypic association is not confirmed.

Differential diagnosis

Diseases that have a similar and fairly overlapping phenotype to that of congenital defects in bile acid synthesis include:

Progressive familial intrahepatic cholestasis, which is a group of diseases characterized by early onset cholestasis, which evolves over time to fibrosis and cirrhosis. These diseases are mainly autosomal recessive and are due to mutations in the genes ATP8B1, ABCB11, ABCB4, TJP2 and NR1H4.

Metabolic disorders that cause neonatal hepatitis such as alpha-1-antitrypsin deficiency (ZZ phenotype) due to mutations in the SERPINA1 gene, Alagille syndrome due to mutations in the JAG1 and NOTCH2 genes, familial hypercholanemia due to mutations in the TJP2 genes, BAAT and SLC10A1, cystic fibrosis (CFTR), and other metabolic diseases such as galactosemia (GALT gene), type I tyrosinemia (FAH gene), hereditary fructose intolerance (ALDOB gene).

Biliary atresia which is characterized by the alteration of the extrahepatic bile transport system. This condition leads to jaundice, hepatomegaly, fibrosis and cirrhosis. Generally these patients have elevated GGT levels.

Defects of peroxisome biogenesis (spectrum of Zellweger syndrome) which include a group of rare diseases characterized by neuronal migration defects in the brain, craniofacial dysmorphism, profound hypotonia, neonatal seizures and liver dysfunction. The phenotype is highly variable and can range from severe neonatal forms to milder forms that are identified in adulthood.

Genetic testing strategy

Considering the clinical overlap between the various forms of congenital defect of bile acid synthesis, it is recommended to proceed with next generation sequencing panel testing that includes all the genes associated with these diseases. Breda Genetics offers the analysis of genes for congenital defects of bile acid synthesis through whole exome or whole genome-based multi-gene panels sequencing. Furthermore, in the event of a negative result, it is possible to proceed with the analysis of large deletion/duplications on the genes of interest, even if so far they have not been reported in the literature.

Panel testing recommended at Breda Genetics for this condition:

Congenital bile acid synthesis defect (ABCD3, ACOX2, AKR1D1, AMACR, CYP7B1, HSD3B7)


Gonzales E, Matarazzo L, Franchi-Abella S, Dabadie A, Cohen J, Habes D, Hillaire S, Guettier C, Taburet AM, Myara A, Jacquemin E. Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood. Orphanet J Rare Dis. 2018 Oct 29;13(1):190. doi: 10.1186/s13023-018-0920-5. PMID: 30373615.

Jahnel J, Zöhrer E, Fischler B, D’Antiga L, Debray D, Dezsofi A, Haas D, Hadzic N, Jacquemin E, Lamireau T, Maggiore G, McKiernan PJ, Calvo PL, Verkade HJ, Hierro L, McLin V, Baumann U, Gonzales E. Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis: Results of a European Survey. J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):864-868. doi: 10.1097/MPG.0000000000001546. PMID: 28267072.

Haas D, Gan-Schreier H, Langhans CD, Rohrer T, Engelmann G, Heverin M, Russell DW, Clayton PT, Hoffmann GF, Okun JG. Differential diagnosis in patients with suspected bile acid synthesis defects. World J Gastroenterol. 2012 Mar 14;18(10):1067-76. doi: 10.3748/wjg.v18.i10.1067. PMID: 22416181.

OMIM Phenotypic Series – PS607765

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