Bile acid synthesis disorders (BASDs) are a group of rare metabolic disorders characterized by defects in the creation (synthesis) of bile acids. Bile acids are chemical compounds found in the liver that have several roles in the body including promoting the flow and excretion of bile and assisting in the intestinal absorption of fat and fat-soluble vitamins. Bile acids are formed from cholesterol and, therefore, bile acid synthesis serves as the main pathway in breaking down and eliminating cholesterol from the body (cholesterol degradation). The failure to produce normal or functional bile acids results in the accumulation of abnormal bile acids and other substances that normal would be broken down (intermediary metabolites) within the body. The resulting accumulation of abnormal bile acids, intermediary metabolites and cholesterol in the body can damage certain organ systems. The main symptom of most (but not all) BASDs is interruption or suppression of the flow of bile from the liver (cholestasis) and fat-soluble vitamin malabsorption. Additional symptoms such as progressive neurological disease may develop in certain cases and can occur in the absence of liver disease. In many cases, symptoms or signs are present at birth or during the newborn period. If untreated, the more severe forms of these disorders can eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure. Many of these disorders can be successfully treated by replacing the missing bile acids (bile acid replacement therapy). BASDs are caused by mutations in specific genes; most of these mutations are inherited as autosomal recessive traits.
Disorders of bile acid synthesis can be broadly classified as primary or secondary. Primary BASDs involve congenital deficiencies in enzymes required for bringing about chemical reactions (catalyzing) necessary to synthesize the two main bile acids known as cholic acid and chenodeoxycholic acid. Secondary disorders include disorders that are involved in the transport of bile acids such as low gamma-GT familial intrahepatic cholestasis and MDR3 deficiency (known collectively as primary familial intrahepatic cholestasis), Smith-Lemli-Optiz syndrome, which impairs the supply of cholesterol in the body, and Zellweger spectrum disorders, which are classified as peroxisomal disorders, but are involved in bile acid synthesis as well. This report only covers certain primary bile acid synthesis disorders. NORD has individual reports on the secondary types. For more information, choose the specific disorder name as your search term in the Rare Disease Database.
Although researchers have been able to establish clear syndromes with characteristic or “core” symptoms, much about bile acid synthesis disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing these disorders prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The age of onset, specific symptoms, and rate of progression can vary greatly from one individual to another depending, in part, on the specific underlying defect. Although BASDs are usually detected in newborns or infants, milder forms of these disorders with later onset exist including cases with onset during adulthood.
Cholestasis in these disorders is intrahepatic, which means it occurs due to defects in the bile ducts within the liver rather than in the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs. Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).
Some of the symptoms of cholestasis result from impairment of the digestive system to properly absorb fat, fat-soluble vitamins, and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and can result is various symptoms including rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and development delays (vitamin E deficiency), and blood clotting problems leading to easy bleeding and bruising (vitamin K deficiency).
In some cases, progressive neurological disease has been described that develops later during childhood or during adulthood. Vitamin E deficiency from undiagnosed liver disease may contribute to neurological disease. In other cases, the cause of neurological disease may be different. For example, in CTX neurological disease results from the accumulation or storage of cholesterol-like, fatty substances in nerve cells and the brain.
In some cases, without treatment liver abnormalities can progress to cause serious life-threatening complications such as the formation of fibrous, scar tissue (fibrosis) and liver regeneration with scarring (cirrhosis), high blood pressure of the main vein of the liver (portal hypertension), and abnormal fluid retention and swelling in the abdomen (ascites). Eventually, liver disease can progress to cause liver failure.
3-BETA-HYDROXY-DELTA-5-C27-STEROID OXIDOREDUCTASE DEFICIENCY
This disorder is sometimes referred to as 3HSD deficiency or bile acid synthesis defect 1. It is believed to be the most common form of BASDs. The clinical picture of this disorder can vary greatly. Generally, affected individuals will develop cholestasis and fat-soluble vitamin malabsorption (and various abnormalities secondary to vitamin deficiency) during infancy. If untreated, progressive liver disease occurs.
In recent years, cases of idiopathic cholestasis that develop during adulthood (late onset liver disease) have been attributed to 3beta-dehydrogenase deficiency. Some of these individuals presented with jaundice during infancy, but improved and were not diagnosed with 3beta-dehydrogenase deficiency until later during life.
DELTA4 3-OXOSTEROID 5BETA REDUCTASE DEFICIENCY
This disorder is sometimes referred to as 5beta-reductase deficiency or bile acid synthesis defect 2. The clinical picture of this disorder is similar to that of 3beta-dehyddrogenase deficiency, but generally is more severe and, if untreated, can rapidly progress to cirrhosis and liver failure. 5beta-reductase deficiency can present as neonatal cholestasis or as liver failure that resembles liver disease seen in neonatal hemochromatosis (for more information, choose “neonatal hemochromatosis” as your search term in the Rare Disease Database.)
OXYSTEROL 7-ALPHA-HYDROXYLASE DEFICIENCY
This disorder is sometimes referred to as bile acid synthesis defect 3. Only a few cases have been reported in the medical literature. Affected infants have exhibited severe neonatal cholestasis, disease affecting the blood’s ability to clot (coagulopathy), hepatosplenomegaly, and, if untreated, cirrhosis and liver failure early in life. Researchers speculate that due to the severity most cases of this disorder prove fatal before birth or shortly after birth.
ALPHA-METHYLACYL-COA RACEMASE (AMACR) DEFICIENCY
This disorder is sometimes referred to as 2-methylacyl-CoA racemase deficiency or bile acid synthesis defect 4. The disorder was first reported in three adults presenting with sensory motor neuropathy, a condition in which there is disease of the peripheral nerves (those outside the central nervous system) that control response to pain and temperature and muscle coordination. Sensory motor neuropathy may cause abnormal sensations such as numbness or a feeling of pins and needles in the arms and legs, weakness of the muscles, and problems with balance and coordination. Adults with this disorder may lack symptoms (asymptomatic) until sensory motor neuropathy develops or they may have mild liver disease during childhood. It is not known if asymptomatic adults who develop neurological disease had mild, undiagnosed liver disease that led to fat-soluble vitamin deficiency that eventually caused the neurological findings. This disorder has also been reported in infants who present with severe fat and fat-soluble vitamin deficiencies and mild cholestasis. Fewer than 10 cases have been reported in the medical literature
STEROL 27-HYDROXYLASE DEFICIENCY (CEREBROTENDINOUS XANTHOMATOSIS)
This disorder is also known as cerebrotendinous xanthomatosis (CTX). CTX is highly variable and is associated with a wide range of potential abnormalities. Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease. It is now know that CTX can present in childhood with cholestatic liver disease that can be severe or can be mild and resolve on its own in individuals who may later develop other complications of the disorder such as neurological disease.
In CTX, cholestanol deposits accumulate in nerve cells and membranes, causing damage to the brain, spinal cord, tendons, lens of the eyes and arteries. Affected individuals may develop cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, progressive neurological problems develop in adulthood potentially causing paralysis, ataxia, and dementia. Coronary heart disease is also common. Many individuals with the adult symptoms of CTX experienced prolonged cholestatic jaundice during infancy.
NORD has an individual report on CTX. For more information, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.
TRIHYDROXYCHOLESTANIC ACID (THCA) COA OXIDASE DEFICIENCY
This form has been reported in several individuals and is characterized primarily by neurological findings including ataxia, which often became apparent by 3 and half years of age. Liver disease has not been described in this form of BSAD.
CHOLESTEROL 7ALPHA-HYDROXYLASE DEFICIENCY
This form of BASD is distinct from most other forms because liver disease is usually absent. Affected individuals often develop markedly elevated levels of total and low-density lipoproteins (LDL), premature gallstones, and premature coronary and peripheral vascular disease.
The final step in bile acid synthesis involves the joining together (conjugation) of two amino acids, glycine and taurine. Disorders involving this step are known as “defective bile acid amidation due to failure to conjugate with glycine and/or taurine” or more simply amidation defects. Two disorders in this subcategory have been identified.
Bile Acid CoA Ligase Deficiency
This disorder is characterized by neonatal cholestasis, fat and fat-soluble vitamin malabsorption and growth failure. Fewer than 10 cases have been reported in the medical literature.
Amino Acid N-Acyltransferase Deficiency
This disorder was initially described in several individuals within a large Amish kindred. Affected individuals developed pruritus, variable growth deficiency, and fat malabsorption (familial hypercholanemia). More recently a report has appeared that included description of 10 affected patients with only one from an Amish kindred. The presentation was quite varied in this case series with one family member having liver failure in infancy; however, most patients presented with poor growth and fat soluble vitamin deficiencies.
Bile acid synthesis disorders are caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In all known BASDs, these mutations are believed to be inherited as autosomal recessive traits.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Bile acid synthesis disorders result from improper synthesis of bile acids, particularly the two primary bile acids cholic acid and chenodeoxycholic acid. The principle bile acids are synthesized by the liver through a series of complex chemical reactions involving at least 17 enzymatic steps. These reactions mainly occur within specialized liver cells known as hepatocytes. Each “step” requires a corresponding specialized protein known as an enzyme. Each gene associated with a bile acid disorder creates (encodes) a specific enzyme. When a gene that encodes a bile acid enzyme is mutated, it leads to low levels of functional versions of the corresponding enzyme. When one enzyme in the process is absent or deficient, it leads to diminished production of bile and potentially a bile acid synthesis disorder.
One of the main functions of bile acids is to promote the flow of bile. Abnormal bile acid formation results in improper or hampered bile flow. Bile is created in the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.
3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency is caused by mutations of the HSD3B7 gene on short arm of chromosome 16 (16p11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
Delta4-3-oxosteroid 5-beta-reductase deficiency is caused by mutations in the AKR1D1 gene located on the long arm of chromosome 7 (7q33).
Cholesterol 7alpha-hydroxylase deficiency is caused by mutations in the CYP7A1 gene located on the long arm of chromosome 8 (8q12.1).
Oxysterol 7-alpha-hydroxylase deficiency is caused by mutations in the CYP7B1 gene located on the long arm of chromosome 8 (8q12.3).
Alpha-methylacyl-CoA racemase deficiency is caused by mutations in the AMACR gene located on the short arm of chromosome 5 (5p13.2).
Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) is caused by mutations in the CYP27A1 gene located on the long arm of chromosome 2 (2q35).
Amino acid n-acyltransferase deficiency is caused by mutations in the BAAT gene located on the long arm of chromosome 9 (9q31.1).
Bile acid CoA ligase deficiency is caused by mutations in the SLC27A5 gene located on the long arm of chromosome 19 (19q13.43).
Bile acid synthesis disorders affect males and females in equal numbers. Individuals of any race or ethnic group can be affected. The incidence and prevalence of BASDs are unknown. These disorders have been estimated to account for as many as 1-2% of all childhood cholestatic disorders. However, many cases go undiagnosed or misdiagnosed making it difficult to determine their true frequency in the general population. CTX has an estimated prevalence of 1 in 70,000 individuals in the general population. It is estimated that BASDs have prevalence of 1 in 50,000 in the general population.
A diagnosis of a bile acid synthesis disorder should be suspected in infants or young children who have jaundice, other symptoms of cholestatic liver disease with an unknown cause, or fat soluble vitamin deficiency and growth failure. The identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation can support a suspected diagnosis. However, symptoms of BASDs overlap with numerous other liver disorders. Confirmation of a BASD requires examination by tests performed at or assessed by specialized diagnostic laboratories.
Early detection and prompt diagnosis of BASDs is extremely important as many individuals who show a dramatic response to oral bile acid replacement therapy.
Clinical Testing and Workup
Certain examinations such as a specific serologic tests and a liver biopsy may be performed to rule out more common causes of cholestasis. For example, serum evaluation of an enzyme known as gamma glutamyl transpeptidase (GGT) can help to identify the cause of cholestasis. This enzyme is often markedly elevated in individuals with cholestasis caused by an underlying liver disease. However, in individuals with BASD and related disorders levels of GGT are normal or low. A liver biopsy involves the surgical removal and microscopic examination of a piece of liver tissue. A liver biopsy can provide important clues to the underlying cause of cholestasis.
If more common causes of cholestasis are ruled out, laboratory analysis of certain body fluids (e.g. bile, blood and urine) is necessary. Specialized techniques known as fast atom bombardment-mass spectrometry (FABS-MS), electrospray ionization mass spectrometry (ESI-MS), and gas chromatography-mass spectrometry (GC-MS) may be used. For the most part, these tests are only available at certain laboratories. For more information on laboratories that can process these tests, contact the Council for Bile Acid Deficiency Diseases listed in the Resources section of this report.
Mass spectrometry involves creating charged particles (ions) from molecules. These ions can be analyzed to provide information about molecular weight and chemical structure. Each molecule has a unique weight, which is referred to as its mass. A specialized instrument called a spectrometer allows physicians to collect, sort and study these molecules differentiating them by their unique masses. In an individual suspected of having a BASD, a urine sample is used.
In FABS-MS, the sample is placed in the spectrometer and is bombarded with an energetic beam of inert gas atoms such as Xenon or Argon. Physicians are able to tell how much of a specific compound is in a sample. The turnaround time for this procedure can sometimes be slow.
ESI-MS is similar a procedure. However, this techniques produces multiple charged ions and particularly useful for thermally labile, high molecular mass substances. This procedure is relatively simple and the turnaround rapid.
In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. GC-MS can be a time-consuming technique.
Molecular genetic testing can confirm a diagnosis of a BASD in some cases. Molecular genetic testing can detect mutations in specific genes known to cause specific BASDs, but is available only as a diagnostic service at specialized laboratories. For more information of laboratories that provide molecular genetic testing for BSADs, contact the Council for Bile Acid Deficiency Diseases listed in the Resources section of this report.
The treatment of BASDs is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, liver specialists (hepatologists), nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with BASDs.
Although treatment trials may be lacking, many affected individuals have dramatically responded to treatment by restoring one of the missing primary bile acids to the body (bile acid replacement therapy). This therapy involves the oral administration one of the two primary bile acids, cholic acid or chenodeoxycholic acid. Replacement of the missing bile acids has led to improvement or normalization of liver function in individuals with specific types of BASDs.
Cholic acid can be prescribed under a treatment use of investigational drugs or a “treatment IND.” A treatment IND allows the use of a drug for a patient or group of patients in whom that drug has not been approved by the Food and Drug Administration (FDA). Cholic acid replacement therapy has proven beneficial in treating individuals with 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency; delta4-3-oxosteroid 5-beta-reductase deficiency; and alpha-methylacyl-CoA racemase deficiency. Most affected individuals experience a correction of all liver functions over a period of several weeks or months.
Cholic acid replacement therapy is not used for amidation defects because these individuals do not lack cholic acid. These two disorders can be treated with the bile acid, glycocholic acid, which is also available under a treatment IND from the FDA. This therapy has proven effective in treating individuals with amino acid n-acyltransferase deficiency and bile acid CoA ligase deficiency.
Cholic acid replacement therapy is not effective for the treatment of oxysterol 7-alpha-hydroxylase deficiency. Ursodeoxycholic acid worsened the condition. Two infants reported in the medical literature were successfully treated by a liver transplant and one with chenodeoxycholic acid.
Chenodeoxycholic and cholic acid have been used to treat individuals with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). This therapy has led to significant improvement in affected individuals. It tends to be most effective when given in conjunction with a drug that inhibits HMG-CoA reductase, an enzyme that plays a role the creation (biosynthesis) of cholesterol in the liver. There are concerns that treatment with an HMG-CoA reductase inhibitor could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX.
Ursodeoxycholic acid has provided short-term benefit to some individuals with BSADs. However, its long-term benefit is limited because it cannot compensate for the basic underlying defects and ultimately affected individuals experience continued formation of abnormal bile acids and toxic metabolites.
Treatment of BASDs is also symptomatic and supportive. For example, supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E, and K.
Individuals who do not respond to other treatment options may ultimately require a liver transplant. A liver transplant carries risk and may result in post-operative complications. After a liver transplant, affected individuals are required to take medication for the rest of their lives for immunosuppression to prevent rejection.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Heubi JE. Bile Acid Physiology and Alterations in the Enterohepatic Circulation. In: Pediatric Gastrointestinal and Liver Disease, 4th edition. Wyllie R, Hymans J, Kay M, editors. 2011 Elsevier Saunders, Philadelphia, PA. Pp. 20-27.
Setchell KDR, O’Connell NC. Disorders of Bile Acid Synthesis and Metabolism. In: Liver Disease in Children, 3rd edition. Suchy FJ, Sokol RJ, Balistreri WJ, editors. 2007 Cambridge University Press, New York, NY. Pp. 736-766.
Setchell KD, Heubi JE, Shah S, et al. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology. 2013;144:945-955. http://www.ncbi.nlm.nih.gov/pubmed/23415802
Haas D, Gan-Schreier H, Langhans CD, et al. Differential diagnosis in patients with suspected bile acid synthesis defects. World J Gastroenterol. 2012;18:1067-1076. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296980/
Hadzic N, Bull LN, Clayton PT, Knisely AS. Diagnosis in bile acid-CoA: amino acid N-acyltransferase deficiency. World J Gastroenterol. 2012;18:3322-3326. http://www.ncbi.nlm.nih.gov/pubmed/22783059
Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis. 2011;34:593-604. http://www.ncbi.nlm.nih.gov/pubmed/21229319
Mizuochi T, Kimura A, Suzuki M, et al. Successful heterozygous living donor liver transplantation for an oxysterol 7alpha-hydroxylase deficiency in a Japanese patient. Liver Transpl. 2011;17:1059-1065. http://www.ncbi.nlm.nih.gov/pubmed/21567895
Monte MJ, Marin JJG, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol. 2009;15:804-816. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653380/#!po=18.3333
Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009;137:1310-1320. http://www.ncbi.nlm.nih.gov/pubmed/19622360
Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:456-468. http://www.ncbi.nlm.nih.gov/pubmed/18577977
Balistreri WF. Inherited disorders of bile acid transport and or synthesis. Gastroenterol Hepatol. 2007;3:343-345. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099314/
Heubi JE, Setchell KD, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27:282-284. http://www.ncbi.nlm.nih.gov/pubmed/17682975
Fischler B, Bodin K, Stjernman H, et al. Cholestatic liver disease in adults may be due to an inherited defect in bile acid biosynthesis. J Intern Med. 2007;262:254-262. http://www.ncbi.nlm.nih.gov/pubmed/17645593
Setchell KD, Heubi JE. Defects in bile acid biosynthesis – diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006;43:S17-22. http://www.ncbi.nlm.nih.gov/pubmed/16819396
Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthesis defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315-334. http://www.ncbi.nlm.nih.gov/pubmed/15383928
Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7 alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest. 2002;110:109-117. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151029/
Heubi J. Bile Acid Synthesis Defects. Orphanet Encyclopedia, January 2011. Available at: http://www.orpha.net/ Accessed on: January 9, 2014.
Federico A, Dotti MT, Gallus GN. Cerebrotendinous Xanthomatosis. 2003 Jul 16 [Updated 2013 Aug 1]. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1409/ Accessed on: January 9, 2014.