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NORD is very grateful to Andrea DeBarber, PhD, Research Assistant Professor, Physiology & Pharmacology Department, Oregon Health & Science University, for assistance in the preparation of this report.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene, resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodeoxycholic acid. Deposits of cholesterol and cholestanol (a derivative of cholesterol) accumulate in the nerve cells and membranes potentially causing damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals can experience diarrhea and cataracts in childhood and may develop benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, CTX can lead to progressive neurologic problems in young adulthood such as seizures, ataxia and dementia. Coronary heart disease is common. Some individuals with the adult symptoms of CTX experienced prolonged cholestatic jaundice during infancy. The specific symptoms and progression of this disorder can vary greatly from one individual to another. Long-term therapy with chenodeoxycholic acid has been effective in treating affected individuals.
CTX was first described in the medical literature in1937. CTX is classified as a bile acid synthesis disorder (due to the underlying genetic mutation that causes deficiency in an important enzyme in the bile acid synthesis pathway; sterol 27-hydroxylase). Bile acids (chenodeoxycholic and cholic acid) are synthesized in the liver. They are an important component of bile and help the intestine to absorb fats. The disorder can also be classified as a lipid storage disorder (due to fat deposition in various tissues of the body) or a leukodystrophy (due to the involvement of central nervous system white matter).
The presentation of 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 known that CTX can occasionally 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. Cholestatic liver disease refers to the interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis 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.
Generally, systemic symptoms develop earlier than neurologic symptoms. The first symptom may be chronic diarrhea in infancy. Diarrhea is often resistant to treatment (intractable). Cataracts in the first decade of life are the first symptom in about 75% of those affected. Tendinous xanthomas (fatty tumors) appear in the second or third decade and can be located on the Achilles tendon, extensor tendons of the elbows and hands, and the knees.
Most affected individuals experience a decline in mental function beginning at puberty, but some show impairment beginning in childhood. Cognitive impairment can be mild to severe but becomes progressively worse without treatment. The mean age of diagnosis is around 35-37 years old at which time neurological involvement has often become significant and characteristic of CTX. Seizures have also been reported. Psychiatric abnormalities including behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies can also occur, although specific expression varies greatly. Increased muscle tone and stiffness (spasticity) almost always occurs. In some cases, additional neurologic findings may occur including impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain’s cerebellum (cerebellar ataxia); symptoms that resemble Parkinson disease (atypical parkinsonism); and dystonia, which is a general term for a large group of movement disorders that vary in their symptoms, causes, progression, and treatments. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). As the disorder progresses affected individuals can become incapacitated with motor dysfunction, and affected individuals may die prematurely due to advancing neurological deterioration.
Cardiovascular disease has been reported in individuals with CTX, although the exact prevalence of this finding is unknown. Hardening of the arteries (atherosclerosis) and coronary heart disease may occur. Additional symptoms that have been reported include underactivity of the thyroid (hypothyroidism) and skeletal abnormalities such as porous, brittle bones (osteoporosis) and a higher incidence of bone fractures.
CTX is caused by mutations in the CYP27A1 gene located on the long arm (q) of chromosome 2 (2q35). 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 or enzyme may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In CTX, the gene mutation is inherited in an autosomal recessive manner.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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.
Mutations in the CYP27A1 gene result in deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into the bile acid chenodeoxycholic acid. The block in synthesis of this bile acid causes accumulation of bile acid precursors in blood and tissues of affected individuals, in particular 7?-hydroxy-4-cholesten-3-one and 7?,12? dihydroxy-4-cholesten-3-one. The most damaging consequence of sterol 27-hydroxylase deficiency is thought to be accumulation in blood and tissues of cholestanol, formed in a pathway from 7?-hydroxy-4-cholesten-3-one. Cholestanol deposits accumulate in nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries.
The prevalence of CTX is not known, but, based on a 1:115 carrier frequency determined for the deleterious c.1183C>T mutation, the prevalence of CTX due only to this mutation is estimated at around 1:52,000 individuals in the general population. Despite this observation only around three hundred cases of CTX have been described worldwide. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the true frequency in the general population. Affected individuals have been reported in the USA, Israel, Italy, Japan, the Netherlands, Belgium, Brazil, Canada, France, Iran, Norway, Tunisia, Spain, China and Sweden. Populations with a higher prevalence of CTX exist, for example in an isolated Israeli Druze community a carrier frequency of 1:11 for the deleterious c.355delC mutation was determined, leading to an estimated prevalence of CTX at 1:440 individuals.
Symptoms of the following disorders can be similar to those of CTX. Comparisons may be useful for a differential diagnosis.
Sitosterolemia is a rare autosomal recessive genetic condition caused by an abnormality in the ABCG8 gene or the ABCG5 gene, resulting in an accumulation of cholesterol and other types of lipids called sterols in body tissues. Symptoms include clusters of fatty tumors in the skin of joints (tuberous xanthomas), on the tendons (tendon xanthomas), plaque deposits in the arteries (atherosclerosis), and coronary artery disease. Joint stiffness and pain can develop. In some cases affected individuals may have low levels of circulating red blood cells due to the premature destruction of red blood cells (hemolytic anemia).
Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. Additional symptoms include the formation of fatty tumors of the tendons (tendinous xanthomas), cholesterol deposits on the eyelids (xanthelasmas), and a curved appearance of the corneas of the eyes (corneal arcus). (For more information on this disorder, choose "hypercholesterolemia" as your search term in the Rare Disease Database.)
CTX is diagnosed based on a thorough clinical evaluation, a detailed patient and family history, identification of characteristic findings, and a variety of specialized tests including genetic testing and biochemical tests on blood and urine.
Molecular genetic testing can confirm a diagnosis of CTX by detecting mutations in the CYP27A1 gene known to cause the disorder. However, molecular genetic testing is available only as a diagnostic service at specialized laboratories. This type of testing can confirm the presence of mutations that have already been described in the literature to cause CTX. Sometimes novel (unknown) mutations are uncovered by genetic testing and in these cases biochemical testing will confirm the biochemical defect is present.
Certain specialized laboratories can conduct analysis to detect biochemical features that are indicative of CTX. Due to the nature of the biochemical defect, the cholestanol concentration in blood (or plasma derived from blood) and in tissues is high, the plasma cholesterol concentration is normal to low, the plasma bile acid precursor concentration is high, and the concentration of bile alcohols in bile, urine and plasma is increased. Some cholic acid can be synthesized in CTX through bile alcohols formed by microsomal hydroxylation. Due to deficient mitochondrial sterol 27-hydroxylase activity there is a markedly decreased formation of chenodeoxycholic acid.
Biochemical testing to measure plasma cholestanol is usually done through a procedure known as gas chromatography-mass spectrometry (GC-MS). 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. Complex sample preparation and a lengthy analysis time make GC-MS testing a time-consuming technique.
CTX is a candidate disorder to screen for in newborns. A faster testing technique than GC-MS is required to screen newborn dried bloodspots for CTX, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS). Researchers have developed an LC-MS/MS test for CTX with potential to screen newborn dried bloodspots for the disorder. The LC-MS/MS test measures blood 7?,12? dihydroxy-4-cholesten-3-one, a bile acid precursor that accumulates in CTX.
LC-MS/MS measurement of bile acid precursors may also be useful to discriminate between negative and CTX positive plasma samples, especially diagnostically challenging CTX positive samples with relatively low cholestanol concentrations. The LC-MS/MS test, with simple sample preparation and a rapid analysis time, can be performed by most laboratories, which can potentially provide wide availability of testing for CTX.
In some cases, specialized imaging techniques may include computerized tomography (CT) scanning of the head and magnetic resonance imaging (MRI) of the brain may assist in assessing disease progression in individuals suspected of CTX. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. These tests may show cerebellar lesions and white matter damage in individuals with CTX.
Because oral bile acid replacement therapy can halt disease progression or prevent symptoms from occurring in asymptomatic individuals, early diagnosis of CTX is extremely important to prevent disease complications. Successful long-term treatment of a number of affected individuals identified as children has been reported in the literature.
Treatment with chenodeoxycholic acid normalizes the production of cholestanol. The efficacy of treatment with chenodeoxycholic acid can be monitored with GC-MS testing to confirm a decrease in blood cholestanol. Treatment can prevent symptoms in asymptomatic individuals and stop the progression of disease symptoms in affected individuals. After significant disease progression, treatment does not readily reverse neurological deficits that have already occurred.
It may be effective to give a drug that inhibits HMG-CoA reductase, (an enzyme that plays a role in the creation of cholesterol in the liver) in conjunction with chenodeoxycholic acid. There are concerns that treatment with HMG-CoA reductase inhibitors (better known as statins) could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX. HMG-CoA reductase inhibitors can also cause muscle damage.
In October 2009, the U.S. Food and Drug Administration (FDA) re-approved an artificially made (synthetic) form of chenodeoxycholic acid known as Chenodal® as a treatment for gallstones. However, this drug is also used as a first-line therapy to treat individuals with CTX. Chenodal received an orphan drug designation from the FDA for the treatment of CTX in the U.S. in 2010. A patient assistance program, the Chenodal Total Care Program, may help patients who require financial assistance obtain this drug. The number for the program is 1.866.758.7068.
Cholic acid, another bile acid, has also been used to treat young children with CTX. However, cholic acid is generally not as effective as chenodeoxycholic acid, but does lack the potential toxic effects on the liver (hepatotoxicity) sometimes associated with chenodeoxycholic acid.
Genetic counseling will be of benefit for affected families and individuals. Additional treatment is symptomatic and supportive. For example, cataract surgery is usually necessary before 50 years of age.
Currently there are no clinical trials being conducted for CTX. Information on new 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 website.
For information about clinical trials being conducted at the National Institutes of Health (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, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at email@example.com.)
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Report last updated: 2014/09/11 00:00:00 GMT+0