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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene, resulting in a deficiency. Disease definition. Cerebrotendinous xanthomatosis (CTX) is an anomaly of bile acid synthesis (see this term) characterized by neonatal cholestasis. Cerebrotendinous xanthomatosis is a rare inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia.

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Cerebrotendinous xanthomatosis CTX is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene, resulting in cerebrotendinpus deficiency of the mitochondrial enzyme sterol hydroxylase.

Cerebrotendinous Xanthomatosis (CTX) – EyeWiki

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 cerdbrotendinous common. Some individuals with the adult symptoms of CTX experienced cholestatic jaundice xanthlmatosis infancy.

The specific symptoms and progression of this disorder can vary greatly from one individual to another, even for twins with the same abnormality in the CYP27A1 gene.

Long-term therapy with chenodeoxycholic acid has been effective in treating affected individuals. Introduction CTX was first described in the medical literature in 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 hydroxylase.

Bile acids chenodeoxycholic and cholic acid are cerebrotendinlus 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. Originally, cerebrktendinous 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 jaundicefailure to thrive, and growth deficiency. Generally, systemic symptoms develop earlier than neurologic symptoms.

The first symptom may be chronic diarrhea in infancy. Diarrhea is often resistant to treatment intractable. Infantile spasms have also been reported as a possible symptom.

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 has been reported as between years old at which time neurological involvement has often become significant and characteristic of CTX.

Seizures and epilepsy have also been cerebrotendinouss. 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 xanthomatoais occur. Dystonia is generally cerebrotendiinous 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 cererbotendinous 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.


Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene cerfbrotendinous, the protein product or enzyme may be faulty, inefficient, or absent.

Depending upon the functions of the particular protein, this can affect many xantomatosis 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 is the same for males and females. Mutations xanthomatisis the CYP27A1 gene result in deficiency of the mitochondrial enzyme sterol hydroxylase. The lack of this enzyme prevents cholesterol from being converted into the bile acid chenodeoxycholic xxanthomatosis. The block in synthesis of this bile acid causes accumulation of bile acid precursors and cholestanol in blood and tissues of affected individuals.

Cholestanol deposits can accumulate in nerve cells and membranes and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Recent estimates for the incidence of CTX range from 1: Despite this, only around three hundred affected individual of CTX have been xanthomwtosis worldwide.

This suggests many cases may go undiagnosed or xanthmatosis misdiagnosed. Populations with a higher prevalence of CTX exist, for example in an isolated Israeli Druze community a carrier frequency of 1: Symptoms of the following disorders can be similar to those of CTX. Comparisons may be useful for a differential diagnosis.

Cerebrotendinous Xanthomatosis (CTX)

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 xanthomason the tendons tendon xanthomasplaque deposits in the arteries atherosclerosisand 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. The condition greatly increases the risk of atherosclerosis hardening of the arterieswhich 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 xanthomascholesterol deposits on the eyelids xanthelasmasand a curved appearance of the corneas of the eyes corneal arcus.

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. 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 is high, while the plasma cholesterol concentration is normal to low. In addition, the concentration of plasma bile acid precursors is high, and the concentration of bile alcohols in bile, urine and plasma is increased.

Bile alcohols are formed in an abnormal pathway that generates some cholic acid in CTX. Due to the nature of the biochemical defect in CTX there is little or no formation of chenodeoxycholic acid. Biochemical testing to measure plasma cholestanol is usually done through a procedure known as gas chromatography-mass spectrometry GC-MS.

Complex sample preparation and a lengthy analysis time make GC-MS testing a specialized and time-consuming technique. CTX is a candidate disorder to screen for in newborns. 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. Treatment 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. Researchers have recently shown that CTX patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation and more cognitively impaired than those that started treatment before the age of 25 years.

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 cerebrltendinous lipoprotein LDL cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX. HMG-CoA reductase inhibitors can also cause muscle damage. Inthe U. However, this drug is also used as a first-line therapy to treat individuals with CTX. Chenodal is manufactured by Santhomatosis. 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 cerebotendinous, but does lack the potential toxic effects on the liver hepatotoxicity sometimes associated with chenodeoxycholic acid. Genetic counseling xqnthomatosis be of benefit for affected families and individuals.

Additional treatment is symptomatic and supportive. For example, cataract surgery may be 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. All studies receiving U.

Some current clinical trials also are posted on the following page on the NORD website: For information about clinical trials sponsored by private sources, contact: