NORD gratefully acknowledges Andrea DeBarber, PhD, Research Assistant Professor, Physiology & Pharmacology Department, Oregon Health & Science University, for assistance in the preparation of this report.
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). Infantile spasms have also been reported as a possible symptom. Cataracts in the first decades of life are the initial 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 has been reported as between 35-37 years old at which time neurological involvement has often become significant and characteristic of CTX. Seizures and epilepsy 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) can occur.
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 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 1:134,970 to 1:461,358 in Europeans and even higher in Asians (~1:70,000). Despite this, only around three hundred affected individual of CTX have been described worldwide. This suggests many cases may go undiagnosed or are misdiagnosed. 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.
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. 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. 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 7alpha, 12Alpha-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. 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 low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX. HMG-CoA reductase inhibitors can also cause muscle damage.
In 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. Chenodal is manufactured by Retrophin.
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 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.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:
Tollfree: (800) 411-1222
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Email: [email protected]
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:
For information about clinical trials conducted in Europe, contact:
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