Cerebrotendinous xanthomatosis is a disorder characterized by abnormal storage of fats lipids in many areas of the body. People with this disorder cannot break down certain lipids effectively, specifically different forms of cholesterol, so these fats accumulate in the body in the form of fatty yellow nodules called xanthomas. These xanthomas are most commonly found in the brain and in connective tissue called tendons that attach muscle to bone, which is reflected in the condition name cerebro- meaning brain and -tendinous referring to tendons. People with cerebrotendinous xanthomatosis often develop neurological problems in early adulthood that are thought to be caused by an abnormal accumulation of fats and an increasing number of xanthomas in the brain.
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Cerebrotendinous Xanthomatosis CTX is a rare and presumably underdiagnosed, autosomal recessive, metabolic storage disorder. CTX is caused by caused by mutations in the CYP27A1 gene, which encodes for a sterol hydroxylase enzyme important in bile acid synthesis.
At least 50 pathogenic mutations have been found in the CYP27A1 gene. Sterol hydroxylase deficiency leads to 5-alpha-cholestanol accumulation in the blood and tissues of affected patients; this includes the brain, connective tissue, and the crystalline lens. The hallmark manifestations of CTX have a variable onset and severity, which may lead to delayed-diagnosis and under-diagnosis.
Irreversible neurological deterioration is present in late disease. Eye care professionals are in a unique position to identify and diagnose CTX at a time when serious disability can be prevented. The mean age of diagnosis is The prevalence of CTX in the US population is estimated to be as high as 3 to 5 per ,, predicting a minimum number of 8, affected individuals.
CTX is likely underdiagnosed with known patients in the US numbering less than Approximately cases have been reported worldwide. This disorder is more common in the Moroccan Jewish population with a reported incidence of 1 in This gene is responsible for producing an enzyme called sterol hydroxylase. Under normal conditions, sterol hydroxylase works in a pathway to break down cholesterol into bile acids necessary for the body to digest fats.
As chenodeoxycholic acid a potent inhibitor of cholesterol 7-alpha-hydroxylase is decreased, cholesterol cannot be properly excreted in the form of bile acids. These conditions lead to a significant increase in the levels of bile alcohols and levels of cholestanol, a byproduct of abnormal bile acid synthesis.
Figure 1: Mutations in the CYP27A1 gene prevent critical steps in the bile acid synthesis that leads to bile acid deficiency, which results in a buildup of cholestanol throughout the body that causes distinctive clinical manifestations.
Image permission and courtesy of Retrophin, Inc. These bile alcohols are excreted in bile, urine, and feces, but cholestanol accumulates, especially in the brain, peripheral nerves, lenses, and tendons, and causes the signs and symptoms of CTX. Typical clinical characteristics of CTX may include some combination of infantile-onset chronic diarrhea, bilateral cataracts with juvenile onset, tendon xanthomas, psychiatric and abnormal behavioral symptoms, and cognitive and other neurologic impairments.
Clinical features are variable in severity and onset. Figure 2: The hallmark manifestations of CTX have variable onset and severity, which may lead to delayed-diagnosis and under-diagnosis. Mean age of diagnosis is Bilateral cataracts, caused by cholestanol buildup in the crystalline lens, usually develop within the first 3 decades of life; often between the ages of 4 and 18 years of age.
This manifestation is almost a universal characteristic of CTX. These patients develop irregular cortical opacities, anterior polar cataracts, or dense posterior subscapular cataracts. Fleck lenticular deposits may be an early sign of CTX. Figure 3. Top two images show fleck opacities and posterior capsular opacities of the crystalline lens in the right eye of a 14 year old affected with CTX.
Bottom two images show fleck opacities and anterior opacities of the crystalline lens in the right eye of a 10 year old affected with CTX. Image with permission from Dr Arif O. Khan; courtesy Arif O. Khan, MD et al. Other ocular findings include palpebral xanthelasmas, optic nerve atrophy, and proptosis. Some studies have shown findings such as retinal vessel sclerosis, cholesterol-like deposits along vascular arcades, and myelinated nerve fibers. Chronic diarrhea is often the first systemic manifestation of CTX.
This may begin when the affected individual is still an infant. An evaluation of an individual with a suspicion for CTX should include a direct inquiry as to a past medical history of unexplained bouts of diarrhea during the childhood period. Patients with CTX often have an increased incidence of prolonged unexplained neonatal cholestatic jaundice. Tendon xanthomas, caused by cholestanol buildup in the tendons, usually appear late in the disease, commonly in the second or third decade.
Most often these xanthomas occur on the Achilles tendons. These xanthomas can also occur on the extensor tendons of the elbow and hand, patellar tendon, and neck tendons. Xanthomas have also been reported in the lung, bones, and central nervous system. The presence of tendon xanthomas in a patient with normal plasma cholesterol levels and normal lipoprotein profile should trigger an investigation of CTX as a potential underlying cause.
Neurologic signs and symptoms of CTX usually appear after the second decade. Psychiatric manifestations or learning disabilities may appear earlier in the disease. More than half of affected patients develop dementia, with deterioration of cognitive function starting in their 20s. Although not generally considered a hallmark manifestation, a significant amount of individuals with CTX have reported seizure activity.
Psychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts have been documented. Lipid deposits and white matter loss in the brain has been reported in patients with advanced CTX. Familial hypercholesterolemia and other forms of autosomal dominant hypercholesterolemias are potential causes of tendon xanthomas.
With familial hypercholesterolemia, however, laboratory testing typically shows increased levels of total cholesterol and LDL cholesterol, which are not features of CTX. Sitosterolemia is an inherited sterol storage disease characterized by tendon xanthomas and by strong predisposition to premature atherosclerosis.
However, primary neurologic signs, diarrhea, and cataracts are not present in this disease. SLOS is an autosomal recessive disorder associated with mutations in DHCR7 gene that reduces or eliminates the activity of 7-dehydrocholesterol reductase. This enzyme is responsible for the final step of cholesterol production. The diagnosis of CTX is often delayed until the fourth decade of life.
CTX should be suspected in patients with some combination of infantile onset diarrhea, juvenile onset bilateral cataracts, adolescent to young adult-onset tendon xanthoma, and adult-onset progressive neurologic dysfunction.
It may show bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Other MRI findings may show signal alterations of the cerebral peduncle, corona radiate, and subcortical white matter.
Biochemical testing can be performed which may show high plasma and tissue cholestanol concentration. A normal to low plasma cholesterol concentration is seen. Markedly decreased formation of chenodeoxycholic acid from impaired primary bile acid synthesis, and increased concentration of bile alcohols and their glycoconjugates in bile, urine, and plasma are features.
Increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid from changes in the blood-brain barrier can be seen. This is the gold standard for diagnosis. The most frequent mutations of the CYP27A1 gene are distributed from exons 1 to 8.
The majority of mutations are amino acid substitutions; splice site mutations have also been reported. Enzyme assays for reduced activity of sterol hydroxylase enzymatic activity can be performed as well. There are proposed suspicion index tables that include family history, systemic symptoms, and neurologic factors that can be used to help aid in the diagnosis of CTX. Those with high plasma cholestanol concentrations should proceed to CYP27A1 gene sequencing.
There has been no suitable test to screen newborn dried bloodspots DBS for CTX, however development of a methodology to enable sensitive detection of ketosterol bile acid precursors that accumulate has been investigated and reported by DeBarber AE et al. Berginer VM et al. Treatment of CTX in the preclinical stage can reportedly prevent the onset of disease complications. Because of this, the value of an early diagnosis for CTX is extremely important.
Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Cerebrotendinous xanthomatosis CTX is an anomaly of bile acid synthesis see this term characterized by neonatal cholestasis, childhood-onset cataract, adolescent to young adult-onset tendon xanthomata, and brain xanthomata with adult-onset neurologic dysfunction. More than patients have been reported worldwide. The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy.
Cerebrotendineous xanthomatosis also called cerebral cholesterosis ,  is an autosomal recessive form of xanthomatosis. An inherited disorder associated with the deposition of a steroid known as cholestanol in the brain and other tissues and with elevated levels of cholesterol in plasma but with normal total cholesterol level; it is characterized by progressive cerebellar ataxia beginning after puberty and by juvenile cataracts , juvenile or infantile onset chronic diarrhea, childhood neurological deficit, and tendineous or tuberous xanthomas. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Elevated levels of serum cholestanol are diagnostic of CTX. Alternatively analysis of hydroxycholesterol and 7 alpha hydroxycholesterol can be used. Genetic testing of the CYP27A1 gene is confirmatory and is increasingly being used as a first line test as part of symptom specific gene panels genetic eye disease, ataxia, dementia.