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Cerebrotendinous Xanthomatosis

NORD is very grateful to Antonio Federico, MD, Director, Neurology and Neurometabolic Diseases, University of Siena Medical School, Siena, Italy, for assistance in the preparation of this report.

Synonyms of Cerebrotendinous Xanthomatosis

  • cerebral cholesterinosis
  • CTX
  • sterol 27-hydroxylase deficiency

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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 chenodexoycholic acid. Cholestanol deposits accumulate in the nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals experience cataracts in childhood, and benign, fatty tumors (xanthomas) of the tendons during adolescence. This leads to progressive neurologic problems in adulthood such as paralysis, ataxia and dementia. Coronary heart disease is common.

Symptoms

The first symptoms of CTX may be chronic diarrhea in infancy. Cataracts in the first decade of life are the first symptom in about 75% of those affected. Xanthomas appear in the second or third decade and can be located in the Achilles tendon, extensor tendons of the elbow and hand, and knee. Most affected individuals experience a decline in mental function beginning at puberty, but some show impairment beginning in childhood. Dementia and a slow loss in mental function occur in more than half of those affected. Symptoms such as seizures, behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies are common. Spasticity almost always occurs between 20-30 years of age.

Causes

CTX is an autosomal recessive genetic condition 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 the bile acid chenodeoxycholic acid that helps the intestine absorb fats. Cholestanol deposits accumulate and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries.

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.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

The prevalence of CTX is not known. Affected individuals have been reported in the USA, Israel, Italy, Japan, the Netherlands, Belgium, Brazil, Canada, France, Iran, Norway, Tunisia, Spain, China and Sweden.

Related Disorders

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 fats 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.

Familial hypercholesterolemia is an autosomal dominant genetic disorder characterized by a high level of low-density lipoprotein (LDL) cholesterol in blood serum. Symptoms include fatty tumors of the tendons (tendinous xanthomas), a curved appearance of the corneas of the eyes (corneal arcus), and coronary artery disease in the fourth or fifth decade.

Standard Therapies

Diagnosis
CTX is diagnosed by performing several biochemical tests on blood and urine. Cholestanol concentration in blood plasma and in tissues is high, plasma cholesterol concentration is normal to low, and the concentration of bile alcohols in bile, urine and plasma is increased. Molecular genetic testing for the abnormal CYP27A1 gene is available on a research basis only.

Treatment
Long-term treatment with chenodeoxycholic acid (CDCA) can block the production of cholestanol. CDCA can stop the progression of disease symptoms and may lead to improvement in some affected individuals. HMG-CoA reductase inhibitors are sometimes used in combination with CDCA because they also lower both cholesterol and cholestanol concentrations to avoid coronary heart disease.

In October 2009, the Food and Drug Administration approved Chenodal as a treatment for CTX. This drug is marketed in the U.S. By Manchester Pharmaceuticals, Inc. A patient assistance program, the Chenodal Total Care Program, may help patients who need financial assistance obtain this drug. The number for the program is 866 758 7068.

Cataract surgery is usually necessary before 50 years of age.

Investigational Therapies

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 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
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

A Phase II clinical trial is in progress at the Oregon Health and Science University. The purpose is to help evaluate the drugs lovastatin and chenodeoxycholic acid, and cholesterol- and cholestanol-free diets, as therapies for people with CTX. For information, contact Sonja Connor at Connors@ohsu.edu or (503) 494-7775.

Organizations related to Cerebrotendinous Xanthomatosis

References

JOURNAL ARTICLES
Guerrera S, Stromillo ML, Mignarri A, et al. Clinical relevance of brain volume changes in patients with cerebrotendinous xanthomatosis. J Neurol Neurosurg Psychiatry. 2010;81(11):1189-93.

Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27(2):143-9.

Inglese M, DeStefano N, Pagani E, et al. Quantification of brain damage in cerebrotendinous xanthomatoisis with magnetization transfer MR imaging. AJNR Am J Neuroradiol 2003;24:495-500.

Dotti MT, Rufa A, Federico A. Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings. J Inherit Metab Dis. 2001;24:696-706.

Federico A, Dotti MT. Cerebrotendinous xanthomatosis. Neurology. 2001;57:1743.

Federico A, Dotti MT. Cerebrotendinous xanthomatosis. In: Moser HW (ed) Handbook of Clinical Neurology, Volume 22. Neurodystrophies and neurolipidoses. Amsterdam, Elsevier Science BV, 1996:599-613.

Federico A, Dotti MT. Treatment of cerebrotendinous xanthomatosis. Neurology 1994;44:2218.

Calli JJ, Hsieh CL, Franke U, et al. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 1991;266:7779-83.

Dotti MT, Salen G and Federico A. Cerebrotendinous xanthomatosis as a multisystem disease mimicking premature aging. Dev Neurosci 1991;13:371-6.

FROM THE INTERNET
Mignarri A, Rossi S, Ballerini M, et al. Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis.[published online ahead of print November 21, 2010] J Neurol. 2010. http://www.ncbi.nlm.nih.gov/pubmed/21104094. Accessed March 15, 2011.

Federico A, Dotti MT, Gallus GN. (Updated 11/16/10). Cerebrotendinous Xanthomatosis. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2011. Available at http://www.genetests.org. Accessed 3/15/11.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cerebrotendinous Xanthomatosis. Entry No: 213700. Last Updated January 7, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 15, 2011.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2011/03/15 00:00:00 GMT+0

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