Cerebrotendinous xanthomatosis is a rare genetic metabolic disorder of cholesterol and bile acid metabolism that results in systemic and neurologic abnormalities. Typically, the disease begins in infancy with chronic diarrhea. Cataracts become evident in childhood or adolescence, and xanthomata develop in the second and third decades of life. Significant neurologic impairment also occurs; this often includes seizures, dementia, and cerebellar and extrapyramidal dysfunction, typically beginning in the third decade of life and progressing until death, often in the sixth decade of life if the condition goes untreated. The presentation and course widely vary, and treatment can dramatically alter the natural history, especially with early initiation.
The disease was first described in 1937 by Van Bogaert and colleagues and has since been characterized clinically, biochemically, and genetically. [1, 2] In 1968, Menkes et al described the accumulation of cholestanol, the primary metabolite found in elevated concentrations in cerebrotendinous xanthomatosis, in tissues of the CNS.  In 1971, Salen found that chenodeoxycholic acid (CDCA), an important bile acid, was virtually absent in patients with clinical symptoms of the disease.  This led to successful trials of therapy with CDCA replacement, in 1975 by Salen  and later with Berginer,  that was found to normalize the biochemical phenotype and prevent disease progression. In 1980, defects in mitochondrial sterol 27-hydroxylase were implicated in the biochemical pathophysiology of the disease by Oftebro et al.  In 1991, mutations in the gene CYP27A1 were discovered as causative. [8, 9, 10] Since then, more than 50 mutations have been described.
The primary enzymatic defect in cerebrotendinous xanthomatosis is in mitochondrial sterol 27-hydroxylase, a key enzyme in the complicated process of bile acid synthesis from cholesterol. Defective enzymatic function disrupts bile acid synthesis. Defects in the enzyme result in decreased synthesis of CDCA; this, in turn, disrupts feedback regulation on cholesterol 7-alpha-hydroxylase, which is the rate-limiting step in bile acid synthesis. Therefore, bile acid precursors accumulate in tissues. Cholestanol is formed in a pathway from the bile acid precursor 7-alpha-hydroxy-4-cholesten-3-one.  Deposition of cholestanol and cholesterol in the CNS (the brain and spinal cord), muscle (including the heart), blood vessels, eye, and tendon results in a degenerative process that worsens over time unless treated.
Patients with cerebrotendinous xanthomatosis appear to have a diffuse decrease in total brain volume, the decrease being predominantly in cortical grey matter rather than white matter. This finding provides additional evidence that cerebrotendinous xanthomatosis is a primary neuronal disorder. 
More than 300 patients have been diagnosed worldwide, with an estimated prevalence of 1 case per 50,000 individuals in white populations. [9, 15] Genetic islands of increased CYP27A1 mutation frequency exist; for example, there is an estimated disease prevalence of 1:440 for the Druze population in Israel. 
Given the estimates of incidence, as many as 8,000-14,000 people in the United States may have cerebrotendinous xanthomatosis. These are far more cases than have actually been diagnosed, and experts strongly believe that the condition is seriously underdiagnosed in the United States.
Cases have been reported in China, Canada, Belgium, Brazil, Saudi Arabia, India, Germany, Taiwan, France, Switzerland, South Africa, Australia, Israel, and Argentina; a large representation has been reported among Spanish  and Scandinavian populations, as well as in Italy and Japan. A founder effect and high rate of consanguinity appear to be responsible for a high prevalence among the Druze population. [16, 18]
Mutation analysis internationally reveals the following high frequency alleles: T339M in Dutch patients, R474(Q-W) in Japanese patients, and A216P in Italian patients. 
Life expectancy is lowered; however, no formal epidemiologic studies have been published. Death can be as early as infancy, although it is more common between the fourth and sixth decades of life, with progressive incapacitation usually occurring in the fourth and fifth decades of life. Causes of death reported in the literature include myocardial infarction and progressive mental deterioration with pseudobulbar palsies. 
Morbidity begins with intractable diarrhea. Presenile cataracts result in vision abnormalities. Xanthomas can cause motor restriction and joint deformities, resulting in various orthopedic sequelae. Vascular abnormalities such as premature atherosclerosis (especially in the carotid and coronary vessels) can lead to stroke and myocardial infarction. The primary neurologic manifestations of the disease are associated with complications that range from treatable seizures to neurologic devastation. The severity of disease widely varies.
Series of patients have been described in the Netherlands, Italy, Spain and Japan, with scattered case reports around the world (see International). No current data on US prevalence among Hispanics or African Americans are available.
No sex predilection has been reported for this autosomal recessive disorder, although animal models exhibit sex differences.
Cerebrotendinous xanthomatosis can present at any age, from the neonatal period to the sixth decade of life or later.
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