Cerebrotendinous Xanthomatosis (CTX)

Updated: Dec 08, 2021
  • Author: Austin Larson, MD; Chief Editor: Maria Descartes, MD  more...
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Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of cholesterol and bile acid metabolism that results in systemic and neurologic abnormalities. [1] The disease may become apparent in infancy, with chronic diarrhea or through liver disease/jaundice. Cataracts can become evident in childhood or adolescence, and xanthomata can develop in the second and third decades of life. Significant neurologic impairment may also occur; this often includes seizures, dementia, spasticity, gait impairment, and cerebellar and extrapyramidal dysfunction, typically beginning in the third decade of life and progressing until premature death, often in the sixth decade of life if the condition goes untreated. The presentation and course vary widely, 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. [2, 3] In 1968, Menkes et al described the accumulation of cholestanol, the primary metabolite found in elevated concentrations in CTX, in tissues of the CNS. [4] In 1971, Salen found that chenodeoxycholic acid (CDCA), an important bile acid, was virtually absent in patients with clinical symptoms of the disease. [5] This led to successful trials of therapy with CDCA replacement, in 1975 by Salen [6] and later with Berginer, [7] 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. [8] In 1991, mutations in the gene CYP27A1 were determined to be the genetic cause of CTX. [9, 10, 11]  



The enzymatic defect that causes CTX is in mitochondrial sterol 27-hydroxylase, a key enzyme in the pathway necessary for synthesis of bile acids from cholesterol. Deficiency of the enzyme results in impaired synthesis of the mature bile acids CDCAoxycholic acid (CDCA) and cholic acid. The mature bile acids (primarily CDCA) are responsible for negative feedback on cholesterol 7-alpha-hydroxylase, which is the initial and rate-limiting step in bile acid synthesis. With no inhibition of flux into the metabolic pathway, cholesterol-derived bile acid precursors accumulate in tissues and are thought to cause the symptoms of CTX.

Cholestanol is formed in a pathway from the bile acid precursor 7-alpha-hydroxy-4-cholesten-3-one. [12] Deposition of cholestanol and other intermediate metabolites in the CNS (the brain and spinal cord), muscle (including the heart), blood vessels, eyes, and tendons results in progressive dysfunction unless treatment is initiated to prevent further accumulation of toxic metabolites. 

While the general framework of tissue dysfunction due to accumulation of toxic metabolites is settled, there is ongoing study of the specific mechanisms of neurotoxicity. [13, 14]  Patients with CTX 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 CTX is a primary neuronal disorder. [15]





More than 300 cases have been published worldwide, with an estimated prevalence of 1 case per 50,000 individuals in populations of European descent. [10, 16] Populations with increased CYP27A1 mutation frequency exist due to founder effects; for example, there is an estimated disease prevalence of 1:440 for the Druze population in Israel. [17]

United States

Given the estimates of prevalence, as many as 8,000-14,000 people in the United States may have CTX. These are far more cases than have actually been diagnosed, and it is likely that the condition is underdiagnosed.


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 [18] and Scandinavian populations, as well as in Italy and Japan. A nationwide survey in Japan revealed an average 16.5-year diagnostic delay after onset of the presenting symptom, providing further evidence that CTX may be underdiagnosed. [19] A founder effect and high rate of consanguineous marriages are responsible for a high prevalence of CTX in the Druze population. [17, 20]

Mutation analysis internationally reveals the following high frequency alleles: T339M in Dutch patients, R474(Q-W) in Japanese patients, and A216P in Italian patients. [10]  The prevalence of CTX has been estimated in different populations based on the allele frequency of known mutations and presumed deleterious genetic variants in a large cohort of individuals that have undergone exome sequencing. [21]


Life expectancy is lowered; however, no formal epidemiologic studies have been published. One analysis found that 14/194 (7%) of published patients had died with a cumulative incidence of death of 50% at age 60 years. [22] Causes of death reported in the literature include myocardial infarction and progressive neurological deterioration. [23]  

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 specific data on minority populations in the United States 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 with certain symptoms being more common at different ages. 



If CTX is untreated, life expectancy is into the fifth and sixth decades; however, confirmed deaths have been reported as early as age 4 months. This is a progressive and terminal disease if left untreated. Treated patients may have a normal lifespan.