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Cerebrotendinous xanthomatosis

Synonym(s) CTX
Sterol 27-hydroxylase deficiency
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
  • E75.5
  • C0238052
  • D019294
MedDRA -


Disease definition

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 300 patients have been reported worldwide. Prevalence is estimated to be approximately 1/50,000 among Caucasians.

Clinical description

The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Infants may present with cholestasis and liver dysfunction. Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck). Some patients show intellectual impairment from infancy, but most have normal or subnormal intellectual function until puberty. Adult-onset progressive neurologic dysfunction includes dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures, and neuropathy. Dementia occurs in the 20s in over 50% of cases. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies may be prominent. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy.


CTX is caused by mutations in the sterol 27-hydroxylase gene (CYP27A1; 2q33-qter). Sterol 27-hydroxylase catalyzes the first step in the oxidation of the side-chain of sterol intermediates in the bile acid synthesis (BAS) pathway. Defective enzymatic function disrupts bile acid synthesis leading to cholesterol and cholestanol deposits, which result in a degenerative process.

Diagnostic methods

Mass spectrometry analysis of urine enables early diagnosis in children by showing characteristic bile alcohol metabolites. Diagnosis in adults is based on two of the following criteria: intractable diarrhea, presenile cataracts, tendinous xanthomata and neurologic abnormalities, and abnormal amounts of cholestanol in serum and tendons. Plasma cholesterol concentration may be low or normal. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Molecular genetic testing in a certified laboratory may be used to confirm the diagnosis.

Differential diagnosis

Differential diagnoses include other causes of xanthomata such as sitosterolemia and hyperlipemia (especially type IIa, also known as familial hypercholesterolemia [see these terms]), and for infants presenting with cholestasis, all other causes of neonatal cholestasis.

Antenatal diagnosis

Antenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling should be offered to affected families.

Management and treatment

First-line treatment is based on chenodeoxycholic acid (CDCA) replacement therapy, which normalizes BAS and cholestanol concentrations, and improves neurological symptoms. Inhibitors of HMG-CoA reductase may also be used alone or in combination with CDCA, although they may induce muscle damage. Cataract extraction is typically required by age 50 years. Cholic acid treatment has also been used. It is not as effective as CDCA in suppressing BAS and the production of cholestanol, but lacks the hepatotoxicity of CDCA.


Early diagnosis and treatment are crucial to prevent progressive accumulation of cholestanol and cholesterol: disease progression may be halted and in some cases reversed. Treated patients may have a normal lifespan. In untreated patients, life expectancy is 50 to 60 years. Some early deaths in infancy have also been reported.

Expert reviewer(s)

  • Pr James HEUBI

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Detailed information

Review article
Clinical practice guidelines
Clinical genetics review
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