What causes cerebrotendinous xanthomatosis (CTX)?

Updated: Jun 20, 2019
  • Author: Robert D Steiner, MD; Chief Editor: Maria Descartes, MD  more...
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Cerebrotendinous xanthomatosis is a defect in bile acid synthesis, with subsequent overproduction and accumulation of cholestanol in multiple tissues of the body. It is caused by a defect in the CYP27A1 gene that codes for sterol 27-hydoxylase. The gene is located at 2q33-qter. It is an autosomal recessive disorder.

A recent review and update by Gallus et al identified mutations in exons 1-8 of the CYP27A1 gene but none in exon 9. [10] More than 50 mutations have been identified. Half of these are found in exons 6-8, and many have effects on enzyme heme-binding and adrenodoxin-binding sites. In one study, mutation analysis revealed mutations of all types, including missense (45%), nonsense (20%), splice site (18%), deletion (14%), and insertion (2%). [10]

Typically, affected individuals have mutations in both alleles; although sometimes homozygous, a substantial number of compound heterozygote patients have been described. Two heterozygous patients with clinical disease and decreased enzyme function have been reported, but no second mutation was identified despite an extensive search. [11, 47]

CYP27A1 was recently identified as a candidate gene for sporadic amyotrophic lateral sclerosis (ALS). [48] This is of interest as cerebrotendinous xanthomatosis can present as a clinical mimic of ALS with progressive upper motor neuron loss.

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