What is the pathophysiology of cerebrotendinous xanthomatosis (CTX)?

Updated: Jun 20, 2019
  • Author: Robert D Steiner, MD; Chief Editor: Maria Descartes, MD  more...
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Answer

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. [12] 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.

The mechanisms leading to brain involvement have been debated. [13, 14]

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. [15]


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