On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis

Abstract

The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanolcontaining brain xanthomas. The cholestanol in the brain may be derived from the circulation or from 7a-hydroxylated intermediates in bile acid synthesis, present at 50-to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7a-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

“…Some data demonstrate an intact BBB in CTX patients, indicating that cholestanol accumulation may result from impaired removal of cholestanol or from synthesis of cholestanol in the brain from cholesterol or a circulating precursor that enters the brain (Bhattacharyya et al 2007). The bile acid precursor, 7α-hydroxy-4-cholesten-3-one (which passes through the BBB at a markedly higher rate compared with cholestanol), can be efficiently converted to cholestanol by neurons, astrocytes, microglia, and human monocyte-derived macrophages, thereby leading to accumulation of cholestanol in the brain (Panzenboeck et al 2007;Bavner et al 2010). However, some data suggest that the BBB may be impaired in patients with CTX; specifically, the observation of increased cholestanol and apolipoprotein B concentrations in the cerebrospinal fluid (CSF) of CTX patients indicates enhanced permeability of the BBB .…”

“…Specifically, it inhibits CYP7A1 through a pathway mediated by nuclear receptor farnesoid X receptor (FXR) (Ellis et al 2003). Suppression of CYP7A1 reduces production of cholestanol and normalizes levels of 7α-hydroxy-4-cholesten-3-one (Björkhem et al 1987), a bile acid precursor capable of efficient transfer across the BBB and which is converted to cholestanol in neuronal glial cells (Panzenboeck et al 2007). CDCA also reduces susceptibility of LDL to oxidative modification and enhances cholesteryl ester transfer protein (CETP) activity, affecting two processes thought to contribute to the formation of xanthomas (Kinoshita et al 2004).…”

Nueva mutación para xantomatosis cerebrotendinosa causa demencia temprana familiar en Colombia

“…They appear during childhood or adolescence with learning impairments, mental retardation, behavioral changes, personality disorders or they appear when the disease has progressed. Dementia and other psychiatric manifestations are the result of the alterations in multiple neuronal networks in the white matter with myelin-lipid substrate and demyelinitization disorders (30)(31)(32)(33)(34)(35).…”

Cerebrotendinous Xanthomatosis Presenting with Infantile Spasms and Intellectual Disability

“…Biallelic pathogenic variants in the gene CYP27A1 cause deficiency of the enzyme produced by CYP27A1, sterol 27-hydroxylase, resulting in the accumulation of cholesterol, cholestanol, and other intermediates in tissues and the pathology that characterizes CTX (Panzenboeck et al 2007). Elevated cholestanol in serum and elevated urine bile alcohols are characteristic diagnostic findings in patients with CTX.…”

“…Serum levels of 7a4C are more significantly elevated in individuals with CTX than other metabolites, and 7a4C levels exhibit dramatic responses to treatment (Mignarri et al 2016). 7a4C crosses the blood-brain barrier more efficiently than cholestanol and may be a significant contributing factor to pathogenesis in the central nervous system (Panzenboeck et al 2007).…”