Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis

Abstract

Cholestanol and 7αC4 represent important markers for CTX diagnosis and monitoring of therapy. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol, since 7αC4 better mirrors 7α-hydroxylation rate and is thought to be correlated with cholestanol accumulation in the brain. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis at any stage of disease. Lathosterol and plant sterols should be considered as additional markers for diagnosis and monitoring of therapy. Further studies including long-term assessment of bile acid intermediates in cerebrospinal fluid are needed in patients who show clinical progression despite treatment.

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

“…Cholesterol concentrations in tissue are increased (Salen 1971), but plasma cholesterol levels [total, high-density lipoprotein (HDL), and/or lowdensity lipoprotein (LDL)] are low to normal, HDL composition is abnormal, and hepatic expression of LDL receptors is increased (Shore et al 1981;Ballantyne et al 1987). Concentrations of bile acid precursors in plasma (7α-hydroxy-4-cholesten-3-one and lathosterol) and bile (lathosterol) are increased, as are levels of plant sterols (campesterol and sitosterol) in plasma and bile (Mignarri et al 2016;Kuriyama et al 1991a;DeBarber et al 2010). Elevated plant sterols and lathosterol are nonspecific findings.…”

“…However, advanced symptoms that have been present for many years are unlikely to significantly improve (Berginer et al 2009). It reduces levels of circulating cholestanol, other sterols (e.g., lanosterol, campesterol, sitosterol), and bile acid precursors (e.g., 7-α-hydroxy-4-cholesten-3-one) (Berginer et al 1984;Kuriyama et al 1994;Salen et al 1975;Björkhem et al 1987;Mignarri et al 2016;DeBarber et al 2010); bile alcohol levels in plasma, bile, and urine (Batta et al 1987;Batta et al 2004); and cholic acid levels (Salen et al 1994). It increases CDCA levels in bile (Salen et al 1994), and normalizes lipid levels (Kuriyama et al 1994;Tint et al 1989).…”

Cerebrotendinous Xanthomatosis Presenting with Infantile Spasms and Intellectual Disability

“…In addition, 7a-hydroxy-4-cholesten-3-one (7a4C) is helpful in diagnosis and monitoring of treatment for 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).…”

Unique case of cerebrotendinous xanthomatosis revisited: All the mutations responsible for this disease are present in the CYP27A1 gene

“…With one possible exception (cf below), patients with both clinical and biochemical CTX have been found to be either homozygous or compound heterozygous for mutations within the reading frame of CYP27A1. It should be emphasized that the disease penetrance of a specific mutation seems to be variable and that the age at which the disease gives clinical symptoms may vary [2]. Biochemical evaluation does not reveal significant differences between stable and worsening patients [2].…”

“…It should be emphasized that the disease penetrance of a specific mutation seems to be variable and that the age at which the disease gives clinical symptoms may vary [2]. Biochemical evaluation does not reveal significant differences between stable and worsening patients [2]. Given the progressive nature of the disease, early diagnosis and treatment are regarded to be of utmost value.…”