Lipid Abnormalities in Cerebrotendinous Xanthomatosis: Comparison
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Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by pathogenic variants in CYP27A1, leading to a deficiency in sterol 27-hydroxylase. This defect results in the accumulation of cholestanol and bile alcohols in various tissues, including the brain, tendons, and peripheral nerves. Elevated levels of cholestanol are consistently observed. Most patients present normal or low serum cholesterol levels. The decrease in chenodeoxycholic acid (CDCA) leads to increased synthesis of cholesterol metabolites such as bile alcohols 23S-pentol and 25-tetrol 3-glucuronide, which may serve as surrogate follow-up markers in patients with CTX. Lipid abnormalities in CTX have clinical implications. Cholestanol deposition in tissues contributes to the clinical manifestations, including neurological symptoms and tendon xanthomas. Dyslipidemia and abnormal cholesterol metabolism may also contribute to the increased risk of atherosclerosis and cardiovascular complications observed in some CTX patients.

  • cerebrotendinous xanthomatosis
  • cholestanol
  • cholesterol
  • lipid
  • chenodeoxycholic acid

1. Introduction

Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disorder related to bile acid synthesis pathways. This autosomal recessive disease is caused by pathogenic variants in CYP27A1, which codes sterol 27-hydroxylase, an enzyme of the cytochrome P450 oxidase system with an important role in cholesterol metabolism and bile acid synthesis. Reduced activity of this enzyme leads to increased lipid content formation and accumulation in multiple tissues, which are mainly the brain, eye lenses and tendons [1,2][1][2].
Despite being considered rare, CTX has recently been pointed out as considerably underdiagnosed, which might be related to the high heterogeneity of clinical presentation with a wide range of symptoms, severity and age of onset [3,4][3][4]. Typical manifestations include tendon xanthomas, osteoporosis, coronary heart disease and progressive neuropsychiatric symptoms. The neurologic disturbances comprise peripheral neuropathy, pyramidal signs (such as spastic paraparesis), cerebellar ataxia, cognitive impairment and movement disorders. In childhood and adolescence, the primary findings are bilateral juvenile cataracts, chronic diarrhea and intellectual disability [2,3,5][2][3][5]. It should be noted that one of the earliest manifestations of CTX is neonatal cholestatic jaundice, a condition that, although self-limited and uncomplicated in most cases, occasionally progresses to a severe form with the requirement for liver transplantation and high lethality [2,6][2][6].
The presence of two of the four main characteristics (cataract, diarrhea, progressive neurological involvement and tendon xanthomas) in young individuals incites a more thorough biochemical study for CTX [7]. In this context, the main plasmatic marker is the increase in cholestanol serum levels [4], although it is expected that other substances are also altered, such as low or normal cholesterol serum levels and increased plasmatic and urinary levels for bile alcohols [8,9][8][9]. Radiologic analysis can also strengthen the diagnostic suspicion of CTX. The most typical findings are symmetrical abnormalities in the dentate nucleus, as shown by T2W and FLAIR brain MRI [10]. About 84% of CTX patients present an abnormal neuroimage, although these abnormalities may manifest late in the disease’s course [5]. Some diagnostic criteria have been proposed, among which the Mignarri suspicion index must be highlighted [11]. The presence of biallelic pathogenic CYP27A1 variants and elevated cholestanol, performed in a suggestive clinical context, establishes the diagnosis of CTX [12].
CTX treatment is carried out with chenodeoxycholic acid (CDCA), which inhibits the accumulation of cholestanol by reducing bile acid production [7]. It mainly aims to stabilize the progression of neurological manifestations but may also lead to symptom improvement in some patients [13]. The establishment of an early treatment seems to influence the therapeutic response positively [14]. On the other hand, some individuals with CTX continue to have their neurological function deteriorate even after the beginning of treatment with CDCA, especially when it is started late in the disease’s course [15].

2. Cholesterol Metabolism in CTX

CTX originates from a deficiency in the activity of the sterol enzyme 27-hydroxylase. This disorder, therefore, compromises the alternative pathway’s function, altering the metabolism of cholesterol-derived sterols [6]. The alternative pathway has CDCA as its final product. With the impairment of this metabolic route already in the initial stages, there is a decrease in the production of this substance [2]. CDCA plays an important role in the metabolism of cholesterol, as it exercises control over the classical pathway through negative feedback, regulating the activity of cholesterol 7α-hydroxylase, which is responsible for the limiting step in the process of bile acid synthesis. Therefore, with CDCA deficiency, there is a stimulation of the classical pathway, leading to the accumulation of intermediates in the plasma and in various tissues (especially cholestanol), in addition to an increase in the excretion of bile alcohols [2,5,8][2][5][8]. Salen and Grundy (1973) used a radioactive cholestanol labeling method in hospitalized patients to observe the metabolism of cholesterol, cholestanol and bile acids in people affected by CTX. They observed that the plasma cholestanol concentration, miscible molecules and cholestanol synthesis rates were 2–5 times higher in CTX patients when compared with the controls [33][16]. Accumulation of lipid metabolites can lead to pathological repercussions throughout the organism [15]. Salen et al. (1991) [16][17] verified that the proportions of plasmatic cholestanol, which are normally 0.1–0.2% of total cholesterols, were 10–100 times higher in patients with CTX and could reach 2% levels. Furthermore, this proportion can reach up to 50% in the CNS and up to 10% in tendons and the bile. The loss of function of the enzyme CYP27A1 has been reported in certain types of cancer, such as bladder urothelial carcinoma, breast invasive ductal carcinoma, renal clear cell carcinoma, prostate adenocarcinoma and cutaneous melanoma [34][18]. Cholesterol availability promotes bladder cancer cell proliferation in vitro, and CYP27A1 activity leads to 27-hydroxycholesterol production and decreased cholesterol levels, thus inhibiting cancer cell proliferation [35][19]. Thus, CYP27A1 functions as a cellular cholesterol sensor in cancer cells. The relationship between CTX and cancer predisposition as well as a possible effect of CDCA in regulating this pathway in cancer warrant further studies. The mechanisms by which the accumulation of cholesterol metabolites in the CNS occurs are still not precisely known, as cholestanol has a limited ability to cross the blood–brain barrier (BBB). Among the main hypotheses are that the precursor 7α-hydroxy-4-cholesten-3-one crosses the BBB more easily and can be converted into cholestanol by neurons, microglia and astrocytes. In addition, high levels of cholestanol and apolipoprotein B were found in the cerebrospinal fluid (CSF) of patients with CTX, indicating a possible blood–brain barrier dysfunction in these patients [36][20]. Inoue et al. (1999) [37][21] conducted an experiment with rats on a hypercholestanolemic diet and concluded that cholestanol induces apoptosis of the cerebellar neuronal cells, especially for Purkinje cells, a factor that led the rats to present ataxia and tremor. Bogaert et al. (1969) [38][22]. described the autopsy of ataxic CTX patients, demonstrating the destruction of the dentate and fastigial nucleus, in addition to a reduction in Purkinje cells. Those histologic alterations were manifested in magnetic resonance neuroimaging studies as signal intensity changes in the deep cerebellar white matter and particularly in the dentate nucleus (Figure 1).
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Figure 1. Neuroimaging patterns observed in CTX. Axial brain MRI disclosed signal change in deep cerebellar white matter and dentate nucleus (white arrows) which were hypointense on T1W (A) and hyperintense in T2W (B) and FLAIR sequences (C). Coronal brain MRI showed hypointensity in the deep cerebellar white matter on T1W imaging (D).

3. Metabolic Abnormalities and Laboratory Diagnosis of CTX

Cerebrotendinous xanthomatosis is a biochemical defect that comes with identifiable metabolic changes. The disruption of the classic pathway of cholesterol metabolism generates precursor accumulation, which is identified in the serum, CSF, urine, bile and traditionally affected CTX tissues. These biochemical markers are useful in both diagnosis and treatment follow-ups.

4. CTX Treatment and Its Effect on Metabolism

Chenodeoxycholic acid (CDCA), an exogen bile acid, is considered the standard treatment for the disease and is the most efficient option for reverting the biochemical abnormalities of CTX and modifying the disease’s course [12,13,15,33,61,78,79,80,81,82][12][13][15][16][23][24][25][26][27][28]. The main objectives of CDCA therapy are to reduce the synthesis of cholesterol, the plasmatic concentrations of cholestanol and the accumulation of cholestanol [18][29], providing better outcomes for patients [83][30]. Many studies evaluated the metabolic effects of CDCA therapy in CTX patients. The main metabolic alteration provoked by the treatment was a reduction in serum cholestanol to normal levels in the majority of patients [1,7,12,14,15,33,40,44,53,54,68,69,70,79,84,85,86,87,88,89,90,91][1][7][12][14][15][16][25][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. A reduction in cholestanol titers in the CSF and blood cell membranes was also reported [1,16,68,79,92][1][17][25][35][46]. It is possible that CDCA also lowers the BBB permeability to serum cholestanol, reducing the accumulation of this metabolite in the CNS [78,93][24][47]. However, the reduction in cholestanol levels in response to therapy is slow compared with other biomarkers [56,83][30][48]. Several studies reported that CDCA therapy also lowers the high bile alcohol titers in the serum, bile and urine [1,7,40,44,56,71,79,83,84,85,86,94,95,96][1][7][25][30][31][32][38][39][40][48][49][50][51][52]. The normalization of serum bile alcohol levels and urinary and biliary excretion of these metabolites demonstrates CDCA’s capability to inhibit abnormal bile acid synthesis [56,72,83,94][30][48][50][53]. The reduction in the serum levels of bile alcohols occurs before the normalization of serum cholestanol. The bile acid serum and urine titers also decrease with treatment [44,56][32][48], and CDCA represents the main bile compound with a parallel reduction in cholic and ursodeoxycholic acid. The titers of both the tetrols (represented by 5β-cholestane-3α, 7α, 12α and 25-tetrol) and pentols (represented by 5β-cholestane-3α, 7α, 12α, 23R and 25-pentol, 5β-cholestane-3α, 7α, 12α, 24ξ and 25-pentol and 5β-cholestane-3α, 7α, 12α, 22ξ and 25-pentol) in the urine and serum were reduced [56][48]. Different papers have observed different cholesterol responses to treatment with CDCA. In general, the serum cholesterol concentration remains stable with treatment [1,40][1][31]. Some studies have observed a reduction in cholesterol synthesis with CDCA, but no considerable changes were observed in the serum concentration of this molecule [44,97,98,99][32][54][55][56]. Despite this, older trials have evaluated cases of patients who had increased serum cholesterol levels after starting this therapy [56,97][48][54]. In addition, CDCA caused a reduction in serum HDL [100][57] and LDL catabolism [97][54]. It was also seen to reduce the susceptibility of LDL to oxidation [100][57], preventing the formation of oxidized LDL, an important component of xanthomas [100,101,102,103,104][57][58][59][60][61]. Decreases in 7α-hydroxycholesterol [1[1][55],98], 7a-hydroxy-4-cholesten-3-one (7α-HCO/7αC4) [1[1][7][30][31][34][40][41][43][44][45][56],7,40,54,83,86,87,89,90,91,99], lathosterol and lanosterol were also reported. The levels of other sterols, such as campesterol and sitosterol, were also lowered during treatment [1,40,44,54,83,89,99][1][30][31][32][34][43][56]. CDCA also induced a reduction in A1 apolipoprotein, B apolipoprotein and albumin in CSF, indicating the reestablishment of the selective permeability of the BBB [79][25]. The biochemical effects of CDCA therapy in CTX patients are achieved by inhibiting the classic pathway of cholesterol metabolism via negative feedback over the 7α-hydroxylase enzyme [78,83[24][30][50][62],94,105], reducing abnormal bile acid synthesis [3,40,83,97,99,106][3][30][31][54][56][63]. With the reduction in bile acid synthesis, the production of intermediate metabolites such as 7α-hydroxy-4-cholesten-3-one [49,54,89,90,99][34][43][44][56][64] and cholestanol [12,83,94,97,99][12][30][50][54][56] is lowered. Excretion of bile alcohols and cholesterol consumption, which stimulates de novo synthesis in a feedback loop, are also inhibited [40,44,83,107][30][31][32][65]. Aside from CDCA therapy, several studies reported different responses to alternative treatments. A well-studied therapy is the use of cholic acid, which showed clinical improvement or stability in some patients [105,108][62][66]. Some of the results obtained with the administration of cholic acid were a reduction in cholestanol blood and CSF levels [58[62][66][67],105,108], in bile acid synthesis, in urinary excretion of bile alcohol and in the abnormal bile acid tilter in urine [105][62]. Some efficacy was observed in the inhibition of 7α-hydroxylase enzyme activity [105,108][62][66]. In a 2019 study with CA, 53% of patients had reduced cholestanol levels, and none had adverse effects [108][66]. However, cholic acid is not as effective as CDCA, presenting a much smaller capacity for reversing biochemical abnormalities [109,110,111,112,113][68][69][70][71][72]. In general, there are contradictory results concerning the utility of cholic acid in CTX treatment and no consensus on its beneficial effects [13,106,114][13][63][73]. Despite this, cholic acid is often used when patients present side effects of CDCA [105,108,115][62][66][74]. Another possible treatment that has been considered is the use of HMG-CoA inhibitors. Controversial results have been observed regarding the clinical and metabolic response to this treatment, which vary among articles [2,5,11][2][5][11]. Several studies reported beneficial effects of statin use in reducing cholestanol [18[29][39][44][66][67][75][76][77],58,85,90,108,116,117,118], cholesterol and other plant sterol levels and improving lipoprotein and cholesterol metabolism [13,84,89,119][13][38][43][78]. In some studies, clinical improvement was observed with the association of statins with CDCA [81,84][27][38]. In a consensus statement, using the Delphi method, the association of statins to CDCA was suggested to improve or stabilize the prognoses of patients [13]. However, in other studies, statins failed to decrease abnormal bile acid production or stabilize symptoms [56,119][48][78]. Other previously tested treatments that did not achieve satisfactory results are ursodeoxycholic acid (UDCA), LDL apheresis, cholestyramine and clofibrate [13,33,71,83,84,96,109,110,111,120,121,122,123][13][16][30][38][49][52][68][69][70][79][80][81][82].

5. Diet Effects in CTX

Currently, there is limited evidence on the association between cerebrotendinous xanthomatosis and dietary patterns, as very few studies investigated either the pathological or therapeutic potentials of one’s diet. In mice and rats, cholestanol ingestion can increase the cholestanol concentration in the plasma, liver and cerebellum of these animals compared with a control group with no such diet alteration [124,125][83][84]. In another study with CTX animal models fed cholestanol, the rats showed lipid accumulation in the Purkinje cells of the cerebellum, while the mice showed corneal opacifications without the presence of xanthomas [126][85]. A reduction in the plasmatic concentration of cholesterol was also noted in the rat models [124[83][84],125], suggesting there might be competition between cholestanol and cholesterol for intestinal absorption, even though cholestanol is known to be more poorly absorbed than cholesterol [125][84]. The prevalence of cardiovascular disease (CVD) can reach 10–20% in CTX, leading to coronary artery disease at an early age [4,15,127][4][15][86]. In this context, patients with CTX must be screened for CVD and receive dietary recommendations for atherosclerosis prevention [128][87]. A clinical trial reported clinical improvement in patients treated with a cholesterol-restricted diet in addition to conventional pharmacologic treatment with CDCA. However, a direct association was not established between dietary changes and the observed outcomes [129][88].

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