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PubMed1992

Somatosensory and motor evoked potentials in the assessment of cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid: a preliminary study.

We studied two unrelated patients with cerebrotendinous xanthomatosis, in whom clinical examination revealed central nervous system long tract involvement. Brain and spinal cord magnetic resonance imaging showed no signs supporting the involvement of the long pathways. Somatosensory and motor evoked potentials demonstrated central sensory and motor conduction abnormalities, which suggested distal degeneration of longer fibers, rather than scattered focal lesions in the CNS. In one of the patients the neurophysiological study was repeated 6 and 12 months after the beginning of treatment with chenodeoxycholic acid, showing a progressive improvement. Therefore, our data suggest that central motor and sensory conduction studies may be useful in the assessment of the disease and in monitoring treatment.

Adult↗

PubMed1993

Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism.

A condition of osteopenia in some cerebrotendinous xanthomatosis (CTX) patients led us to investigate bone metabolism in 8 patients belonging to 5 families. Serum calcium, phosphate and vitamin D metabolites were in the normal range; a reduction in total body density and impairment of intestinal radiocalcium absorption were found in the majority of our patients.

Absorptiometry, Photon↗

PubMed1993

Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)-apheresis.

We studied the effects of LDL-apheresis on the biochemical and clinical abnormalities of 5 patients with cerebrotendinous xanthomatosis (CTX). Levels of both cholestanol and cholesterol decreased to approximately 60% of those of pretreatment after one perfusion and gradually returned to their initial levels within 2 weeks. Improvement of clinical manifestations and regression of Achilles tendon xanthomas were detected after several perfusions, though dramatic changes could not be recognized. EEG abnormalities were improved immediately after LDL-apheresis in one patient. We conclude that LDL-apheresis may affect the serum cholestanol level and clinical manifestations in patients with CTX.

Achilles Tendon↗

PubMed1995

Mitochondrial enzyme deficiency in cerebrotendinous xanthomatosis.

We report reduced respiratory chain enzyme activity in isolated muscle mitochondria and high levels of serum and CSF pyruvate and lactate in a case of cerebrotendinous xanthomatosis. These findings raise the question of the pathogenetic role of mitochondrial dysfunction in this syndrome.

Adult↗

PubMed1994

Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study.

We describe MRI findings in 13 persons with typical clinical, EEG, CT and biochemical features of cerebrotendinous xanthomatosis (CTX). MRI showed brain (13/13) and cerebellar (12/13) atrophy and diffuse white matter hypodensity (4/13) presumably reflecting sterol infiltration with demyelination. Focal lesions were rare (2/13). Mass effect, edema or enhancement were not observed. Treatment with chenodeoxycholic acid (CDCA) 750 mg/day orally improved neurological and biochemical abnormalities. MRI appears to be of little value in following improvement after treatment has begun. Otherwise, the MRI studies are very sensitive and useful in diagnosing early incomplete forms of CTX.

Adolescent↗

PubMed1994

Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use.

Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX). CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67.3% reduction), lathosterol (50.8%), campesterol (61.7%) and sitosterol (12.7%). However, the sera of the patients changed to be "atherogenic"; total cholesterol, triglyceride and low-density lipoprotein (LDL)-cholesterol were increased, while high-density lipoprotein (HDL)-cholesterol was decreased. Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly "anti-atherogenic", but the reductions of cholestanol (30.4%), lathosterol (44.0%), campesterol (22.9%) and sitosterol (9.6%) were inadequate. Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone. The sera of the patients were apparently more "anti-atherogenic" than those after CDCA treatment. Serum cholestanol concentration was still 2.7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed. Plant sterol levels were also within the normal range. The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels. In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs.

Adult↗

PubMed1996

PET analysis of a case of cerebrotendinous xanthomatosis presenting hemiparkinsonism.

We describe a 34-year-old Japanese woman presenting gait difficulty and Achilles tendon swelling. The patient was diagnosed as having cerebrotendinous xanthomatosis (CTX) based on the high serum cholestanol level and diminished enzymatic activity of 27-hydroxylase of fibroblasts from her skin. Her clinical presentation was atypical regarding the presence of hemiparkinsonism and absence of apparent cataract, dementia, and cerebellar ataxia. Although MRI studies could not detect any abnormality in the basal ganglia or midbrain, PET analysis using [18F]-6-fluoro-L-dopa revealed reduced uptake of dopamine into the putamen, suggesting the impairment of presynaptic dopaminergic neurons.

Adult↗

PubMed1977

Evidence for the early reduction of the 24,25 double bond in the conversion of lanosterol to cholesterol in cerebrotendinous xanthomatosis.

The metabolism of lanosterol and 24,25-dihydrolanosterol (DL) was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse labeling with a mixture of DL-2-14C and 3S,4S,3R,4R-(4-3H)mevalonate. Sterols were isolated from the feces and purified by silver nitrate thin-layer chromatography, and their identities were confirmed by gas-liquid chromatography and mass spectrometry. Their specific activities were then determined and plotted as a function of time. These isotope ratio measurements and specific activity decay curves were consistent with 24,25-dihydrolanosterol and delta7-cholestenol being intermediates in the synthesis of cholesterol from mevalonate and lanosterol, and they suggested that reduction of the lanosterol side chain may occur as an early step in the synthesis of cholesterol. These results are in contrast to the results reported after the administration of triparanol, a delta24-reductase inhibitor.

Brain Diseases, Metabolic↗

PubMed1983

Normocholesterolemic tendon xanthomatosis with overproduction of apolipoprotein B.

This report describes a 46-yr-old man with normocholesterolemic tendon xanthomatosis. He had severe bilateral xanthomas of Achilles tendons and small lesions on patellar tendons; biopsy of the latter revealed a fibroxanthoma of high cholesterol content. He did not have clinical evidence of atherosclerotic disease. The patient's total cholesterol (TC) and triglycerides (TG) were 245 and 258 mg/dl, respectively. LDL-TC was 168 mg/dl and HDL-TC was 32 mg/dl. VLDL consisted mainly of small particles (SfO 20-100) which were unusually rich in apolipoproteins B and E (and low in apo Cs). Plasma LDL-apo B was not increased (85-120 mg/dl), but VLDL-apo B was distinctly elevated (58 mg/dl). The synthesis rate of apoLDL (29.9 mg/kg/d) was increased markedly compared to a matched control (13.9 mg/kg/d) and to a patient with familial hypercholestrolemia (15.9 mg/kg/d). The concentration of apoLDL in our patient was not increased; this was because of an associated high FCR (0.484 day-1). His HDL was relatively low in TC but high in TG, which caused an increase in HDL2b. The patient's xanthomata may have been the result of an overproduction of apo B possibly combined with a defect in HDL metabolism.

Apolipoproteins↗

PubMed1987

Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.

Apolipoproteins↗

PubMed1988

The effect of abnormal plasma and cellular sterol content and composition on low density lipoprotein uptake and degradation by monocytes and lymphocytes in sitosterolemia with xanthomatosis.

The hypothesis that abnormal low density lipoprotein (LDL) sterol content and composition in sitosterolemia with xanthomatosis affects LDL uptake and/or degradation was tested. Monocytes and lymphocytes from three patients and 12 age- and sex-matched controls were incubated at 37 degrees C in lipid-free medium with 125I-labeled LDL prepared from sitosterolemic patients (LDLs) and controls (LDLn) in the presence or absence of excess unlabeled lipoproteins. Normal monocytes and lymphocytes took up and degraded LDLs 13% to 30% less than LDLn (P less than .05). Sitosterolemic monocytes and lymphocytes degraded LDLn 13% and LDLs 67% more actively than control cells (P less than .05). Sitosterolemic monocytes contained three times more sterols and stanols than controls (P less than .01), of which 12% were plant sterols and 2% were 5 alpha-saturated stanols. In one patient, stimulating bile acid synthesis by ileal bypass surgery reduced plasma and monocyte sterol and stanol concentrations about 60%, and was associated with a 40% to 50% increase in LDLn and LDLs receptor-mediated degradation. The decreased uptake and degradation of LDLs relative to LDLn by normal cells suggest that abnormal plant sterols in LDLs may reduce its affinity for the native LDL receptor. Increased receptor-mediated uptake and degradation of LDLs by sitosterolemic cells in the presence of high cellular sterol content may result from failure of the sitosterolemic cells to down-regulate LDL receptor synthesis. Ileal bypass surgery increased cellular LDL receptor activity, reduced plasma and cellular sterol concentrations, and may diminish the risk of premature atherosclerosis in sitosterolemia.

Adult↗

PubMed1990

Decreased cholesterol biosynthesis in sitosterolemia with xanthomatosis: diminished mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and enzyme protein associated with increased low-density lipoprotein receptor function.

We investigated the mechanism for reduced cholesterol biosynthesis in sitosterolemia with xanthomatosis. The conversion of acetate to cholesterol and total and active hydroxymethylglutaryl (HMG) coenzyme A (CoA) reductase activities, enzyme protein mass, and catalytic efficiency were related to low-density lipoprotein (LDL) receptor function in freshly isolated mononuclear leukocytes collected at 9 AM after a 12-hour fast from two affected sisters and 12 control subjects. Active HMG-CoA reductase activity was determined in mononuclear leukocyte microsomes prepared and assayed in the presence of sodium fluoride, while total HMG-CoA reductase activity was determined in the absence of the phosphatase inhibitor. Enzyme protein was assayed using rabbit polyclonal anti-rat liver microsomal HMG-CoA reductase serum. The rates at which [14C]acetate was transformed to cholesterol by sitosterolemic mononuclear leukocytes were decreased 29% and 41%, respectively, compared with the mean value for mononuclear leukocytes from 12 control subjects. Similarly, total HMG-CoA reductase activities were 71% and 68% lower in sitosterolemic mononuclear leukocyte microsomes and were associated with 62% and 65% less enzyme protein than the mean for the control microsomal preparations. This marked decrease in HMG-CoA reductase protein mass in sitosterolemic microsomes was partially compensated for by an increase in the proportion of active enzyme. Sitosterolemic plasma and mononuclear leukocyte cholesterol concentrations were not significantly different from control values, although total sterol levels were increased about 20% because of abundant plant sterols. In contrast, receptor-mediated LDL degradation by sitosterolemic mononuclear leukocytes was increased 50% over control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Combined treatment with chenodeoxycholic acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis.

We studied the effect of chenodeoxycholic acid (CDCA) and a competitive HMG-CoA reductase inhibitor, pravastatin, on clinical symptoms and sterol metabolism in a 36-year-old Japanese man with cerebrotendinous xanthomatosis (CTX). He had marked tendon xanthomas and mild dementia, with obvious electroencephalographic (EEG) abnormalities. He was treated for 2 years with CDCA alone (0.6 g/d) and then for a further year with the combination of pravastatin (10 mg/d) and CDCA (0.6 g/d). For the following year, he was given pravastatin alone, and then was returned to combined treatment again. The plasma cholestanol level before treatment was 3.12 mg/dL, which was 20 times above the control level. After CDCA alone, the plasma cholestanol was reduced to 1.96 mg/dL, and this was further reduced to 0.92 mg/dL by combination therapy with CDCA and pravastatin. However, after the discontinuation of CDCA, his cholestanol levels returned to the pretreatment levels despite the continuing of pravastatin treatment. When the combination therapy was restarted, his cholestanol level was once again markedly reduced. His clinical symptoms showed a close association with the plasma cholestanol level; the xanthomas regressed remarkably and the mental retardation improved in association with normalization of EEG findings during treatment with CDCA alone or in combination with pravastatin. However, during treatment with pravastatin alone, his tendon xanthomas enlarged again and slow waves reappeared on the EEG. Because inhibition of cholesterol synthesis by treatment with the HMG-CoA reductase inhibitor alone was not effective in causing a reduction of cholestanol, the increase in plasma cholestanol levels in CTX may not have been solely due to increased cholesterol synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis.

Significant osteoporosis determined by skeleton radiography and bone densitometry was found in 15 patients with cerebrotendinous xanthomatosis (CTX) whose mean age was 31 +/- 11 years. In three CTX patients, bone biopsies confirmed osteoporosis. Nine patients also sustained bone fractures following minimal trauma. Serum 25-hydroxyvitamin D ([25-OHD] 14.6 +/- 6.6 ng/mL v [normal] 30.4 +/- 8.0 ng/mL; P < .001) and 24,25-dihydroxyvitamin D ([24,25(OH)2D] 1.2 +/- 0.4 ng/mL v [normal] 2.7 +/- 0.8 ng/mL; P < .001) levels were low. Serum concentrations of 1,25(OH)2D, calcium, inorganic phosphorus, alkaline phosphatase, parathyroid hormone, and calcitonin were normal. Patients showed classic manifestations of CTX, including dementia, pyramidal and cerebellar insufficiency, peripheral neuropathy, cataracts, and tendon xanthomas associated with elevated serum cholestanol concentrations. These results demonstrate that extensive osteoporosis and increased risk of bone fractures are components of this inherited disease.

Adolescent↗

PubMed1994

Comparative effects of lovastatin and chenodeoxycholic acid on plasma cholestanol levels and abnormal bile acid metabolism in cerebrotendinous xanthomatosis.

We investigated the effect of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin and the primary bile acid chenodeoxycholic acid (CDCA) on plasma sterol and bile alcohol concentrations and the excretion of bile alcohols in urine in a 38-year-old homozygote with cerebrotendinous xanthomatosis (CTX). Untreated, plasma cholesterol concentrations were less than normal (171 +/- 5 v 185 +/- 3 mg/dL, P < .05) while plasma cholestanol levels were more than 20 times higher than the control mean (2.26 +/- 0.17 v 0.1 +/- 0.1 mg/dL, P < .0001). Plasma and urinary bile alcohol concentrations were markedly increased (12.6 +/- 0.6 and 154 micrograms/mL, respectively, v trace amounts in controls), with the ratio of 5 beta-cholestane-3 alpha,7 alpha,12 alpha, 25-tetrol to 5 beta-cholestane, 3 alpha,7 alpha,12 alpha,23 (22 and 24),25-pentols being 1.6 in plasma and reversed to 0.15 in urine. Treatment with lovastatin (40 mg/d) reduced plasma cholesterol concentrations 13%, but failed to decrease plasma cholestanol or bile alcohol levels. Abundant amounts of bile alcohols continued to be excreted in urine. In contrast, CDCA (750 mg/d) inhibited abnormal bile acid synthesis, as evidence by a 17-fold decrease in total bile alcohol levels in plasma and a 29-fold decrease in urine and the virtual elimination of cholic acid and deoxycholic acid from the bile. Plasma cholestanol concentrations also decreased 85%, but cholesterol levels increased 14%. The combination of CDCA with lovastatin did not improve plasma cholestanol or bile alcohol concentrations compared with CDCA treatment alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Gingival and cutaneous xanthomatosis associated with primary biliary cirrhosis. Report of a case.

The first comprehensive case report of intraoral xanthomatosis associated with primary biliary cirrhosis is detailed. The lesions were present along the free gingival margin and labial vestibule. Crevicular fluid was noted to be tinged yellow. Generalized cutaneous eruptions were also seen. The xanthomas were attributed to the underlying hyperlipoproteinemia. Advanced progression of the hepatic disease necessitated a liver transplant. Disappearance of both oral and skin lesions were subsequently observed.

Adult↗

PubMed1978

Identifications of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 beta-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 alpha-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 beta-tetrol in cerebrotendinous xanthomatosis.

The bile alcohols present in the feces of a patient with cerebrotendinous xanthomatosis were studied. Three bile alcohols which are different from any known natural bile alcohol were isolated as minor components of the fecal bile alcohol fraction. The structures of these compounds were established as 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 beta-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 alpha-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 beta-tetrol by comparison with synthetic samples.

Adult↗

PubMed1979

Configurational assignment of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol excreted by patients with cerebrotendinous xanthomatosis (a circular dichroism study).

The absolute configuration of the C27 pentahydroxy bile alcohol present in bile and feces of two patients with cerebrotendinous xanthomatosis (CTX) was determined by circular dichroism (CD) spectroscopy. Under anhydrous conditions CD spectra of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol in the presence of Eu (fod) 3[tris (1, 1, 1, 2, 2, 3, 3-hepta fluoro-7, 7-dimethyl-octane-4, 6-dionato) europium (III)] exhibited a large induced split Cotton effect at ca. 310 nm. From the induced circular dichroism of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol with Eu(fod) 3 it was concluded that the CTX bile alcohol has the 1, 3 glycol structure with carbon 23 having the R configuration. This information will be useful in elucidating a structural mechanism for the conversion of 5 beta-cholestranepentols into bile acids in man and rat.

Bile↗