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PubMed2000

MRI of the brain in cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease).

The clinical, biochemical and magnetic resonance imaging findings of two patients with cerebrotendinous xanthomatosis are reported. This is a rare hereditary disease. Early recognition of this entity is important in view of the existing treatment possibilities. Magnetic resonance imaging findings typically include a bilateral and almost symmetrical increase of the signal intensity on the T2-weighted images in the cerebellar and periventricular cerebral white matter, the basal ganglia, the dentate nuclei and the brainstem as well as cerebellar and cerebral atrophy.

Adult↗
PubMed1998

Cerebrotendinous xanthomatosis: evidence of lipomatous hypertrophy of the atrial septum.

Premature atherosclerosis and cardiac complications have been reported among the systemic manifestations of cerebrotendinous xanthomatosis (CTX), a rare bile acid disorder with predominantly neurological features. In some cases, myocardial infarction has been the cause of sudden death. We examined nine CTX patients to determine whether they also had clinical or subclinical signs of cardiovascular disorders. In four of them, transthoracic echocardiography showed thickening of the interatrial septum compatible with lipomatous hypertrophy. The unexpected association of the two abnormalities is unlikely to be coincidental and suggests that careful cardiac examination should be considered, even in the absence of clinical manifestations.

Adult↗
PubMed1998

Treatment and follow-up of children with cerebrotendinous xanthomatosis.

UNLABELLED: The clinical spectrum and the effects of treatment over a period of 5 years in five children with cerebrotendinous xanthomatosis (CTX) are described. In all children biochemical, neuroradiological, and neurophysiological studies were done. CTX was diagnosed and effects of therapy were evaluated by determination of the serum cholestanol/cholesterol ratio (CCR) and the urinary excretion of bile alcohols. All children were treated with chenodeoxycholic acid (15 mg/kg/day) in three divided oral doses. Diarrhoea and juvenile cataract were the main clinical features. Psychomotor retardation, pyramidal and cerebellar signs were also found. After starting treatment, biochemical abnormalities normalized and diarrhoea disappeared. After 1 year of therapy there was no further delay in motor development, and in three children the intelligence quotient improved. EEG abnormalities disappeared. After 5 years of therapy the children are in a stable clinical condition. CONCLUSION: The clinical, biochemical and neurophysiological abnormalities in five children with CTX showed a remarkable improvement after starting treatment with chenodeoxycholic acid. The early diagnosis of CTX and the start of treatment with chenodeoxycholic acid has prevented neurological deterioration for a period of 5 years.

Adolescent↗
PubMed1996

Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis.

This report concerns two new mutations in the sterol 27-hydroxylase gene in two patients with cerebrotendinous xanthomatosis (CTX). In a Surinam-Creole patient (patient A), a G deletion on position cDNA 546/547 in exon 3 led to a frameshift and the introduction of a premature termination codon. In a Dutch patient (patient B), a C-->T transition at position 496 in exon 3 also led to a premature termination codon. Patient A was homozygous for the mutation, whereas patient B was compound heterozygous, a C-->T transition also being found in exon 6 at position 1204. The two new mutations were confirmed by restriction analysis with the restriction enzymes FokI and MaeI, respectively.

Adult↗
PubMed2004

Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDL apheresis.

The concentrations of serum cholesterol, cholestanol and non-cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188+/-10 mg/dl and 0.54+/-0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low-density lipoprotein (LDL)-apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48+/-0.03 mg/dl immediately before and 0.32+/-0.02 mg/dl directly after LDL-apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL-apheresis during this treatment period averaged 122+/-4 mg/dl and 55+/-10 mg/dl, and 0.42+/-0.02 mg/dl and 0.18+/-0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy.

Blood Component Removal↗
PubMed2006

Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to defective activity of the mitochondrial enzyme sterol 27-hydroxylase. In 1991, sterol 27-hydroxylase gene (CYP27A1) was localised on the long arm of chromosome 2 [1]. Clinical characteristics of CTX are diarrhoea, cataracts, tendon xanthomas and neurological manifestations including dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absence or inactive form of the sterol 27-hydroxylase. In this review, according with the aims of this section of the journal, we describe the different pathogenetic mutations in the CYP27A1 gene and the main clinical and pathogenetic aspects that may help clinical neurologists in the diagnosis of CTX.

Cholestanetriol 26-Monooxygenase↗
PubMed1976

Primary hyperlipoproteinemia in xanthomatosis.

Blood lipid values, clinical data and effects of therapy are reported on 74 patients with hyperlipidemia and xanthomatosis. A natural subdivision into two groups was observed on the basis of low density lipoprotein lipid values: one corresponding to Frederickson's type II, characterized by elevated low density lipoproteins, tendinous xanthomata, absence of eruptive xanthomata and a high incidence of cardiovascular diseases and the other resembling Frederickson's type III, with elevated very low density lipoproteins, eruptive xanthomata, xanthomata striata palmaria, elevated cholesterol/triglyceride ratios in the very low density lipoproteins and irregular appearance of floating beta lipoproteins. The latter group consisted of 32 patients in whom cardiovascular symptoms were relatively rare, despite mean cholesterol levels of 500 mg/dl.

Adult↗
PubMed1982

Serum bile acid profiles in cerebrotendinous xanthomatosis.

Non-sulfated bile acid concentrations in sera of 10 cases of cerebrotendinous xanthomatosis (CTX) were determined by mass fragmentography. Total bile acid (TBA) in serum was 0.492 +/- 0.436 microgram/ml (mean +/- SD) which was significantly lower than that (1.481 +/- 0.571) in healthy control sera. Cholic acid was 0.342 +/- 0.291 microgram/ml and was the dominant bile acid, which constituted 69.5% of TBA in serum. Chenodeoxycholic acid was 0.111 +/- 0.133 microgram/ml being a minor component in CTX sera, although it was the major bile acid in healthy control sera. Other bile acids such as deoxycholic acid, lithocholic acid and ursodeoxycholic acid were scarcely detected. Subnormal TBA level and deranged bile acid composition in CTX sera may reflect the defect of bile acid biosynthesis in CTX patients. Determination of serum bile acid may be useful in the diagnosis of CTX.

Adult↗
PubMed1983

Diagnosis of cerebrotendinous xanthomatosis (CTX) and effect of chenodeoxycholic acid therapy by analysis of urine using capillary gas chromatography.

By means of capillary gas chromatography urine samples of patients with cerebrotendinous xanthomatosis (CTX) were investigated before and during treatment by oral administration of chenodeoxycholic acid. The occurrence of various conjugated bile alcohols, presumably glucuronides, was demonstrated, the major compound being 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 xi, 25-pentol. In the bile acid fraction norcholic acid and hydroxycholic acid were shown to be present in considerable amounts. In this way the presence of CTX can be demonstrated conclusively. After chenodeoxycholic acid therapy the excretion of both abnormal bile acids as well as of bile alcohols rapidly decreased within a few weeks, showing the effectiveness of the treatment. By early discovery and subsequent therapy it may be possible to prevent the onset of the detrimental symptoms such as mental deficiency, caused by the accumulation of cholestanol and cholesterol in CTX patients.

Bile Acids and Salts↗
PubMed1986

Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patients with cerebrotendinous xanthomatosis.

We studied the mitochondrial cytochrome P-450-linked monooxygenase system in livers of two patients with cerebrotendinous xanthomatosis (CTX). The three components of this system, which catalyzes steroid 27-hydroxylation, NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27, were stained on a nitrocellulose sheet with antibodies against NADPH-adrenodoxin reductase, adrenodoxin, and cytochrome P-450scc, respectively, from bovine adrenocortical mitochondria. The concentrations of hepatoredoxin in the patients were not significantly different from a control, but the level of NADPH-hepatoredoxin reductase was three times that of the control. Cytochrome P-450s27 was not detected in the patients, but it was present (22.8 pmol/mg of protein) in the control liver. This implies that a defect of mitochondrial cytochrome P-450s27 prevents steroid 27-hydroxylation of hepatic mitochondria in patients with CTX.

Adrenal Cortex↗
PubMed1990

Reduction of urinary bile alcohol excretion and serum cholestanol in patients with cerebrotendinous xanthomatosis after oral administration of deoxycholic acid.

Deoxycholic acid and chenodeoxycholic acid were administered alternately to four patients with cerebrotendinous xanthomatosis. During this oral therapy serum cholestanol and urinary bile alcohols were determined. Both showed a marked decrease after the start of the two different therapies. It can be concluded that not only chenodeoxycholic acid but also deoxycholic acid is able to suppress endogenous human bile acid synthesis, which is in accordance with other experiments describing the effect of feeding of various bile acids on endogenous bile acid synthesis.

Adult↗
PubMed1991

Atherogenic risk factors in cerebrotendinous xanthomatosis.

In a study of coronary artery disease in patients with cerebrotendinous xanthomatosis (CTX), we documented the presence or absence of atherogenic risk factors and performed detailed analyses of serum lipid and lipoprotein profiles. Four of the seven patients examined had coronary arterial narrowing and/or obstruction, but multiple atherogenic risk factors were not found in any of these patients. Total cholesterol (T.ch) levels and low density lipoprotein-cholesterol (LDL-ch) levels were lower, and high density lipoprotein2-cholesterol (HDL2-ch) levels were higher in CTX patients than in controls. Triglyceride and very low density lipoprotein (VLDL) levels were significantly lower in the former. Indices correlating with the risk of atherosclerosis, such as the atherogenic index, and the ratios of apolipoprotein B/apolipoprotein AI, HDL2-ch/LDL-ch, HDL2-ch/HDL3-ch, indicated that CTX serum was, in fact, 'anti-atherogenic'. However, coronary artery disease is frequently seen in patients with CTX. This discrepancy suggests the existence of a unique mechanism by which atherosclerosis is induced in patients with CTX. We discuss a mechanism of disturbed lipoprotein metabolism which might be responsible for the deposition of sterols in the tissues of patients with CTX.

Adult↗
PubMed1976

Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosis. A comparative study of genetic and environmental factors in 274 heterozygous cases.

The incidence of ischaemic diseases in familial hypercholesterolaemia and xanthomatosis (familial Type II) was studied in a group of 158 men and 116 women. (1) Men and women did not differ with regard to the inherited metabolic disease. Levels of serum cholesterol, the marker of the genetic defect, were not statistically different, and cholesterol deposition in tissues, visualized by skin tendon xanthomas, was not sex related. (2) Men and women were different with regard to ischaemic diseases. The incidence was much lower in women, and the mean age of onset 9 years later. Moreover, there was a sex difference in the nature of the ischaemic disease, with a high male predominance of myocardial infarction. (3) Since the major risk factor hypercholesterolaemia could not explain such a difference, the role of other risk factors was investigated. It was shown that the incidence of ischaemic diseases was increased in women by cigarette smoking and hypertension, and that the difference in age of onset between males and females was no longer seen in smoking women. It is suggested that the genetic factor is responsible for the atherosclerotic lesion in both sexes and that other factors playing a role in ischaemic complications including tobacco and hypertension may explain the difference between men and women.

Adult↗
PubMed1988

Immunoglobulin-bound lipoproteins (Ig-Lp) as markers of familial hypercholesterolemia, xanthomatosis and atherosclerosis.

In autoimmune hyper- or dislipidemia secondary to a monoclonal antilipoprotein gammapathy, immunoglobulin-lipoprotein (Ig-Lp) complexes are found in the circulating blood. In order to determine their possible significance in common types of hyperlipidemia we compared the Ig-Lp content of sera from 98 healthy blood donors and 155 outpatients from a Lipid Clinic, including 91 cases of hypercholesterolemia (55 familial and 36 non-familial), 15 cases of hypertriglyceridemia, 20 cases of mixed hyperlipidemia and 29 miscellaneous cases. Detection of the Ig-Lp was performed by an ELISA technique with polyclonal affinity purified anti-LDL + HDL as capture antibodies and peroxidase-labeled anti-Ig antibodies specific for IgA, IgG, IgM heavy chains as indicators. Two cases of monoclonal gammapathy (one IgA K and one IgG L) with dislipidemia served as positive controls for the test. IgG, IgA and IgM Lp were found in the sera of the blood donors, in very small quantities when compared with the monoclonal gammapathy cases. All three types of Ig-Lp were also found in the different hyperlipidemic populations studied. When blood donors were compared to hyperlipidemic patients, no difference was observed for IgG Lp. A significant increase in IgM Lp was found in patients with familial hypercholesterolemia (P less than 0.01). An increase in IgA Lp was also found in hypercholesterolemia, familial or not (P less than 0.01), and in patients with corneal arcus (P less than 0.0001), ischaemic disease (P less than 0.01), tendon xanthomas (P less than 0.05) or xanthelasma (P less than 0.05). Furthermore, in a group of 18 paired parents from 9 different families, positive interparent correlations were found for IgM Lp (r = 0.78; P = 0.013) and IgG Lp (r = 0.69; P = 0.038). Therefore IgM Lp may be markers for subpopulations of familial hypercholesterolemia, and IgA Lp markers for the risk of atherosclerotic ischemic disease and deposition of lipids in the cornea. It may be (1) that natural clones of autoanti-lipoprotein antibodies are responsible for the minute quantities of Ig-Lp found in normal people; (2) that the marked development of one of these clones is the cause of autoimmune hyper- or dyslipidemia and xanthomatosis associated with monoclonal gammapathy; (3) that the limited development of a clone produces the Ig-Lp particles found in hypercholesterolemic patients; (4) that there are types of Ig-Lp particles (IgA Lp) that may be harmful for tissues independently of hypercholesterolemia.

Adult↗
PubMed1987

Polyneuropathy with lipid deposits in Schwann cells and axonal degeneration in cerebrotendinous xanthomatosis.

The present paper is a histological, histochemical and electron microscopic study of biopsied specimens from both right and left Achilles tendon, sural nerve and gastrocnemius muscle in a case of peripheral neuropathy with decreased sensory conduction velocity within a cerebrotendinous xanthomatosis confirmed biochemically in a 29-year-old woman. The tendon specimens contained large deposits of complex, non-homogeneous lipids, distributed intra- and extracellularly. The right sural nerve specimen showed a very severe neuropathy with massive diffuse myelinated fiber loss, presence of foamy macrophages and lipid droplets in Schwann cells. Segmental de- and remyelination was noted in 17% of the teased myelinated fibers. No onion bulbs were observed. Two years later, the left sural nerve specimen revealed a mild diffuse myelinated fiber loss, a more active segmental de- and remyelination (23%) without onion bulbs, and an active regeneration. Lipid storage aspects were absent. The gastrocnemius muscle specimens exhibited slight alterations of neurogenic origin. The pathogenesis of this neuropathy is discussed.

Achilles Tendon↗
PubMed1989

Type IIa hyperlipoproteinemia masquerading as cerebrotendinous xanthomatosis.

We describe an adult patient with type IIa hyperlipoproteinemia, presenting with Achilles tendon xanthomas, cataracts, dementia, ataxia, pyramidal tract signs, and peripheral neuropathy, which are commonly seen in cerebrotendinous xanthomatosis (CTX). However, the diagnosis of CTX was excluded on the basis of the cholestanol level and the normal cholestanol/cholesterol ratio in his serum and tendon. The pathomechanism for some of the clinical manifestations in type IIa hyperlipoproteinemia and CTX might be caused by a common biochemical disturbance.

Aged↗
PubMed1991

Cerebrotendinous xanthomatosis: clinical and biochemical evaluation of eight patients and review of the literature.

We present the clinical and laboratory findings of 8 patients with cerebrotendinous xanthomatosis. The clinical features consisted of a combination of bilateral Achilles tendon xanthomas, cataracts, low intelligence, pyramidal signs, cerebellar signs, convulsions, peripheral neuropathy, foot deformity, cardiovascular disease or atherosclerosis, EEG abnormality, and increased CSF protein. Increased cholesterol was present in the serum, CSF and red cell membrane of all 8 patients. The bile of one patient with late age onset of the disease showed an attenuated production of bile acids and bile alcohols. Three of the 7 had obstruction and/or marked narrowing of the coronary arteries. Data on 136 patients reported throughout the world are reviewed.

Achilles Tendon↗