ABSTRACT
The authors report the clinical findings in 10 Italian cases of cerebrotendinous xanthomatosis (CTX). In addition to the classical neurological manifestations, the presence of psychiatric symptoms and osteopenia is stressed. Chronic treatment with chenodeoxycholic acid resulted in decreased plasma cholestanol levels and improvement of some central and peripheral neurophysiological parameters including EEG, VEP, SEP and conduction velocities. Due to the presence of cataracts, ischemic heart disease, premature atherosclerosis, mental deterioration and osteoporosis, usually found in old age, CTX can be considered a useful model of premature ageing.
Subject(s)
Brain Diseases, Metabolic/pathology , Lipid Metabolism, Inborn Errors/pathology , Tendons , Xanthomatosis/pathology , Aging/pathology , Bone Diseases, Metabolic/etiology , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic/drug therapy , Brain Diseases, Metabolic/genetics , Chenodeoxycholic Acid/therapeutic use , Cholestanol/blood , Cholestanol/cerebrospinal fluid , Electroencephalography , Female , Follow-Up Studies , Fractures, Spontaneous/etiology , Genetic Carrier Screening , Humans , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/genetics , Magnetic Resonance Imaging , Male , Mental Disorders/etiology , Pedigree , Tendons/pathology , Tomography, X-Ray Computed , Xanthomatosis/diagnosis , Xanthomatosis/drug therapy , Xanthomatosis/geneticsABSTRACT
We investigated the effect of chenodeoxycholic acid on cerebrospinal fluid sterol and protein composition in six patients with cerebrotendinous xanthomatosis, a progressive neurologic disease, and in 11 control subjects. In the cerebrospinal fluid from the controls, the mean (+/- SD) levels of cholesterol and cholestanol were 400 +/- 300 and 4 +/- 7 micrograms per deciliter, respectively. The levels were almost 1.5 and 20 times higher in cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis. Cholestanol levels were also markedly elevated in the plasma of untreated patients, but their plasma cholesterol levels (215 +/- 61 mg per deciliter) were not different from control values. Treatment with chenodeoxycholic acid reduced cerebrospinal fluid cholesterol by 34 percent and cholestanol threefold. Plasma cholestanol levels also decreased sharply. Normal cerebrospinal fluid contained small quantities of albumin, apolipoproteins, and lecithin:cholesterol acyltransferase. In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated. Apolipoprotein AIV and apolipoprotein E concentrations were comparable to those in controls, and apolipoprotein AII was considerably decreased. During treatment, the concentrations of albumin and apolipoproteins AI and B declined. These results suggest that increased cerebrospinal fluid sterols are derived from plasma lipoproteins by means of a defective blood-brain barrier in patients with cerebrotendinous xanthomatosis. Therapy with chenodeoxycholic acid reestablished selective permeability of the blood-brain barrier and normalized the concentrations of sterol and apolipoprotein in the cerebrospinal fluid.
Subject(s)
Apolipoproteins B/cerebrospinal fluid , Brain Diseases, Metabolic/cerebrospinal fluid , Chenodeoxycholic Acid/therapeutic use , Cholestanol/cerebrospinal fluid , Cholesterol/analogs & derivatives , Xanthomatosis/cerebrospinal fluid , Albumins/cerebrospinal fluid , Apolipoproteins/cerebrospinal fluid , Blood-Brain Barrier/drug effects , Brain Diseases, Metabolic/drug therapy , Chenodeoxycholic Acid/pharmacology , Cholestanol/blood , Cholesterol/cerebrospinal fluid , Female , Humans , Male , Phosphatidylcholine-Sterol O-Acyltransferase/cerebrospinal fluid , Tendons , Xanthomatosis/drug therapyABSTRACT
The concentration ratios of cholestanol/cholesterol in biological materials (serum, cerebrospinal fluid and tendon biopsy) were determined using a capillary gas chromatographic method. The method was validated by gas chromatography-mass spectrometry. The ratio was determined in several groups of patients: (a) patients with cerebrotendinous xanthomatosis (in serum, cerebrospinal fluid and tendon biopsy), before and during chenodeoxycholic acid therapy, (b) patients receiving cholestyramine therapy (in serum), (c) patients suffering from various liver diseases (in serum) and (d) one patient before and after liver transplantation (in serum). It can be concluded that the cholestanol/cholesterol concentration ratio is a potentially useful parameter for monitoring liver diseases but is not specific for establishing the diagnosis of cerebrotendinous xanthomatosis.
