Xanthomatosis

The term cardiovascular xanthomatosis will be used for the sum of valvular (see fig. 5) and arterial atheromatous lesions which are found in subjects with EFH. Although its use serves to emphasize some peculiarities of both kinds of lesions as compared to general atherosclerosis (age of victim, preponderance of foam cells) it does not imply that atherosclerosis in EFH can be reliably distinguished on morphological grounds from other atherosclerosis. 

The incidence and prevalence of signs and symptoms of atherosclerosis is high in subjects with EFH. An early discussion relevant to this subject was published from Addison s school (Fagge 1872). Cardiovascular xanthomatosis has been 

Disturbances of peripheral and cerebral circulation in EFH are much less common than coronary insufficiency (Gueavich and Venegas 1962). One reason for this phenomenon is that patients may not survive until large vessels become occluded. Besides, the epidemiology of cerebrovascular disease differs in several aspects from that of coronary heart disease. 

A diagnosis of valvular xanthomatosis may be made after exclusion of congenital and rheumatic heart disease by a search for skin and tendon xanthomas and determination of plasma lipid levels. 

Age (years) Cholesterol, 1 mean and 90 % limits mg/100 ml Phospholipid, mean and 90 % limits mg/100 ml 

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CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Ishibashi S, Goldstein JL, Brown MS, Herz J, Bums DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994 93(5) 1885—1893. 

Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with this disease. 

Cali JJ, Hsieh CL, Francke U, Russell DW. 1991. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 266 7779-7783. 

Guyant-Marechal L, Verrips A, Girard C, Wevers RA, Zijlstra F, et al. 2005. Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. Am J Med Genet A 139 114-117. 

Lorincz MT, Rainier S, Thomas D, Fink JK. 2005. Cerebro-tendinous xanthomatosis possible higher prevalence than previously recognized. Arch Neurol 62 1459-1463. 

Miki H, Takeuchi H, Yamada A, Nishioka M, Matsuzawa Y, et al. 1986. 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. Clin Chim Acta 160 255-263. 

Wakamatsu N, Hayashi M, Kawai H, Kondo H, Gotoda Y, et al. 1999. Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism. J Neurol Neurosurg Psychiatry 67 195-198. 

Atypical dysbetalipoproteinemia, associated with the APOE-313 phenotype rather than the classic APOE-212 phenotype, is characterized by severe hypercholesterolemia and hypertriglyceridemia, xanthomatosis, premature vascular disease, and a preponderance of 3-VLDL. Subjects with atypical dysbetalipoproteinemia are homozygous for an amino acid substitution in APOE at residue 158 (495). In AD, APOE-4 carriers show lower levels of APOE in the CSF compared to controls (496). 

Pitt JJ (2007) High-throughput urine screening for Smith-Lemli-Opitz syndrome and ce-rebrotendinous xanthomatosis using negative electrospray tandem mass spectrometry. Clin Chim Acta 380 81-88... 

Defective side-chain oxidation is found in patients affected by cerebrotendinous xanthomatosis (CTX), an autosomal recessive defect characterised by deficit of mitochondrial 27-hydroxylase. The CTX defect leads to an accumulation of cholestanol and cholesterol in most tissues, while serum concentrations of CA, as well as other BAs, are sensibly low. 

Yagu, H., Kitamine, T., Osuga, J., Tozawa, R., Chen, Z., et al. (2000) Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. J. Biol. Chem. 275,21324-21330. 

Salen, G., Shefer, S., and Berginer, V. M., Familial diseases with storage of sterols other than with cholesterol Cerebrotendinous xanthomatosis and sitosterolemia with xanthomatosis. In The Metabolic Basis of Inherited Disease (J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.), 5th Ed., pp. 713-730. McGraw-Hill, New York, 1983. 

Xanthomatosis, an autosomal recessive inherited disorder, was described by A. Abramov, S. Schorr and M. Wolman in 1956. Probably, this rare clinical picture (about 40 cases have been reported to... 

Berginer, VJM., Salen, G., Shefer, S. Long-term treatment of cerebro-tendinous xanthomatosis with chenodeoxycholic acid. New EngJ. X Med. 1984 311 1649-1652... 

Leitersdorf, E., Meiner, V. Cerebrotendinous xanthomatosis. Curr. Opin. Lipidol. 1994 5 138-142... 

Nakamura, T., Matsuzawa, Y., Takemura, K., Knbo, M., Mikl, H., Tarui, S. Combined treatment with chenodeoxychohc acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis. Metabolism 1991 40 741-746... 

Salen, G., Berginer, V.M., Shore, V., Horak, I., Horak, E., Tint, G.S., Shefer, S. Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. New Engl. J. Med. 1987 316 1233-1238... 

Structure and Biosynthesis of Bile Alcohols Disorders of Cholesterol Side-Chain Oxidation in Cerebrotendinous Xanthomatosis... 

In 1971, Salen reported (12) that the rare inheirted lipid storage disease, cerebrotendinoux xanthomatosis (CTX), was associated with defective bile acid synthesis. The major and prominent clinical features in CTX syndrome were tendon xanthomas, juvenille cataracts, dementia, pyramidal paresis, cerebellar ataxis, abnormal electroencephalogram (EEC), and cerebral computed tomographic (CT) scans, premature atherosclerosis, pulmonary dysfunction and osteoporosis. Low serum levels of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were also detected in these patients in association with osteoporosis and frequent bone fractures (13,14). The disease is inherited as an autosomal recessive trait, but is usually detected in adults when cholesterol and cholestanol have accumulated over many years (13-16). Major biochemical... 

Isolation and Characterization of Bile Alcohols in Cerebrotendinous Xanthomatosis ( CTX1... 

While these studies were in progress, Reshef etal. reported the analysis of die sterol 27-hydroxylase gene mutant allele in a Jewish family of Algerian origin (64). They further stated that the CTX disorder which is characterized by extensive nervous system involvement, juvenile cataracts, tendon xanthomatosis and premature atheroselerosis was caused by the sterol 27-... 

Salen, G. (1971). Cholestanol deposition in cerebrotendinous xanthomatosis a possible mechanism. Ann. Intern. Med. 75 843-851. 

Menkes, J. H., Schimschok, J. R. and Swanson, P. D. (1968). Cerebrotendinous xanthomatosis The storage of cholestanol within the nervous system. Arch. Neurol. 19 47-53... 

Salen, G. and Grundy S. M. (1973). The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. /. Clin. Invest. 52 2822-2835. 

Setoguchi, T., Salen, G., Tint, G. S. and Mosbach, E. H. (1974). A biochemical abnormality in cerebrotendinous xanthomatosis incomplete oxidation of the cholesterol side chain. J. Clin. Invest. 53 1393-1401. 

Yashuara, M., Kuramoto, T. and Hoshita, T. (1978). Identification of 5P-cholestane-3a,7a,12a,23P-tetrol, 5P-cholestane-3a,7a,12a,24a-tetrol and 5P-cholestane-3a,7a,12a,24P-tetroI in cerebrotendinous xanthomatosis. Steroids. 31 333-345. 

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