Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism

Federico, Antonio; Dotti, Maria Teresa; Lorè, F; Nuti, Ranuccio

doi:10.1016/0022-510x(93)90068-a

Cited by 49 publications

(30 citation statements)

References 15 publications

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“…It does, however, reduce abnormally elevated levels of cholestanol, apolipoprotein-B, apolipoprotein-A1, and albumin in the CSF and re-establishes the selective impermeability of the BBB . Improvements in neurophysiologic investigations: NCV and/or VEP (Ginanneschi et al 2013;Mondelli et al 1992;Mondelli et al 2001), EEG (Berginer et al 1984;van Heijst et al 1998), and bone mineral density (BMD) (Federico et al 1993;Martini et al 2013) have also been reported.…”

Section: Treatmentmentioning

confidence: 96%

“…Osteoporosis and an increased risk of fractures are often present in adults, although serum calcium, phosphate, and vitamin D metabolite levels are generally normal (Berginer et al 1993;Federico et al 1993;Martini et al 2013). Premature atherosclerosis has been reported in several cases despite the fact that patients with CTX generally do not have significantly elevated plasma cholesterol levels (Salen 1971;Fujiyama et al 1991;Valdivielso et al 2004).…”

Section: Clinical Presentationmentioning

confidence: 99%

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Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27‐hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction. Although CTX is a rare disorder, it is thought to be underdiagnosed, as presenting signs and symptoms may be nonspecific with significant overlap with other more common conditions. There is marked variability in signs and symptoms, severity, and age of onset between patients. The disease course is progressive and potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. Improved screening and awareness of the condition may help facilitate early diagnosis and treatment.

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Section: Treatmentmentioning

confidence: 96%

Section: Clinical Presentationmentioning

confidence: 99%

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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“…También suprime la biosíntesis de colestanol, normalizándose sus concentraciones en plasma y líquido cefalorraquídeo. Este tratamiento mejora las manifestaciones neurológi-cas 27,28 , manifestaciones sistémicas como los xantomas [29][30][31][32] e incluso la osteoporosis 33 . Desafortunadamente no hay disponibilidad del medicamento en Chile por lo que en este caso fue necesario importarlo.…”

Section: Discussionunclassified

Xantomatosis cerebrotendínea: Una causa de aumento de volumen bilateral del tendón de Aquiles. Caso clínico

Filippi

et al. 2009

Rev. méd. Chile

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“…In humans, mutations of the CYP27A1 gene cause cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by abnormal synthesis of bile acids with development of cataracts, tendon xanthomas, and progressive neurological deterioration (12)(13)(14). Some patients with CTX have a low or low normal serum 25-OHD and a low bone mass which lead to severe early onset osteoporosis and fractures (15,16). A phenotype-genotype analysis of 79 patients with CTX having 23 different homozygous mutations from 45 families did not find any correlation (13).…”

mentioning

confidence: 99%

“…An argument can be made that CYP27A1 may also play a role in vitamin D metabolism. Again, some patients with CTX have a low bone mass and early onset of severe osteoporosis and fractures associated with a low or low normal serum 16). Bile acid metabolism is altered in CTX.…”

mentioning

confidence: 99%

Mutational analysis of CYP27A1: assessment of 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D

2007

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The CYP27A1 gene encodes a mitochondrial enzyme which modulates the acidic biosynthetic pathway for bile acids beginning with the 27-hydroxylation of cholesterol. CYP27A1 also 25-hydroxylates vitamin D 3 . Gene mutations cause cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder, and may cause 25-hydroxyvitamin D deficiency and early onset osteoporosis and fractures in affected patients. To examine the effects of mutations of CYP27A1 on vitamin D and cholesterol hydroxylating activity, recombinant CYP27A1 and mutant cDNAs produced by site-directed mutagenesis were stably expressed in either Escherichia coli or COS-1 cells. Activities of wild type and mutant enzymes were determined with cholesterol, vitamin D 3 , and 1a-hydroxyvitamin D 3 (1aOHD 3 ) as substrates. Of the 15 mutants tested, 11 expressed protein and 4 expressed little or no protein. Functional heme activity, estimated by reduced CO difference spectra at 450 nm, was absent in 12 mutants. When expressed in E. coli, three mutants, K226R, D321G, and P408S, each known to cause clinically CTX, showed modest decreases in reduced CO spectra peak and either no change or decreases of less than 50% in hydroxylation of cholesterol, vitamin D 3 and 1aOHD 3 compared to wild type. When expressed transiently in COS-1 cells, each of these mutants showed 25-hydroxylation activity for 1aOHD 3 as well as wild type. Thus, 3 mutants, K226R, D321G, and P408S, known to occur clinically with non-functioning mutants, hydroxylated cholesterol, vitamin D 3 and 1aOHD 3 . How they contribute to the pathogenesis of CTX despite being biologically active in vitro remains to be determined. KeywordsCYP, cytochrome P450; CTX, cerebrotendinous xanthomatosis; 25-OHD 3 , 25-hydroxyvitamin D 3 ; 1, 25-(OH) 2 D 3 ; 1, 25-dihydroxyvitamin D 3 ; 1αOHD 3 , 1α-hydroxyvitamin D 3 In humans, 25-hydroxylation of vitamin D takes place in both liver microsomes and mitochondria. 25-Hydroxylation of vitamin D 3 in human liver was first demonstrated in partially purified mitochondrial membranes (1,2). CYP27A1 was later identified as the mitochondrial enzyme responsible for 25-hydroxylation of vitamin D 3 and not vitamin D 2 Address all correspondence and requests for reprints to: Norman H. Bell, M.D., Department of Medicine, Medical University of South Carolina, Strom Thurmond Research Building, Room 550, 114 Doughty Street, Charleston, SC 29403, TEL: (843) FAX (843) 876-5163, Email: E-mail: belln@musc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMetabolism. Author manuscript; availabl...

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Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism

Cited by 49 publications

References 15 publications

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Xantomatosis cerebrotendínea: Una causa de aumento de volumen bilateral del tendón de Aquiles. Caso clínico

Mutational analysis of CYP27A1: assessment of 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D

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