CTX IS RARE AND UNDERDIAGNOSED1
The estimated prevalence of CTX in the general population ranges from 1 in 44,000 to 1 in 3,400,000.2
- CTX occurs at a higher frequency in certain genetically isolated populations.
- These include the Sephardic Jewish population (especially those of North African origin) and the Druze community.3-6
- In people of Moroccan Jewish ancestry, the frequency of genetic variants associated with CTX has been estimated at 1/108, with a disease frequency of approximately 6/70,000.4
CTX IS CAUSED BY MUTATIONS OF THE CYP27A1 GENE7
CTX is caused by mutations of the CYP27A1 gene, which codes for the mitochondrial enzyme of sterol-27-hydroxylase that plays a key role in the conversion of cholesterol to bile acids.7,8
- Sterol-27-hydroxylase deficiency reduces the production of cholic acid and chenodeoxycholic acid (CDCA) — the most common endogenous bile acids.9-11
- Because bile acids are inhibitors of CYP7A1, this negative feedback mechanism is lost and the process of cholesterol elimination is interrupted.9,10
- This leads to increased levels of bile alcohols and other bile acid precursors, including 7-hydroxycholesterol and 7α, 12α-dihydroxy-4-cholesten-3-one and accumulation of cholestanol throughout the body, with toxic effects.9,12,13
Refer to the figure for a graphical representation of the disease mechanism.
MECHANISM OF CTX14
Graphical representation of the etiology and pathogenesis of cerebrotendinous xanthomatosis (CTX)
IN PATIENTS WITH CTX, mutation in the CYP27A1 gene leads to
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References:
1.
Lorincz MT, Rainier S, Thomas D, Fink JK. Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized. Arch Neurol. 2005;62(9):1459-1463. doi:10.1001/archneur.62.9.1459
2.
Steiner RD, DeBarber A, Larson A, et al. Living with cerebrotendinous xanthomatosis: patient, caregiver, and expert perspectives. Adv Ther. 2024;41(2):467-475. doi:10.1007/s12325-023-02687-8
3.
Reshef A, Meiner V, Berginer VM, Leitersdorf E. Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin. J Lipid Res. 1994;35(3):478-483.
4.
Berginer VM, Abeliovich D. Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal-recessive trait with high gene frequency in Sephardim of Moroccan origin. Am J Med Genet. 1981;10(2):151-157. doi:10.1002/ajmg.1320100209
5.
Leitersdorf E, Safadi R, Meiner V, et al. Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Am J Hum Genet. 1994;55(5):907-915.
6.
Berginer VM, Gross B, Morad K, et al. Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat. Pediatrics. 2009;123(1):143-147. doi:10.1542/peds.2008-0192
7.
Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2014;37(3):421-429. doi:10.1007/s10545-013-9674-3
8.
MedlinePlus. CYP27A1 gene. Accessed: April 19, 2024. https://medlineplus.gov/genetics/gene/cyp27a1/
9.
Chiang JY. Regulation of bile acid synthesis. Front Biosci. 1998;3:176-193.
10.
Moghadasian MH. Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Clin Invest Med. 2004;27(1):42-50.
11.
Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med. 1984;311(26):1649-1652. doi:10.1056/NEJM198412273112601
12.
Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27(2):143-149. doi:10.1007/s10072-006-0618-7
13.
Rafiq M, Sharrack N, Shaw PJ, Hadjivassiliou M. A neurological rarity not to be missed: cerebrotendinous xanthomatosis. Pract Neurol. 2011;11(5):296-300. doi:10.1136/practneurol-2011-000003
14.
Patni N, Wilson DP. Cerebrotendinous xanthomatosis. [Updated 2023 Mar 8]. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK395578/
