Cerebrotendinous Xanthomatosis de Cerqueira ACR et al. Figure 2 - Ankle MRI sagittal section in T1 showing Xanthoma of the Achilles in a patient with CTX. several tissues and the absence of CDCA in the bile. These symptoms were determined to be the result of a disorder of hepatic conversion of cholesterol to cholic acid and CDCA.3 In 1975, Salen et al. reported that administration of CDCA dramatically reduced cholestanol synthesis in CTX patients.4 In 1984, Berginer et al. demonstrated that one year of CDCA oral supplementation treatment at 750 mg/ day was sufficient to produce a significant improvement in neurological symptoms, normalization of EEG readings, and a reduction in serum cholestanol in CTX patients.5 In 1991, Cali et al. identified a defect in the gene encoding the 27-hydroxylase enzyme in CTX patients.6 More than fifty different mutations of this gene have since been reported worldwide, and molecular analysis has enabled diagnosis during the pre-symptomatic period.7 The unexplained presence of bilateral cataracts and chronic diarrhea in children suggests a diagnosis of CTX. Tendon xanthomas usually appear in the second or third decade of life, especially in the Achilles tendons. Neuro- logical symptoms usually begin in the second decade of life and include ataxia, pyramidal and extrapyramidal signs, peripheral sensory-motor neuropathy, epilepsy, and dementia.7,8 Psychiatric manifestations such as depression, suicidal thoughts, catatonia, and psychotic symptoms may also present with CTX and usually appear at early stages.9 Other clinical manifestations include osteoporosis, bone fractures, premature arteriosclerosis, and coronary and lung disease.1,8 The mechanism underlying the progressive neurological dysfunction in CTX remains unknown. Some authors support the hypothesis that increased concentrations of apolipoprotein B in the cerebrospinal fluid (CSF) of CTX patients facilitates cholestanol and cholesterol transport across the blood-brain barrier. Presumably, this accumula- tion of cholestanol activates apoptotic pathways, resulting in neuronal death. However, CDCA treatment restores the selective permeability of the blood-brain barrier, normal- izing the concentration of sterols and lipoproteins in the CSF and promoting reversal of the neurological symptoms.1,10 In a recent study, Berginer et al. demonstrated that early diagnosis and initiation of CDCA treatment during the pre-clinical and initial phases of CTX may prevent the development of clinical manifestations of CTX. These 1218 CLINICS 2010;65(11):1217-1218 authors suggest that the following three steps are funda- mental to prevent irreversible damage in patients with CTX: 1) recognition of early symptoms, including chronic diarrhea and juvenile cataracts, by pediatricians, 2) con- firmation of the diagnosis through biochemical and genetic analysis, and 3) immediate CDCA treatment to prevent the CTX phenotype.7 This report describes the case of a patient with clinical, biochemical, and radiological characteristics indicative of CTX. In support of this diagnosis, biochemical analysis demonstrated elevated cholestanol levels. Tendon xantho- mas can occur in other lipidoses, such as familial hyperch- olesterolemia and sitosterolemia, but juvenile cataracts and progressive neurological symptoms are only seen in CTX.1 We were unable to perform molecular genetic analysis in our patient, but MRI analysis of the skull revealed cerebellar atrophy. A similar finding has been reported by other authors, as have bilateral and symmetric hyperintense lesions surrounding the white matter of the dentate nuclei, cerebral atrophy, and demyelinating lesions.11 These changes were not demonstrated in our case due to techno- logical limitations. CDCA treatment was immediately initiated in our patient, and a significant improvement in neurological symptoms was observed after one year of treatment. Furthermore, the clinical improvement correlated with a reduction in cholestanol serum levels. Unfortunately, because treatment was initiated at a late stage in this case, it did not result in a functional cure of CTX. However, the treatment did promote a significant improvement in quality of life and, more importantly, prevented progression of the disease. REFERENCES 1. Moghadasian MH, Salen G, Frohlich J, Scudamo re CH. Cerebrotendinous Xanthomatosis: A Rare Disease with Diverse Manifestations. Arch Neurol. 2002;59:527-9, doi: 10.1001/archneur.59.4. 527. 2. Van-Bogaert L, Scherer HJ, Epstein E. A Cerebral Form of Generalized Cholesterinose [in French]. Paris, , France: Masson et Cie; 1937. 3. Menkes JH, Schimschock JR, Swanson PD. Cerebrotendinous xantho- matosis: the storage of cholestanol within the nervous System. Arch Neurol. 1968;19:47–53. 4. Salen G, Meriwether TW, Nicolau G.Chenodesoxycholic acid inhibits increased cholesterol and cholestanol synthesis in patients with cerebrotendinous xanthomatosis. Biochem Med. 1975;14:57-74, doi: 10. 1016/0006-2944(75)90020-4. 5. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendi- nous xanthomatosis with chenodeoxycholic acid.N Engl J Med. 1984;311:1649–52, doi: 10.1056/NEJM198412273112601. 6. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266:7779–83. 7. Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, et al. Chronic Diarrhea and Juvenile Cataracts: Think Cerebrotendinous Xanthomatosis and Treat. Pediatrics. 2009;123:143–7, doi: 10.1542/peds.2008-0192. 8. Frederico A, Dotti MT. Cerebrotendinous Xanthomatosis: Clinical Manifestations, Diagnostic Criteria, Pathogenesis, and Therapy. J Child Neurol.2003;18:633-8, doi: 10.1177/08830738030180091001. 9. Lee Y, Lin PY, Chiu NM, Chang WN, Wen JK. Cerebrotendinous xanthomatosis with psychiatric disorders: report of three siblings and literature review. Chang Gung Med J. 2002;25:334-40. 10. Salen G, Berginer V, Shore V, Horak I, Horak E, Tint GS, et al. Increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid of patients with cerebrotendinous xanthomatosis: effect of chenodeoxy- cholic acid. N Engl J Med. 1987;316:1233-8, doi: 10.1056/ NEJM198705143162002. 11. De Stefano N, Dotti M, Mortilla M, Frederico A. Magnetic resonance Imaging and spectroscopic changes in brains of patients with cerebro- tendinous xanthomatosis. Brain. 2000;124:121-31, doi: 10.1093/brain/124. 1.121.