Bezerra, Jose Marcelo Ferreira

de Cerqueira, Ana Claudia Rodrigues

Nardi, Antônio Egídio

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Ana Claudia Rodrigues de Cerqueira

Antônio Egídio Nardi

Jose Marcelo Ferreira Bezerra

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Cerebrotendinous xanthomatosis: a treatable hereditary neuro-metabolic disease

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LETTER TO THE EDITORCerebrotendinous xanthomatosis: a treatablehereditary neuro-metabolic diseaseAna Claudia Rodrigues de Cerqueira,I Antoˆnio Egı´dio Nardi,I Jose Marcelo Ferreira BezerraIII Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. II Departamento de Neurologia, Universidade do Estado do Rio deJaneiro, Rio de Janeiro, Brazil.Email: anacerqueira@globo.comTel.: 55 21 2521-6147INTRODUCTIONCerebrotendinous xanthomatosis is a rare autosomalrecessive hereditary disease that is caused by a mutationin the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27). The CYP27 gene is located onchromosome 2q35-qter and is responsible for the conversionof cholesterol into cholic and chenodeoxycholic acid.Cerebrotendinous xanthomatosis results in increased levelsof serum cholestanol, a cholesterol precursor, and increaseddeposition of cholestanol and cholesterol in various tissues,especially the lenses, tendons, and the central nervoussystem. The principal manifestations of Cerebrotendinousxanthomatosis include juvenile cataracts, tendon xantho-mas, and progressive neurological symptoms.1Early recognition of this condition is essential becausecholic and chenodeoxycholic acid replacement therapy canprevent Cerebrotendinous xanthomatosis -induced braindamage, which leads to severe neurological dysfunctionand death. We present the case of a patient with clinical,radiological, and biochemical evidence of Cerebrotendinousxanthomatosis and his response to cholic and chenodeoxy-cholic acid treatment.CASE REPORTThis report describes a 30-year-old male who displayednormal psychomotor development until 10 years of agewhen, according to his mother, he began presentinglearning difficulties and showed progressive cognitivedecline. At 15 years of age, the patient presented progres-sive gait instability and enlargement of the Achilles tendons.At age 17, he suffered his first convulsive episode. Thepatient has suffered a total of four seizures since that time,and his seizure condition is adequately controlled with theuse of anticonvulsants. A family history revealed that thepatient’s parents were cousins. Physical examinationrevealed bilateral Achilles tendon enlargement and bilateralcataracts. A neurological examination identified spasticparaparesis, brisk deep tendon reflexes and extensor plantarresponses, upper limb symmetrical dysmetria and dysdia-dochokinesia, and ataxic-paraparetic gait. The remainder ofthe patient’s physical examination was normal.Magnetic resonance imaging (MRI) of the patient’s skullrevealed mild cerebellar atrophy (Figure 1). MRI of the leftankle showed fusiform thickening of the Achilles tendonwith heterogeneous signals on all sequences, T2-hyperin-tense foci due to the presence of fat, and a slight increase inthe uptake of paramagnetic contrast. These results weresuggestive of a xanthoma of the Achilles tendon (Figure 2).Laboratory tests (complete blood count, biochemistry, liverand kidney function, lipid panel, and coagulation tests)were normal. The patient’s serum cholestanol level was high(28.3 mg/mL, normal value ,6 mg/mL).Based on these findings, the patient was diagnosed withCTX, and treatment with CDCA (750 mg/day) was imme-diately initiated. The drug was imported from Germany.A significant improvement in neurological symptoms wasobserved after one year of follow-up, especially with respectto ataxia and coordination. The patient retains a slightlyataxic gait but presents normal finger-to-nose and fast fingermovements, and his serum cholestanol level has beenreduced to 4.1 mg/mL. In addition, the patient has under-gone eye surgery to treat his cataracts. The patientauthorized the publication of this case report by signing aconsent form.DISCUSSIONVan Bogaert et al. described the first CTX phenotype in1937.2 Subsequent work established several additionalsymptoms of CTX, including cholestanol accumulation inCopyright  2010 CLINICS – This is an Open Access article distributed underthe terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.Figure 1 - Brain MRI sagittal section in T1, showing mildcerebellar atrophy in a patient with CTX.CLINICS 2010;65(11):1217-1218 DOI:10.1590/S1807-593220100011000281217several tissues and the absence of CDCA in the bile. Thesesymptoms were determined to be the result of a disorder ofhepatic conversion of cholesterol to cholic acid and CDCA.3In 1975, Salen et al. reported that administration of CDCAdramatically reduced cholestanol synthesis in CTXpatients.4 In 1984, Berginer et al. demonstrated that oneyear of CDCA oral supplementation treatment at 750 mg/day was sufficient to produce a significant improvement inneurological symptoms, normalization of EEG readings,and a reduction in serum cholestanol in CTX patients.5 In1991, Cali et al. identified a defect in the gene encoding the27-hydroxylase enzyme in CTX patients.6 More than fiftydifferent mutations of this gene have since been reportedworldwide, and molecular analysis has enabled diagnosisduring the pre-symptomatic period.7The unexplained presence of bilateral cataracts andchronic diarrhea in children suggests a diagnosis of CTX.Tendon xanthomas usually appear in the second or thirddecade of life, especially in the Achilles tendons. Neuro-logical symptoms usually begin in the second decade of lifeand include ataxia, pyramidal and extrapyramidal signs,peripheral sensory-motor neuropathy, epilepsy, anddementia.7,8 Psychiatric manifestations such as depression,suicidal thoughts, catatonia, and psychotic symptoms mayalso present with CTX and usually appear at early stages.9Other clinical manifestations include osteoporosis, bonefractures, premature arteriosclerosis, and coronary and lungdisease.1,8The mechanism underlying the progressive neurologicaldysfunction in CTX remains unknown. Some authorssupport the hypothesis that increased concentrations ofapolipoprotein B in the cerebrospinal fluid (CSF) of CTXpatients facilitates cholestanol and cholesterol transportacross the blood-brain barrier. Presumably, this accumula-tion of cholestanol activates apoptotic pathways, resultingin neuronal death. However, CDCA treatment restores theselective permeability of the blood-brain barrier, normal-izing the concentration of sterols and lipoproteins in the CSFand promoting reversal of the neurological symptoms.1,10In a recent study, Berginer et al. demonstrated that earlydiagnosis and initiation of CDCA treatment during thepre-clinical and initial phases of CTX may prevent thedevelopment of clinical manifestations of CTX. Theseauthors suggest that the following three steps are funda-mental to prevent irreversible damage in patients with CTX:1) recognition of early symptoms, including chronicdiarrhea and juvenile cataracts, by pediatricians, 2) con-firmation of the diagnosis through biochemical and geneticanalysis, and 3) immediate CDCA treatment to prevent theCTX phenotype.7This report describes the case of a patient with clinical,biochemical, and radiological characteristics indicative ofCTX. In support of this diagnosis, biochemical analysisdemonstrated elevated cholestanol levels. Tendon xantho-mas can occur in other lipidoses, such as familial hyperch-olesterolemia and sitosterolemia, but juvenile cataracts andprogressive neurological symptoms are only seen in CTX.1We were unable to perform molecular genetic analysis inour patient, but MRI analysis of the skull revealed cerebellaratrophy. A similar finding has been reported by otherauthors, as have bilateral and symmetric hyperintenselesions surrounding the white matter of the dentate nuclei,cerebral atrophy, and demyelinating lesions.11 Thesechanges were not demonstrated in our case due to techno-logical limitations. CDCA treatment was immediatelyinitiated in our patient, and a significant improvement inneurological symptoms was observed after one year oftreatment. Furthermore, the clinical improvement correlatedwith a reduction in cholestanol serum levels. Unfortunately,because treatment was initiated at a late stage in this case, itdid not result in a functional cure of CTX. However, thetreatment did promote a significant improvement in qualityof life and, more importantly, prevented progression of thedisease.REFERENCES1. Moghadasian MH, Salen G, Frohlich J, Scudamore CH.Cerebrotendinous Xanthomatosis: A Rare Disease with DiverseManifestations. 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 GeneralizedCholesterinose [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. ArchNeurol. 1968;19:47–53.4. Salen G, Meriwether TW, Nicolau G.Chenodesoxycholic acid inhibitsincreased cholesterol and cholestanol synthesis in patients withcerebrotendinous 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 acidbiosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinousxanthomatosis. J Biol Chem. 1991;266:7779–83.7. Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, et al. ChronicDiarrhea and Juvenile Cataracts: Think Cerebrotendinous Xanthomatosisand Treat. Pediatrics. 2009;123:143–7, doi: 10.1542/peds.2008-0192.8. Frederico A, Dotti MT. Cerebrotendinous Xanthomatosis: ClinicalManifestations, Diagnostic Criteria, Pathogenesis, and Therapy. J ChildNeurol.2003;18:633-8, doi: 10.1177/08830738030180091001.9. Lee Y, Lin PY, Chiu NM, Chang WN, Wen JK. Cerebrotendinousxanthomatosis with psychiatric disorders: report of three siblings andliterature review. Chang Gung Med J. 2002;25:334-40.10. Salen G, Berginer V, Shore V, Horak I, Horak E, Tint GS, et al. Increasedconcentrations of cholestanol and apolipoprotein B in cerebrospinal fluidof 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 resonanceImaging and spectroscopic changes in brains of patients with cerebro-tendinous xanthomatosis. Brain. 2000;124:121-31, doi: 10.1093/brain/124.1.121.Figure 2 - Ankle MRI sagittal section in T1 showing Xanthoma ofthe Achilles in a patient with CTX.Cerebrotendinous Xanthomatosisde Cerqueira ACR et al.CLINICS 2010;65(11):1217-12181218

A Cerebral Form of Generalized Cholesterinose [in French].

Cerebrotendinous xanthomatosis with psychiatric disorders: report of three siblings and literature review. Chang Gung Med

Cerebrotendinous Xanthomatosis: A Rare Disease with Diverse Manifestations. Arch Neurol.

Cerebrotendinous Xanthomatosis: Clinical Manifestations, Diagnostic Criteria, Pathogenesis, and Therapy.

Cerebrotendinous xanthomatosis: the storage of cholestanol within the nervous System. Arch Neurol.

Increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid of patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid.

Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid.N

Magnetic resonance Imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis.

Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.

Nicolau G.Chenodesoxycholic acid inhibits increased cholesterol and cholestanol synthesis in patients with cerebrotendinous xanthomatosis.

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Cerebrotendinous xanthomatosis: a treatable hereditary neuro‐metabolic disease

Cerebrotendinous xanthomatosis: a treatable hereditary neuro‐metabolic disease

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