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LETTER TO THE EDITOR
Cerebrotendinous xanthomatosis: a treatable hereditary neuro-metabolic disease
Ana Claudia Rodrigues de CerqueiraI,
Corresponding author
anacerqueira@globo.com

Tel.: 55 21 2521-6147
, Antônio Egídio NardiI, Jose Marcelo Ferreira BezerraII
I Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
II Departamento de Neurologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Cerebrotendinous xanthomatosis is a rare autosomal recessive hereditary disease that is caused by a mutation in the gene encoding the mitochondrial enzyme sterol 27-hydroxylase &#40;CYP27&#41;&#46; The CYP27 gene is located on chromosome 2q35-qter and is responsible for the conversion of cholesterol into cholic and chenodeoxycholic acid&#46; Cerebrotendinous xanthomatosis results in increased levels of serum cholestanol&#44; a cholesterol precursor&#44; and increased deposition of cholestanol and cholesterol in various tissues&#44; especially the lenses&#44; tendons&#44; and the central nervous system&#46; The principal manifestations of Cerebrotendinous xanthomatosis include juvenile cataracts&#44; tendon xanthomas&#44; and progressive neurological symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a></p><p id="para20" class="elsevierStylePara elsevierViewall">Early recognition of this condition is essential because cholic and chenodeoxycholic acid replacement therapy can prevent Cerebrotendinous xanthomatosis -induced brain damage&#44; which leads to severe neurological dysfunction and death&#46; We present the case of a patient with clinical&#44; radiological&#44; and biochemical evidence of Cerebrotendinous xanthomatosis and his response to cholic and chenodeoxycholic acid treatment&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">CASE REPORT</span><p id="para30" class="elsevierStylePara elsevierViewall">This report describes a 30-year-old male who displayed normal psychomotor development until 10 years of age when&#44; according to his mother&#44; he began presenting learning difficulties and showed progressive cognitive decline&#46; At 15 years of age&#44; the patient presented progressive gait instability and enlargement of the Achilles tendons&#46; At age 17&#44; he suffered his first convulsive episode&#46; The patient has suffered a total of four seizures since that time&#44; and his seizure condition is adequately controlled with the use of anticonvulsants&#46; A family history revealed that the patient&#39;s parents were cousins&#46; Physical examination revealed bilateral Achilles tendon enlargement and bilateral cataracts&#46; A neurological examination identified spastic paraparesis&#44; brisk deep tendon reflexes and extensor plantar responses&#44; upper limb symmetrical dysmetria and dysdiadochokinesia&#44; and ataxic-paraparetic gait&#46; The remainder of the patient&#39;s physical examination was normal&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">Magnetic resonance imaging &#40;MRI&#41; of the patient&#39;s skull revealed mild cerebellar atrophy &#40;<a class="elsevierStyleCrossRef" href="#fig1-cln_65p1217">Figure 1</a>&#41;&#46; MRI of the left ankle showed fusiform thickening of the Achilles tendon with heterogeneous signals on all sequences&#44; T2-hyperintense foci due to the presence of fat&#44; and a slight increase in the uptake of paramagnetic contrast&#46; These results were suggestive of a xanthoma of the Achilles tendon &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_65p1217">Figure 2</a>&#41;&#46; Laboratory tests &#40;complete blood count&#44; biochemistry&#44; liver and kidney function&#44; lipid panel&#44; and coagulation tests&#41; were normal&#46; The patient&#39;s serum cholestanol level was high &#40;28&#46;3 &#181;g&#47;mL&#44; normal value &#60;6 &#181;g&#47;mL&#41;&#46;</p><elsevierMultimedia ident="fig1-cln_65p1217"></elsevierMultimedia><elsevierMultimedia ident="fig2-cln_65p1217"></elsevierMultimedia><p id="para50" class="elsevierStylePara elsevierViewall">Based on these findings&#44; the patient was diagnosed with CTX&#44; and treatment with CDCA &#40;750 mg&#47;day&#41; was immediately initiated&#46; The drug was imported from Germany&#46; A significant improvement in neurological symptoms was observed after one year of follow-up&#44; especially with respect to ataxia and coordination&#46; The patient retains a slightly ataxic gait but presents normal finger-to-nose and fast finger movements&#44; and his serum cholestanol level has been reduced to 4&#46;1 &#181;g&#47;mL&#46; In addition&#44; the patient has undergone eye surgery to treat his cataracts&#46; The patient authorized the publication of this case report by signing a consent form&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">DISCUSSION</span><p id="para60" class="elsevierStylePara elsevierViewall">Van Bogaert et al&#46; described the first CTX phenotype in 1937&#46;<a class="elsevierStyleCrossRef" href="#bib2">2</a> Subsequent work established several additional symptoms of CTX&#44; including cholestanol accumulation in several tissues and the absence of CDCA in the bile&#46; These symptoms were determined to be the result of a disorder of hepatic conversion of cholesterol to cholic acid and CDCA&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a> In 1975&#44; Salen et al&#46; reported that administration of CDCA dramatically reduced cholestanol synthesis in CTX patients&#46;<a class="elsevierStyleCrossRef" href="#bib4">4</a> In 1984&#44; Berginer et al&#46; demonstrated that one year of CDCA oral supplementation treatment at 750 mg&#47;day was sufficient to produce a significant improvement in neurological symptoms&#44; normalization of EEG readings&#44; and a reduction in serum cholestanol in CTX patients&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a> In 1991&#44; Cali et al&#46; identified a defect in the gene encoding the 27-hydroxylase enzyme in CTX patients&#46;<a class="elsevierStyleCrossRef" href="#bib6">6</a> More than fifty different mutations of this gene have since been reported worldwide&#44; and molecular analysis has enabled diagnosis during the pre-symptomatic period&#46;<a class="elsevierStyleCrossRef" href="#bib7">7</a></p><p id="para70" class="elsevierStylePara elsevierViewall">The unexplained presence of bilateral cataracts and chronic diarrhea in children suggests a diagnosis of CTX&#46; Tendon xanthomas usually appear in the second or third decade of life&#44; especially in the Achilles tendons&#46; Neurological symptoms usually begin in the second decade of life and include ataxia&#44; pyramidal and extrapyramidal signs&#44; peripheral sensory-motor neuropathy&#44; epilepsy&#44; and dementia&#46;<a class="elsevierStyleCrossRefs" href="#bib7">7&#44;8</a> Psychiatric manifestations such as depression&#44; suicidal thoughts&#44; catatonia&#44; and psychotic symptoms may also present with CTX and usually appear at early stages&#46;<a class="elsevierStyleCrossRef" href="#bib9">9</a> Other clinical manifestations include osteoporosis&#44; bone fractures&#44; premature arteriosclerosis&#44; and coronary and lung disease&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;8</a></p><p id="para80" class="elsevierStylePara elsevierViewall">The mechanism underlying the progressive neurological dysfunction in CTX remains unknown&#46; Some authors support the hypothesis that increased concentrations of apolipoprotein B in the cerebrospinal fluid &#40;CSF&#41; of CTX patients facilitates cholestanol and cholesterol transport across the blood-brain barrier&#46; Presumably&#44; this accumulation of cholestanol activates apoptotic pathways&#44; resulting in neuronal death&#46; However&#44; CDCA treatment restores the selective permeability of the blood-brain barrier&#44; normalizing the concentration of sterols and lipoproteins in the CSF and promoting reversal of the neurological symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;10</a></p><p id="para90" class="elsevierStylePara elsevierViewall">In a recent study&#44; Berginer et al&#46; 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&#46; These authors suggest that the following three steps are fundamental to prevent irreversible damage in patients with CTX&#58; 1&#41; recognition of early symptoms&#44; including chronic diarrhea and juvenile cataracts&#44; by pediatricians&#44; 2&#41; confirmation of the diagnosis through biochemical and genetic analysis&#44; and 3&#41; immediate CDCA treatment to prevent the CTX phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib7">7</a></p><p id="para100" class="elsevierStylePara elsevierViewall">This report describes the case of a patient with clinical&#44; biochemical&#44; and radiological characteristics indicative of CTX&#46; In support of this diagnosis&#44; biochemical analysis demonstrated elevated cholestanol levels&#46; Tendon xanthomas can occur in other lipidoses&#44; such as familial hypercholesterolemia and sitosterolemia&#44; but juvenile cataracts and progressive neurological symptoms are only seen in CTX&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a> We were unable to perform molecular genetic analysis in our patient&#44; but MRI analysis of the skull revealed cerebellar atrophy&#46; A similar finding has been reported by other authors&#44; as have bilateral and symmetric hyperintense lesions surrounding the white matter of the dentate nuclei&#44; cerebral atrophy&#44; and demyelinating lesions&#46;<a class="elsevierStyleCrossRef" href="#bib11">11</a> These changes were not demonstrated in our case due to technological limitations&#46; CDCA treatment was immediately initiated in our patient&#44; and a significant improvement in neurological symptoms was observed after one year of treatment&#46; Furthermore&#44; the clinical improvement correlated with a reduction in cholestanol serum levels&#46; Unfortunately&#44; because treatment was initiated at a late stage in this case&#44; it did not result in a functional cure of CTX&#46; However&#44; the treatment did promote a significant improvement in quality of life and&#44; more importantly&#44; prevented progression of the disease&#46;</p></span></span>"
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                      "titulo" => "Chenodesoxycholic acid inhibits increased cholesterol and cholestanol synthesis in patients with cerebrotendinous xanthomatosis"
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                        "tituloSerie" => "Biochem Med"
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