DiagnosisClinical DiagnosisCerebrotendinous xanthomatosis (CTX), a lipid storage disease, is suspected in individuals with the following:Infantile-onset diarrhea Childhood-onset cataract Adolescent- to young adult-onset tendon xanthomas (Figure 1)Adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures) FigureFigure 1. Different localization and severity of tendon xanthomas in CTX. Besides the classic xanthomas of the Achilles tendon (A), xanthomas of the patellar tendon (B), the extensor tendons of the hand (C), and the extensor tendons of the elbow (D) , (more...)MRI. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter (Figure 2). FigureFigure 2. MRI findings in three persons with CTX
A. Signal alterations of cerebral peduncle
B. Signal abnormalities of corona radiata and subcortical white matter
C. Hyperintensities of dentate nuclei and cerebellar white matter (more...)TestingCTX is caused by deficiency of the mitochondrial enzyme sterol 27-hydroxylase with resulting cholestanol and cholesterol accumulation in virtually every tissue.Biochemical testing. The main laboratory abnormalities that distinguish CTX from other conditions with xanthomas include the following: High plasma and tissue cholestanol concentration Normal to low plasma cholesterol concentration Markedly decreased formation of chenodeoxycholic acid resulting from impaired primary bile acid synthesis Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid (CSF) resulting from changes in the blood-brain barrier Table 1. Biochemical Abnormalities in Cerebrotendinous XanthomatosisView in own windowAnalyteSourceConcentrationTest AvailabilityIn CTXNormalCholestanolPlasma≤5-10x normal330±30 µg/dLClinical Bile alcoholsUrine14,000±3500 nmol/LNot detectableResearch onlyPlasma≤500-1000x normal values8.48±3.67Other laboratory abnormalities that are observed but not diagnostic:Increased plasma lactate concentration Increased brain lactate concentration (by MR spectroscopy) Enzyme assay. Sterol 27-hydroxylase enzymatic activity in fibroblasts, liver, and leukocytes is markedly reduced in affected individuals. Note: Measurement of enzyme activity is no longer necessary for diagnosis. Molecular Genetic TestingGene. CYP27A1 is the only gene known to be associated with CTX. Clinical testing Sequence analysis of CYP27A1 detects mutations in approximately 90% of affected individuals. Deletion/duplication analysis. Approximately 14% of described mutations are deletions [Gallus et al 2006] (see Table 3 [pdf]). Table 2. Summary of Molecular Genetic Testing Used in Cerebrotendinous XanthomatosisView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCYP27A1Sequence analysisSequence variants 2~90%ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions / duplications~8% 4 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray array GH (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 4. Personal observation in 55 Italian casesInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband1.Sequence analysis 2.Deletion/duplication analysis (if neither or only one mutation is identified by sequence analysis) 3.Measurement of plasma cholestanol concentration for clinical and metabolic correlation or if sequence analysis is not available Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in CYP27A1.}

Natural HistoryCerebrotendinous xanthomatosis (CTX) is suspected in individuals with infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures). See Figure 3.FigureFigure 3. Clinical features of 49 individuals with CTX (28 males, 21 females) from 36 unrelated families with variable clinical features [Author, personal observation]. Cataracts were present in 45 (92%), tendon xanthomas in 38 (78%), osteoporosis in (more...)Intrafamilial variability is considerable [Dotti et al 1996, Nagai et al 1996, Verrips et al 2000a, Federico & Dotti 2003, Moghadasian 2004].A distinction can be made between systemic signs and neurologic signs, described in detail below.Systemic Signs Enterohepatic system. Chronic diarrhea from infancy may be the earliest clinical manifestation of CTX [Cruysberg et al 1991, Cruysberg 2002]. Gallstones have been reported on occasion. Eye. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. In 25% of individuals, cataracts are first observed after age 40 years. Cataracts may be visually significant opacities requiring lensectomy or visually insignificant cortical opacities. The appearance can include irregular cortical opacities, anterior polar cataracts, and dense posterior subcapsular cataracts [Cruysberg et al 1995].
Other findings include palpebral xanthelasmas [Van Bogaert et al 1937, Philippart & Van Bogaert 1969], optic nerve atrophy [Schimschock et al 1968], and proptosis [Morgan et al 1989]. In 13 individuals reported by Dotti et al [2001] ranging in age from 32 to 54 years, all had cataracts, approximately 50% had optic disk paleness, 30% had signs of premature retinal senescence with retinal vessel sclerosis, 15% had cholesterol-like deposits along vascular arcades, and 15% had myelinated nerve fibers.Xanthomas. These appear in the second or third decade. In addition to the classic xanthomas of the Achilles tendon, xanthomas also occur on the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons (Figure 1). Xanthomas have been reported in the lung, bones, and central nervous system (CNS). Cardiovascular system. Premature atherosclerosis and coronary artery disease have been reported [Schimschock et al 1968, Fujiyama et al 1991, Kerleau et al 1993, Valdivielso et al 2004, Frih-Ayed et al 2005]; however, occurrence of atherosclerosis in CTX homozygotes has been attributed to factors other than mutation of CP27A1 [Leitersdorf et al 1994].
Dotti et al [1998] described lipomatous hypertrophy of the atrial septum.Skeleton. Bone involvement is characterized by granulomatous lesions in the lumbar vertebrae and femur, osteopenia and increased risk of bone fractures, and impaired adsorption of radiocalcium, which improves with chenodeoxycholic acid treatment [Berginer et al 1993, Federico et al 1993]. Osteopenia is evident by total body densitometry in untreated individuals. Individuals may have marked thoracic kyphosis. Endocrine abnormalities. Hypothyroidism has occasionally been reported [Philippart & Van Bogaert 1969, Bouwes Bavinck et al 1986, Idouji et al 1991]. Premature aging. Early-onset cataract, osteopenia with bone fractures and loss of teeth, atherosclerosis, and neurologic impairment with dementia and/or parkinsonism, associated with the characteristic facies, suggest a generalized premature aging process [Dotti et al 1991]. Histologic changes. Histologic liver findings include electron-dense amorphous material surrounded by smooth endoplasmic reticulum [Salen et al 1978] and abnormalities in mitochondria with paracrystalline inclusions and increased number of peroxisomes [Federico 1989]. Xanthomas are characterized by birefringent crystalline material surrounded by numerous multinucleate giant cells with foamy cytoplasm. Neurologic Signs Intellectual disability or dementia following slow deterioration in intellectual abilities occurs in the 20s in more than 50% of individuals [Verrips et al 2000b]. Some individuals show intellectual impairment from early infancy, whereas the majority have normal or only slightly subnormal intellectual function until puberty. In the spinal form, intellect is almost always normal. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs are almost invariably present between ages 20 and 30 years. A spinal form, in which spastic paraparesis is the main clinical symptom, was described by Van Bogaert [1962] and more recently by Verrips et al [1999a]. Extrapyramidal manifestations including dystonia and atypical parkinsonism have been reported on occasion [Fiorelli et al 1990, Rogelet et al 1992, Dotti et al 2000, Grandas et al 2002]. Although palatal myoclonus was observed in the first individual reported [Van Bogaert et al 1937], it was not observed in a large series of affected individuals [Dotti et al 2001]. Seizures are reported in approximately 50% of individuals with CTX [Matsumuro et al 1990, Arlazoroff et al 1991, Dotti et al 1996]. Peripheral neuropathy is evident on electrophysiologic studies [Ohnishi et al 1979, Argov et al 1986, Federico et al 1987, Ben Hamida et al 1991], which reveal decreased nerve conduction velocities (NCV) and abnormalities in somatosensory, motor, brain stem, and visual evoked potentials. Clinical manifestations related to peripheral nerve involvement are distal muscle atrophy and pes cavus. Sensory abnormalities are rarely described. Heterozygotes. A symptomatic heterozygote carrier with biochemically proven CTX has been reported [Sugama et al 2001]. Hansson et al [2007] have described an individual with CTX with a heterozygous CYP27A1 mutation who is likely to have a mutation in some additional gene, possibly encoding for a protein responsible for transport of cholesterol into the mitochondria.Neuropathology. Classic CNS pathology findings in CTX include granulomatous and xanthomatous lesions in the cerebellar hemispheres, globus pallidus, and cerebellar peduncles. Demyelination and gliosis and involvement of the long tract of the spinal cord have been described [Van Bogaert et al 1937, Van Bogaert 1962]. Nerve biopsy reveals primary axonal degeneration, demyelination, and remyelination. Federico et al [1991] found mild myopathic changes of increased variability of fiber size with randomly distributed atrophic fibers. Ultrastructural abnormalities included mitochondrial subsarcolemmal aggregates and morphologic changes of these organelles [Federico et al 1991]. Reduced respiratory chain enzyme activity has been observed [Dotti et al 1995]. Neuroimaging. Changes on CT and MRI include diffuse brain and cerebellar atrophy, white matter signal alterations, and bilateral focal cerebellar lesions [Berginer et al 1981, Waterreus et al 1987, Berginer et al 1994, Dotti et al 1994, De Stefano et al 2001]. MR spectroscopy shows decreased n-acetylaspartate and increased lactate indicative of widespread brain mitochondrial dysfunction [De Stefano et al 2001]. The quantitative assessment of brain damage in CTX with use of magnetization transfer MRI has recently been described [Inglese et al 2003].

Genotype-Phenotype CorrelationsSeveral authors have attempted to correlate genotype to phenotype, but no correlation has been identified [Dotti et al 1996, Verrips et al 2000c]. The interaction of many genes and other factors may influence the clinical presentation.

Differential DiagnosisXanthomas. Differential diagnosis includes: Sitosterolemia, inherited sterol storage disease characterized by tendon xanthomas and by a strong predisposition to premature atherosclerosis. Serum concentration of plant sterols (sitosterol and campesterol) is increased. Primary neurologic signs and cataracts are not present. Spastic paraparesis may occur as a result of spinal cord compression by multiple intradural, extramedullary xanthomas [Hatanaka et al 1990]. Hypercholesterolemia and hyperlipemia (especially type IIa), in which plasma cholestanol level is normal When xanthomas are not evident, the differential diagnosis includes all forms of progressive mental deterioration [Gilad et al 1999, Verrips et al 2000b].Early-onset cataract. Cruysberg [2002] reported that CTX comprises the second-largest group of individuals with early-onset cataract and known neurologic disease. (Myotonic dystrophy type 1 is the largest group.) Unexplained juvenile-onset cataracts associated with infantile-onset chronic diarrhea and intellectual disability or deterioration strongly suggest the possibility of CTX [Cruysberg et al 1991, Cruysberg et al 1995, Verrips et al 2000b]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with cerebrotendinous xanthomatosis, the following evaluations are recommended:EMG and nerve conduction velocity in order to evaluate peripheral neuropathyEEG to evaluate for possible epilepsyCardiologic evaluationLaboratory investigations of lipidsEvaluation for osteoporosisTreatment of ManifestationsClinical improvement of individuals with CTX following chenodeoxycholic acid treatment (CDCA, a drug extensively used in the treatment of bile acid metabolism with cholesterol gallstones) was first reported by Berginer et al [1984]. Long-term CDCA treatment (750 mg/day in adults) normalizes bile acid synthesis (leading to disappearance of abnormal metabolites from serum, bile, and urine), normalizes plasma and CSF concentration of cholestanol by suppressing cholestanol biosynthesis, and improves neurophysiologic findings [Mondelli et al 1992, Mondelli et al 2001] and other clinical manifestations including osteoporosis [Federico et al 1993]. For a recent report, see Bonnot et al [2010].In a study of 11 years of treatment with CDCA, Mondelli et al [2001] reported that four months into treatment, nerve conduction velocities normalized and subsequently remained stable; motor evoked potentials (MEPs) and sensory evoked potentials (SEPs) improved slowly but continuously; and clinical manifestations stabilized, but neurologic deficits did not improve. The contrast between two untreated siblings whose symptoms progressed and a third treated sibling whose symptoms stabilized suggests that treatment is beneficial.Inhibitors of HMG-CoA reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs [Peynet et al 1991, Verrips et al 1999b]. However, because of clinical evidence that HMG-CoA reductase inhibitors may induce muscle damage and even rhabdomyolysis, caution is required in the use of these drugs [Federico & Dotti 1994].Other possible treatments include low-density lipoprotein (LDL) apheresis, but the results are controversial [Mimura et al 1993, Berginer & Salen 1994].CoQ₁₀ treatment may improve muscle weakness. Ca⁺⁺ and vitamin D improve osteoporosis.Liver transplantation, although never performed in individuals with CTX, remains a possibility. Eyes. Cataract extraction is typically required in at least one eye by age 50 years. Symptomatic treatments for epilepsy, spasticity, and parkinsonism have been utilized. Parkinsonism is poorly responsive to levodopa, whereas an antihistamine drug, diphenylpyraline hydrochloride, had an excellent effect in three individuals [Ohno et al 2001]. Prevention of Primary Manifestations Early treatment with CDCA in presymptomatic individuals seems to prevent clinical symptoms (see Treatment of Manifestations).Surveillance Annual follow-up is recommended for the following: Neurologic and neuropsychologic evaluation Cholestanol plasma concentration Brain MRI Echocardiography Total body density (TBD) Evaluation of Relatives at RiskEarly diagnosis of at-risk family members using biochemical testing, or molecular genetic testing if the two disease-causing mutations in the proband are known, allows initiation of treatment that may prevent or limit disease manifestations. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationTherapies with CDCA, simvastatin, and LDL apheresis have recently been reported [Dotti et al 2004].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherTherapies with ursodeoxicolic acid, lovastatin, and cholestyramine have been reported to be ineffective [Tint et al 1989, Batta et al 2004].Caution has been suggested with statins [Federico & Dotti 2001].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cerebrotendinous Xanthomatosis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCYP27A12q35Sterol 26-hydroxylase, mitochondrialCYP27A1 @ LOVDCYP27A1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cerebrotendinous Xanthomatosis (View All in OMIM) View in own window 213700CEREBROTENDINOUS XANTHOMATOSIS; CTX 606530CYTOCHROME P450, SUBFAMILY XXVIIA, POLYPEPTIDE 1; CYP27A1Normal allelic variants. Leitersdorf et al [1993] elucidated the genomic structure, containing nine exons and eight introns (18.6 kb of DNA). Pathologic allelic variants. Cali et al [1991] described the first mutations in CYP27A1. Verrips et al [2000a] reviewed reported mutations and molecular genetic testing in 32 families, of which 21 were Dutch. More recently, CYP27A1 mutations have been reported by Gallus et al [2006]. Many of the reported mutations involve splice sites and are predicted to affect mRNA stability or lead to the formation of abnormal mRNA with translation products that are devoid of an adrenodoxin-binding region (residues 351-356) and/or the heme-binding site (residue 453-464), important for enzyme activity. Apart from 19% nonsense mutations, leading to the formation of truncated peptides devoid of function, approximately 45% of mutations are missense mutations that are predicted to lead to the expression of an abnormal cytochrome P450 27 protein.See Table 3 (pdf). Normal gene product. The mature enzyme consists of 498 amino acids and contains putative binding sites for adrenodoxin and heme encoded by the region between exons 6 and 8. Abnormal gene product. Inactive truncated sterol 27-hydroxylase protein leads to several metabolic derangements including increased cholestanol production and bile alcohols [Bjorkhem & Boberg 1995]. Many mutations are predicted to produce an inactive protein without adrenodoxin and/or heme binding domains; many others produce a protein with no functional domains. The other mutations are pathogenic, probably because they change the stability of the protein structure.