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Cerebrotendinous Xanthomatosis

Synonyms: Cerebral Cholesterinosis, CTX

, MD, , MD, and , DSci.

Author Information
, MD
University of Siena
Siena, Italy
, MD
University of Siena
Siena, Italy
, DSci
University of Siena
Siena, Italy

Initial Posting: ; Last Update: August 1, 2013.


Clinical characteristics.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by 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, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show mental impairment from early infancy, whereas the majority have normal or only slightly subnormal intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the 20s in more than 50% of individuals. 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 almost invariably become evident between ages 20 and 30 years.


CTX is diagnosed by clinical findings and biochemical testing. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include: high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration; decreased chenodeoxycholic acid; increased concentration of bile alcohols and their glyconjugates; and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid. CYP27A1 is the only gene in which mutations are known to cause cerebrotendinous xanthomatosis.


Treatment of manifestations: Long-term treatment with chenodeoxycholic acid (CDCA) normalizes bile acid synthesis, normalizes plasma and CSF concentration of cholestanol, and improves neurophysiologic findings. Inhibitors of HMG-CoA reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage. Cataract extraction is typically required in at least one eye by age 50 years. Epilepsy, spasticity, and parkinsonism are treated symptomatically.

Surveillance: Annual neurologic and neuropsychological evaluation, cholestanol plasma concentration, brain MRI, echocardiogram, and assessment of total body density (TBD).

Evaluation of relatives at risk: Early diagnosis by biochemical testing or molecular genetic testing if the two disease-causing mutations in the family are known allows for early treatment that may prevent or limit disease manifestations.

Genetic counseling.

CTX is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both disease-causing mutations in the family are known.


Clinical Diagnosis

Cerebrotendinous 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)
Figure 1.. Different localization and severity of tendon xanthomas in CTX.

Figure 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) , and have (more...)

MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter (Figure 2).

Figure 2.. MRI findings in three persons with CTX


Figure 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...)


CTX 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 Xanthomatosis (CTX)

In CTXNormal
CholestanolPlasma≤5-10x normal330±30 µg/dL
Bile alcoholsUrine14,000±3500 nmol/LNot detectable
Plasma≤500-1000x normal values8.48±3.67

Other 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 Testing

Gene. CYP27A1 is the only gene in which mutations are known to cause CTX.

Clinical testing

Table 2.

Summary of Molecular Genetic Testing Used in Cerebrotendinous Xanthomatosis

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CYP27A1Sequence analysisSequence variants 4~90%
Deletion/duplication analysis 5Exonic or whole-gene deletions/duplications~8% 6

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a mutation that is present in the indicated gene


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. (see Table 3 [pdf]). For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


In 55 Italian cases [Author, personal observation]

Testing Strategy

To confirm/establish the diagnosis in a proband


Sequence analysis


Deletion/duplication analysis (if neither or only one mutation is identified by sequence analysis)


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.

Clinical Characteristics

Clinical Description

Cerebrotendinous 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.

Figure 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 32 (65%), and diarrhea in 23 (47%).

Figure 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 (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 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 (Figure 1), and the neck tendons. 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, mainly characterized by myelopathy and spastic paraparesis, 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] and Mignarri et al [2011].
  • 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, Mignarri et al 2012b]. 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. However, heterozygotes are generally asymptomatic.

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, Guerrera et al 2010, Androdias et al 2012, Mignarri et al 2012a]. 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 Correlations

Several 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.


Terms used in the past for cerebrotendinous xanthomatosis and no longer in use include the following:

  • Cerebrotendinous cholesterosis
  • Van Bogaert-Scherer-Epstein syndrome


The prevalence of CTX caused by the p.Arg395Cys mutation alone has recently been estimated at approximately one per 50,000 among persons of northern European heritage [Lorincz et al 2005]. Epidemiologic studies are lacking.

Series of affected individuals have been reported in Israel and the US [Berginer et al 1984], Italy [De Stefano et al 2001, Dotti et al 2001], Spain [Pilo-de-la-Fuente et al 2011], Japan [Kuriyama et al 1991], and the Netherlands [Waterreus et al 1987, Verrips et al 2000a]. Affected individuals have been reported in Belgium [Van Bogaert et al 1937, Philippart & Van Bogaert 1969], Brazil [Canelas et al 1983], Canada [Pastershank et al 1974], France [Rogelet et al 1992], Iran [Farpour & Mahloudji 1975], Norway [Schreiner et al 1975], Tunisia [Ben Hamida et al 1991], Spain [Campdelacreu et al 2002], China [Ko & Lee 2001], and Sweden [Rystedt et al 2002].

Differential Diagnosis

Xanthomas. Differential diagnosis includes the following:

  • 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. See Familial Hypercholesterolemia.

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].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with cerebrotendinous xanthomatosis, the following evaluations are recommended:

  • EMG and nerve conduction velocity in order to evaluate peripheral neuropathy
  • EEG to evaluate for possible epilepsy
  • Cardiologic evaluation, including EKG and echocardiogram
  • Laboratory investigations of lipids, including measurement of plasma cholestanol level
  • Evaluation for osteoporosis
  • Medical genetics consultation

Treatment of Manifestations

Chenodeoxycholic acid (CDCA). Long-term treatment with CDCA (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].

Treatment with CDCA has been reported to lead to the following [Mondelli et al 2001]:

  • Normalization of nerve conduction velocities and subsequent stabilization
  • Slow and continuous improvement in motor evoked potentials (MEPs) and sensory evoked potentials (SEPs)
  • Overall stabilization of clinical manifestations without improvement of neurologic deficits.

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].

Low-density lipoprotein (LDL) apheresis has been proposed as a possible treatment; results are controversial [Mimura et al 1993, Berginer & Salen 1994].

CoQ10 treatment may improve muscle weakness.

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 appears to prevent clinical symptoms (see Treatment of Manifestations).

Prevention of Secondary Complications

Calcium and vitamin D improve osteoporosis.


Recommended annual surveillance includes the following:

  • Neurologic and neuropsychologic evaluation
  • Cholestanol plasma concentration
  • Brain MRI
  • Echocardiography
  • Total body density (TBD)

Evaluation of Relatives at Risk

Early 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.

Pregnancy Management

Treatment with chenodeoxycholic acid should not be interrupted during pregnancy.

Therapies Under Investigation

Therapies with CDCA, simvastatin, and LDL apheresis have recently been reported [Dotti et al 2004].

Search for access to information on clinical studies for a wide range of diseases and conditions.


Therapies 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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cerebrotendinous xanthomatosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are generally asymptomatic, although an increased incidence of cardiovascular disorders and gall stones has been observed in obligate carriers [Author, personal observation].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are generally asymptomatic.

Offspring of a proband. The offspring of an individual with CTX are obligate heterozygotes (carriers) for a CYP27A1 disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Disease manifestations in heterozygotes. An increased frequency of cardiovascular disorders and gallstones has been observed in families of affected individuals [Author, personal observation].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
  • Myelin Disorders Bioregistry Project
  • RDCRN Patient Contact Registry: Sterol and Isoprenoid Research Consortium

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)


Gene structure. Leitersdorf et al [1993] elucidated the genomic structure, containing nine exons and eight introns (18.6 kb of DNA). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Cali et al [1991] described the first pathogenic variants 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. 19% of mutations are 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.


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Suggested Reading

  1. Björkhem I, Hansson M. Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge. Biochem Biophys Res Commun. 2010;396:46–9. [PubMed: 20494109]
  2. Keren Z, Falik-Zaccai TC. Cerebrotendinous xanthomatosis (CTX): a treatable lipid storage disease. Pediatr Endocrinol Rev. 2009;7:6–11. [PubMed: 19696711]
  3. Sedel F, Tourbah A, Fontaine B, Lubetzki C, Baumann N, Saudubray JM, Lyon-Caen O. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis. 2008;31:295–307. [PubMed: 18344012]
  4. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:456–68. [PMC free article: PMC3888787] [PubMed: 18577977]

Chapter Notes

Author Notes

Antonio Federico is a full professor of Clinical Neurology and Director of the Department of Neurological and Behavioral Sciences, University of Siena. Maria Teresa Dotti is an associate professor at the University of Siena. Gian Nicola Gallus is a PhD student in the PhD Program of Applied Neurological Sciences, Department of Neurological and Behavioral Sciences, University of Siena.

Revision History

  • 1 August 2013 (me) Comprehensive update posted live
  • 20 October 2011 (cd) Revision: deletion/duplication analysis available clinically
  • 16 November 2010 (me) Comprehensive update posted live
  • 25 January 2008 (cd) Revision: prenatal testing available
  • 7 February 2006 (me) Comprehensive update posted to live Web site
  • 16 July 2003 (me) Review posted to live Web site
  • 18 December 2002 (af) Original submission
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