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Cerebrotendinous Xanthomatosis

, MD, , MD, and , DSci.

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Initial Posting: ; Last Update: April 14, 2016.

Estimated reading time: 21 minutes


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 cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired 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.

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.


The diagnosis of CTX is established in a proband with the above clinical and biochemical findings and/or by the identification of biallelic pathogenic variants in CYP27A1.


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. Coenzyme Q10 treatment may improve muscle weakness. Cataract extraction is typically required in at least one eye by age 50 years. Epilepsy, spasticity, and parkinsonism are treated symptomatically.

Prevention of primary manifestations: Early treatment with CDCA in presymptomatic individuals appears to prevent clinical manifestations.

Prevention of secondary complications: Calcium and vitamin D supplementation improve osteoporosis.

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

Agents/circumstances to avoid: Caution has been suggested with statins.

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

Pregnancy management: Treatment with chenodeoxycholic acid should not be interrupted during pregnancy.

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 CYP27A1 pathogenic variants in the family are known.


Suggestive Findings

Consensus clinical diagnostic criteria for cerebrotendinous xanthomatosis (CTX) have not been published. However, to aid in the diagnosis of CTX, Mignarri et al [2014] have developed a diagnostic flow chart based on an individual’s degree-of-suspicion score as determined by clinical, family history, and radiographic findings. See Mignarri et al [2014] (Table 2. Suspicion index and Figure 1. Diagnostic flow chart).

CTX, a lipid storage disease, should be suspected in individuals with the following clinical, radiographic, and laboratory findings:

Clinical features

  • 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) have been observed. (more...)

Brain imaging

Figure 2.

Figure 2.

MRI findings in three persons with CTX A. Signal alterations of cerebral peduncle

Laboratory findings. CTX is caused by deficiency of the mitochondrial enzyme sterol 27-hydroxylase with resulting cholestanol and cholesterol accumulation in virtually every tissue. Note: Cali et al [1991] reported that the sterol 27-hydroxylase was often referred to in the literature as a sterol 26-hydroxylase; however, in accordance with IUPAC sterol nomenclature and the stereochemistry of the initial reaction catalyzed by this enzyme, the authors of this GeneReview will refer to it as sterol 27-hydroxylase. Laboratory findings include the following:

  • High plasma and tissue cholestanol concentration (Table 1).
  • 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 (Table 1)
  • Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid (CSF) resulting from changes in the blood-brain barrier
  • Increased plasma lactate concentration

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

Establishing the Diagnosis

The diagnosis of CTX is established in a proband with the clinical and biochemical testing findings above and/or by the identification of biallelic pathogenic variants in CYP27A1 on molecular genetic testing (see Table 2).

Molecular testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of CYP27A1 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes CYP27A1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 2.

Molecular Genetic Testing Used in Cerebrotendinous Xanthomatosis

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
CYP27A1Sequence analysis 3>90%
Gene-targeted deletion/duplication analysis 4<8% 5
Unknown 6NA

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected (see Table 3 [pdf]). For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


In 55 Italian cases [Author, personal observation]


Hansson et al [2007] described an affected individual with two pathogenic variants in cis configuration on one allele of CYP27A1; the authors postulated that a second pathogenic variant in another, as-yet-unknown gene that is critical for the activity of sterol 27-hydroxylase may be cause of the phenotype.

Clinical Characteristics

Clinical Description

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). The clinical features of 55 individuals with CTX were reported as follows: cataracts in 49 (89%), tendon xanthomas in 43 (78%), osteoporosis in 20/30 (67%), and diarrhea in 22 (40%). Neurologic involvement included intellectual disability in 33 (60%) and psychiatric disturbances in 24 (44%). Ataxia was observed in 20 (36%), paraparesis in 35 (64%), parkinsonism in five (9%) and peripheral neuropathy in 21/30 (70%). Seizures were observed in 18 (33%) (see Figure 3). Intrafamilial variability is considerable [Dotti et al 1996, Nagai et al 1996, Verrips et al 2000a, Federico & Dotti 2003, Moghadasian 2004, Mignarri et al 2014].

Figure 3. . Clinical features of 55 individuals with CTX (27 males, 28 females) [Mignarri et al 2014]; * refers to features that were assessed in only a subset of the 55 individuals (i.

Figure 3.

Clinical features of 55 individuals with CTX (27 males, 28 females) [Mignarri et al 2014]; * refers to features that were assessed in only a subset of the 55 individuals (i.e., osteoporosis was seen in 20/30 affected individuals).

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.

Khan et al [2013] reported the unique finding of fleck lenticular opacities in three children with CTX; these affected children also had capsular opacities (posterior only or posterior and anterior) that caused visual symptoms.

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) [Brienza et al 2015].

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], as has lipomatous hypertrophy of the atrial septum [Dotti et al 1998]. The increased prevalence of atherosclerosis in individuals with CTX can be partially explained by the following mechanisms: alteration of the plasma lipid and lipoprotein profile; alteration of bile alcohols; lack of sterol 27-hydroxylase activity in the cellular constituents of the atheroma; and absence of a defense mechanism for macrophages in the metabolism of cholesterol into 27-hydroxycholesterol and 3p-hydroxy5-cholestanoic acid [Leitersdorf et al 1994].

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, Martini et al 2013]. 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].

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 cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty. In the spinal form, mainly characterized by myelopathy and spastic paraparesis, intellect is almost always normal.

Neuropsychiatric symptoms including 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, Ginanneschi et al 2013], 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.


The quantitative assessment of brain damage in CTX with use of magnetization transfer MRI has also been described [Inglese et al 2003].

Pathology Findings

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.

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].


Heterozygotes are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders and gall stones to a symptomatic heterozygote with biochemically proven CTX [Sugama et al 2001; Author, personal observation]. Hansson et al [2007] described an individual with CTX with a heterozygous CYP27A1 pathogenic variant and a presumed second pathogenic variant in an undefined gene that possibly encodes a protein responsible for transport of cholesterol into the mitochondria.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have 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:

  • Cerebral cholesterinosis
  • Cerebrotendinous cholesterosis
  • Van Bogaert-Scherer-Epstein syndrome


The prevalence of CTX is estimated at 0.13:100,000 individuals (see Orphanet: Prevalence and incidence of rare diseases: Bibilographic data [pdf]).

The prevalence of CTX caused by biallelic (homozygous) p.Arg395Cys pathogenic variants has been estimated at 1:50,000 among persons of northern European heritage [Lorincz et al 2005].

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 or tuberous xanthomas, a strong predisposition to premature atherosclerosis, and abnormal hematologic findings. 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]. Sitosterolemia is inherited in an autosomal recessive manner and caused by biallelic pathogenic variants in either ABCG5 or ABCG8.
  • Hypercholesterolemia and hyperlipemia (especially type IIa), in which plasma cholestanol level is normal. See Familial Hypercholesterolemia.

When xanthomas are not evident, the differential diagnosis of cerebrotendinous xanthomatosis (CTX), includes all forms of progressive mental deterioration [Gilad et al 1999, Verrips et al 2000b].

Early-onset cataract. Cruysberg [2002] reported that individuals with CTX comprise the second-largest group 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 for peripheral neuropathy
  • Cardiologic evaluation including EKG and echocardiogram
  • Laboratory investigations of lipids including measurement of plasma cholestanol level (if not performed as part of the diagnostic evaluation)
  • Evaluation for osteoporosis
  • Consultation with a clinical geneticist and/or genetic counselor

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 recent reports see: Bonnot et al [2010], Ginanneschi et al [2013], Martini et al [2013], and Yahalom et al [2013].

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 significant improvement of neurologic deficits.
    • In peripheral nerves CDCA treatment did not influence the number of axons activated by maximum electrical stimulation but instead it increased the conduction of the still-excitable fibers. This suggests that CDCA treatment promotes myelin synthesis in nerve fibers with residual unaffected axons.
    • The effect of therapy may therefore depend largely on the extent of irreversible structural damage to axons.
    • CDCA treatment may be more useful when started early. In a case in which treatment onset was at birth the development of disease appears to be delayed [Authors, personal data; Luyckx et al 2014].

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, Dotti et al 2004].

Coenzyme Q10 (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 manifestations (see Treatment of Manifestations).

Prevention of Secondary Complications

Calcium and vitamin D supplementation improve osteoporosis.


Recommended annual surveillance includes the following:

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

Agents/Circumstances to Avoid

Caution in the use of statins has been suggested [Federico & Dotti 2001].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the CYP27A1 pathogenic variants in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment. If the pathogenic variants in the family are not known, biochemical testing of at-risk individuals can be pursued.

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 statins and LDL apheresis have been reported [Dotti et al 2004]. Cholic acid was used to treat two affected sibs from infancy with resulting improvement in symptoms [Pierre et al 2008].

Search in the US and EU Clinical Trials Register in Europe 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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cerebrotendinous xanthomatosis (CTX) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one CYP27A1 pathogenic variant).
  • Heterozygotes (carriers) are generally asymptomatic, although clinical findings have been reported in a few heterozygotes. (See Heterozygotes.)

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.
  • Heterozygotes (carriers) are generally asymptomatic. (See Heterozygotes.)

Offspring of a proband. The offspring of an individual with CTX are obligate heterozygotes (carriers) for a CYP27A1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CYP27A1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CYP27A1 pathogenic variants in the family.

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.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CYP27A1 pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.


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
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
  • National Organization for Rare Disorders (NORD)
    Phone: 800-999-6673
  • Myelin Disorders Bioregistry Project
  • RDCRN Contact Registry for Sterol and Isoprenoid Research (STAIR) 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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CYP27A12q35Sterol 26-hydroxylase, mitochondrialCYP27A1 @ LOVDCYP27A1CYP27A1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cerebrotendinous Xanthomatosis (View All in OMIM)


Gene structure. CYP27A1 has nine exons [Leitersdorf et al 1993]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. CYP27A1 pathogenic variants have been reported by Cali et al [1991], Verrips et al [2000a], and Gallus et al [2006].

See Table 3 (pdf).

Normal gene product. The sterol 27-hydroxylase enzyme consists of 531 amino acids. Residues 1-33 encode the transit peptide that directs the protein to the mitochondrion. The mature mitocondrial peptide has 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 of the reported pathogenic variants 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. Pathogenic nonsense variants are predicted to result in truncated peptides devoid of function. Approximately 50% of pathogenic variants are missense variants that are predicted to lead to the expression of an abnormal sterol 27-hydroxylase.


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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

  • 14 April 2016 (ma) Comprehensive update posted live
  • 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 live
  • 16 July 2003 (me) Review posted live
  • 18 December 2002 (af) Original submission
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