GeneReviews^® [Internet].

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 and/or neonatal cholestasis 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 third decade 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 (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid.

Diagnosis/testing.

The diagnosis of CTX is established in aproband with suggestive findings andbiallelic pathogenic variants inCYP27A1 identified bymolecular genetic testing.

Management.

Targeted therapy: Long-term treatment with chenodeoxycholic acid (CDCA) normalizes plasma and cerebrospinal fluid concentration of cholestanol and improves neurophysiologic findings.

Supportive treatment: Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (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. Cholic acid treatment decreases cholestanol levels and improves neurologic symptoms in the few individuals in whom it has been tried and may be useful in those who experience side effects with CDCA treatments. Cataract extraction is typically required in at least one eye by age 50 years. Epilepsy, spasticity, and parkinsonism are treated symptomatically.

Surveillance: Annual cholestanol plasma concentration, neurologic and neuropsychological evaluation, brain MRI, echocardiogram, and assessment of bone density.

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

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of CDCA treatment and surveillance.

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

Genetic counseling.

CTX is inherited in anautosomal recessive manner. If both parents are known to beheterozygous for aCYP27A1pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being acarrier, and a 25% chance of inheriting neither of thefamilial pathogenic variants. Carrier testing for at-risk family members and prenatal andpreimplantation genetic testing are possible if bothCYP27A1 pathogenic variants in the family are known.

Suggestive Findings

CTX, a lipid storage disease,should be suspected in individuals with the following clinical, laboratory, imaging, and family history findings.

Clinical findings

• Neonatal cholestasis
• 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. 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...)

Laboratory findings

• High plasma and tissue cholestanol concentration (Table 1)
• Normal-to-low plasma cholesterol concentration
• Markedly decreased formation of chenodeoxycholic acid as a result of 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
• Increased plasma lactate concentration

Brain imaging

• Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter (Figure 2) on brain MRI. Additional changes on brain CT and MRI include diffuse brain and cerebellar atrophy, white matter signal alterations, and bilateral focal cerebellar lesions.
• Increased brain lactate and decreased n-acetylaspartate concentration (by MR spectroscopy)

Figure 2.

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

Family history is consistent withautosomal recessive inheritance (e.g., affected sibs and/or parentalconsanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CTXis established in aproband with suggestive findings andbiallelic pathogenic (orlikely pathogenic) variants inCYP27A1 identified bymolecular genetic testing (seeTable 2).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in thisGeneReview is understood to include likely pathogenic variants. (2) Identification ofbiallelicCYP27A1 variants ofuncertain significance (or of one knownCYP27A1 pathogenic variant and oneCYP27A1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination ofgene-targeted testing (single-gene testing,multigene panel) andcomprehensivegenomic testing (exome sequencing,genome sequencing) depending on thephenotype.

Gene-targeted testing requires that the clinician determine whichgene(s) are likely involved, whereasgenomic testing does not. Individuals with the distinctive findings described inSuggestive Findings are likely to be diagnosed using gene-targeted testing (seeOption 1), whereas those in whom the diagnosis of CTX has not been considered are more likely to be diagnosed using genomic testing (seeOption 2).

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). Intrafamilial variability is considerable. A suspicion index for diagnosis has been reported based on clinical and laboratory findings [Mignarri et al 2014].

Gastrointestinal and hepatic findings. Chronic diarrhea from infancy, even in the neonatal period, may be the earliest clinical manifestation of CTX [Cruysberg 2002,Gong et al 2017]. Gallstones have been reported on occasion. Neonatal cholestasis has been identified as a presenting manifestation of CTX [Zhang et al 2021]. Cases with fatal cholestasis [von Bahr et al 2005] and infantile hepatitis in infancy [Clayton et al 2002] have been also reported.

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]. Among large study groups of individuals with juvenile-onset cataracts, CTX was diagnosed in 1.8% in the United States [Freedman et al 2019] and 1.55% in Turkey [Atilla et al 2021].

Other findings include palpebral xanthelasmas, optic nerve atrophy and proptosis, paleness of the optic disk, premature retinal senescence with retinal vessel sclerosis, cholesterol-like deposits along vascular arcades, and myelinated nerve fibers [Dotti et al 2001].

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 (seeFigure 1), and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system [Brienza et al 2015].

Cardiovascular system. Premature atherosclerosis and coronary artery disease have been reported [Valdivielso et al 2004,Androdias et al 2012], as has lipomatous hypertrophy of the atrial septum [Dotti et al 1998,Frih-Ayed et al 2005].

Skeleton. Bone involvement is characterized by granulomatous lesions in the lumbar vertebrae and femur, osteoporosis and increased risk of bone fractures, and impaired adsorption of radiocalcium, which improves with chenodeoxycholic acid treatment [Martini et al 2013]. Osteoporosis is evident by total body densitometry in untreated individuals. Individuals may have marked thoracic kyphosis.

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].

Genotype-Phenotype Correlations

Nogenotype-phenotype correlations forCYP27A1 have been identified.

Nomenclature

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

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

Prevalence

More than 400 individuals with CTX have been reported worldwide [Stelten et al 2021a], with larger groups of affected individuals being reported in the medical literature from Italy, the Netherlands, Germany, Japan, China, Turkey, Israel, and Spain.

Table 4.

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Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CTX, the evaluations summarized inTable 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Caution in the use of statins has been suggested [Federico & Dotti 2001]. SeeTable 7.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of CDCA treatment and surveillance. Early treatment with CDCA in presymptomatic individuals appears to prevent clinical manifestations (seeTreatment of Manifestations). Evaluations can include:

• Molecular genetic testing if theCYP27A1 pathogenic variants in the family are known;
• Biochemical testing including cholestanol plasma concentration if the pathogenic variants in the family are not known.

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Pregnancy Management

Treatment with CDCA should not be interrupted during pregnancy.

Therapies Under Investigation

Gene therapies are under investigation in a mouse model of CTX [Lumbreras et al 2021].

SearchClinicalTrials.gov in the US andEU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Cerebrotendinous xanthomatosis (CTX) is inherited in anautosomal recessive manner.

Risk to Family Members

Parents of aproband

• The parents of an affected child are presumed to beheterozygous for aCYP27A1pathogenic variant.
• If a molecular diagnosis has been established in theproband,molecular genetic testing is recommended for the parents of the proband to confirm that both parents areheterozygous for aCYP27A1pathogenic variant and to allow reliablerecurrence risk assessment.
• If apathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in theproband occurred as ade novo event in the proband or as apostzygoticde novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to havehomozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexondeletion in theproband that was not detected bysequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parentalchromosome with thepathogenic variant that resulted in homozygosity for the pathogenic variant in theproband.
• Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation].

Sibs of aproband

• If both parents are known to beheterozygous for aCYP27A1pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being acarrier, and a 25% chance of inheriting neither of thefamilial pathogenic variants.
• Significant clinical variability may be observed between affected family members: a sib withbiallelic pathogenic variants may experience less severe manifestations with later onset of neurologic signs than theproband [Guenzel et al 2021,Stelten et al 2021b] and may not develop xanthomas [Verrips et al 2000b,Gelzo et al 2021].
• Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation].

Offspring of aproband

• The offspring of an individual with CTX are obligate heterozygotes for aCYP27A1pathogenic variant.
• If the reproductive partner of aproband isheterozygous for aCYP27A1pathogenic variant – a situation more likely to be seen in Israel or Morocco and/or in reproductive partners of Druze ancestry, due to afounder effect – offspring are at risk of inheritingbiallelicCYP27A1 pathogenic variants and being affected with CTX.

Other family members. Each sib of theproband's parents is at a 50% risk of being acarrier of aCYP27A1pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of theCYP27A1 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 and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, seeHuang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once theCYP27A1 pathogenic variants have been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal andpreimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Table A.

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Table B.

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Molecular Pathogenesis

Cerebrotendinous xanthomatosis (CTX) is caused bybiallelic pathogenic variants inCYP27A1. Many of the reported pathogenic variants involve splice sites and are predicted to affectmRNA stability or lead to the formation of abnormal mRNA with translation products that are devoid of an adrenodoxin-binding region and/or the heme-binding site, important for enzyme activity. Other pathogenic variants are predicted to result in truncated peptides devoid of function. The associated deficiency of a functional mitochondrial enzyme sterol 27-hydroxylase causes cholestanol and cholesterol accumulation in virtually every tissue.

Mechanism of disease causation. CTX occurs via aloss-of-function mechanism.

Author Notes

Antonio Federico is Emeritus professor of Clinical Neurology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena Italy.

Gian Nicola Gallus is a postdoctoral fellow in Molecular Biology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy.

Acknowledgments

We acknowledge all our colleagues who in the last 40 years have collaborated with us in the investigation of this condition: Prof GC Guazzi, Prof N De Stefano, Prof A Malandrini, Dr C Battisti, Dr E Cardaioli, Dr P Formichi, Dr S Bianchi, Dr A Rufa, Dr F Sicurelli; particular thanks to Prof MT Dotti and Dr A Mignarri, and all the physicians who referred patients from Italy and abroad. We also acknowledge all our patients.

Author History

Maria Teresa Dotti, MD; University of Siena (2003-2022)
Antonio Federico, MD (2003-present)
Gian Nicola Gallus, DSci (2003-present)

Revision History

• 14 November 2024 (ma) Revision:Targeted Therapy Key Section added
• 17 March 2022 (ha) Comprehensive update posted live
• 14 April 2016 (ma) Comprehensive update posted live
• 1 August 2013 (me) Comprehensive update posted live
• 16 November 2010 (me) Comprehensive update posted live
• 7 February 2006 (me) Comprehensive update posted live
• 16 July 2003 (me) Review posted live
• 18 December 2002 (af) Original submission

Published Guidelines / Consensus Statements

• Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, Mignarri A, Sithole B, Steiner RD, Verma S, Yahalom G, Zubarioglu T, Mochel F, Federico A. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Availableonline. 2021. Accessed 3-9-22.

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