Cerebrotendinous Xanthomatosis

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.

Diagnosis/testing.

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.

Management.

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)

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

• Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter (Figure 2) on brain MRI. Changes on brain 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].
• Increased brain lactate concentration (by MR spectroscopy). MR spectroscopy shows decreased n-acetylaspartate and increased lactate indicative of widespread brain mitochondrial dysfunction [De Stefano et al 2001].

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

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.

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].

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.

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.

Nomenclature

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

Prevalence

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].

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.

Surveillance

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 ClinicalTrials.gov 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.

Other

Therapies with ursodeoxicolic acid, lovastatin, and cholestyramine have been reported to be ineffective [Tint et al 1989, Batta et al 2004].