Cerebrotendinous xanthomatosis

INTRODUCTION — Cerebrotendinous xanthomatosis (CTX; MIM 213700) is an autosomal recessive lipid storage disease caused by disruption of bile acid synthesis that was first described in 1937 [1]. A deficiency of the enzyme sterol 27-hydroxylase causes the accumulation of cholesterol and cholestanol in virtually all tissues [2]. Fat deposition leads to the formation of xanthomas, nodules, and plaques in the central nervous system, eyes, tendons, skin, lungs, and bones.

CTX is one of a group of neurologic disorders, collectively referred to as leukodystrophies, which predominantly affect the central nervous system white matter. These disorders are caused by defects in the synthesis or maintenance of the myelin sheath that insulates the nerves.

The main neurologic features of CTX are cerebellar ataxia, pyramidal tract signs, and intellectual decline. One or more of these is usually apparent by late childhood or early adulthood. The syndrome is slowly progressive, and while there is no cure, its course can be altered with treatment.

This topic will review the pathogenesis, clinical features, diagnosis, and treatment of CTX.

PATHOGENESIS — The pathogenesis of cerebrotendinous xanthomatosis (CTX) involves a genetic defect in the CYP27A1 gene that causes derangements of lipid metabolism.

Genetics — CTX is caused by pathogenic variants in the CYP27A1 gene on chromosome 2q35 that encodes the mitochondrial enzyme sterol 27-hydroxylase [3,4]. Deficiency of this enzyme, a member of the cytochrome P-450 enzyme family, results in increased cholestanol and cholesterol.

Over 100 pathogenic variants have been described in CYP27A1 [5]. No correlation between genotype and phenotype has been established, even within identical twins and other family members [6,7].

Inheritance of CTX is autosomal recessive.

Lipid derangements — The normal catabolism of cholesterol depends on the formation of primary bile acids (cholic acid and chenodeoxycholic acid) through various sterol intermediates. Ten different enzymes are required for the hydroxylation of the four-membered cholesterol ring structure in the endoplasmic reticulum and cytosol, and oxidation of its eight-carbon side chain in the mitochondria and peroxisomes [8-11].

Sterol 27-hydroxylase, in the presence of cofactors ferredoxin and NADPH-ferredoxin reductase, catalyzes the hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol at C27 [3]. The deficiency of sterol 27-hydroxylase leads to the accumulation of cholestanol and cholesterol and their precursors in plasma and tissues and the excretion of glucuronides in urine [12].

The disruption of bile acid synthesis in CTX leads to the upregulation of CYP7A, the gene encoding cholesterol 7 alpha-hydroxylase, which catalyzes the rate-limiting step of bile acid synthesis, the conversion of cholesterol and 7 alpha-hydroxycholesterol to cholestanol [13].

Hydrophobic bile acids are required to activate heterodimers that, in turn, reduce CYP7A transcription. However, in CTX, levels of chenodeoxycholic acid, which is highly hydrophobic, are decreased [14-16]. In fact, the exogenous administration of chenodeoxycholic acid has been shown to downregulate CYP7A transcription [17].

Bile acids are also necessary for feedback inhibition of hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA), which is involved in regulating cholesterol production [15]. In CTX, increased activity of hepatic HMG-CoA reductase causes elevated synthesis of cholesterol, thereby enhancing hepatic secretion of apo B-containing lipoproteins. Low-density lipoprotein (LDL) receptors are upregulated, resulting in normal serum cholesterol levels in CTX [18-20].

Neurologic injury — Although the pathogenesis remains unknown, one hypothesis is that a membrane defect causes the accumulation of sterols in the eyes (blood-lens barrier), central nervous system (CNS) (blood-brain barrier), peripheral nerves (blood-nerve barrier), and vessel walls (endothelial cell membrane) [21].

In human aortic and pulmonary endothelium, sterol 27-hydroxylase may provide local defense against the accumulation of cholesterol in the arterial wall [22]. Cholesterol is a major constituent of the myelin sheath, and its availability in oligodendrocytes is a rate-limiting factor for brain maturation [23]. Cholesterol is also present in the plasma membranes of astrocytes and neurons [24]. Furthermore, sterols are important in membrane permeability. Minor changes in sterol structure, such as the incorporation of cholestanol instead of cholesterol, can have deleterious effects on cell membrane integrity [24].

Cholestanol is thought to be responsible for the neurologic toxicity in CTX. Evidence of a neurotoxic mechanism is supported by the finding of cholestanol deposition in neuronal cells, most notably Purkinje cells, in the cerebellum of rats fed a 1 percent cholestanol diet [25]. Furthermore, in vitro study of cerebellar neuronal cells cultured with cholestanol revealed increased apoptosis [25].

Additional evidence supporting a neurotoxic mechanism comes from a study of 12 patients with CTX who had magnetic resonance spectroscopy (MRS), which revealed decreased N-acetylaspartate (NAA), increased lactate, and normal choline [14]. Decreased NAA is thought to be due to neuronal or axonal damage, and increased lactate is a marker for a defect in mitochondrial metabolism or infiltration of inflammatory cells. The normal choline levels argue against processes that cause membrane breakdown, such as active demyelination.

Mitochondrial dysfunction — As just discussed, the finding of increased lactate on MRS suggests diffuse brain mitochondrial dysfunction in patients with CTX [14]. In addition, abnormal aggregates of mitochondria were observed in muscle biopsies performed in eight patients with CTX [26]. An additional case had decreased activity of respiratory chain enzymes, including cytochrome c oxidase, as well as significantly elevated pyruvate and lactate in the serum and cerebrospinal fluid [27]. Clinically, the patient had a myopathic facies (ie, expressionless with drooping cheeks and inability to smile or frown due to weakness) and generalized muscle weakness, consistent with mitochondrial dysfunction.

The cause of the mitochondrial dysfunction remains unknown, but one hypothesis is that toxic effects of elevated cholestanol or bile acids or membrane alteration may play a role.

EPIDEMIOLOGY — Cerebrotendinous xanthomatosis (CTX) is a rare disease with variable penetrance based upon ancestry. The disease has been reported in numerous countries around the world [14,21,28-33]. The highest estimated prevalence (approximately 8.6 per 100,000) has been reported in Jews of Moroccan origin and the Druze in Israel, where active genetic screening programs exist [34-36]. The estimated prevalence of CTX is 3 to 5 per 100,000 in White Americans [7].

In a 2015 study using exome data (approximately 60,000 samples) and bioinformatics, the estimated incidence of CTX in Americans was between 1:71,677 and 1:148,914, a range more frequent than previously reported [37].

CLINICAL FEATURES — Many systemic and neurologic symptoms have been identified in patients with cerebrotendinous xanthomatosis (CTX), including intractable diarrhea, premature cataracts, tendon xanthomas, and progressive neurologic signs and symptoms [38]. The systemic features typically present earlier than the neurologic manifestations but CTX is not always recognized in these individuals. The mean age at diagnosis ranges from 32 to 41 years (range 5 to 71 years), at a time when the neurologic symptoms are often present [12,39,40]. Clinicians must have a high index of suspicion in any individual with the key features listed below.

Neurologic dysfunction involving cerebral, cerebellar, neuropsychiatric, myelopathic, or peripheral manifestations is usually apparent by late childhood or early adulthood, and progresses during adulthood.

Systemic

Jaundice and diarrhea — Neonatal cholestatic jaundice is often the earliest symptom of CTX, but does not occur in every patient [41]. There is significant clinical heterogeneity, even among siblings with the same pathogenic CYP27A1 variant. For some, the jaundice self-resolves; others require treatment with bile acids (see 'Treatment' below). Fetal demise and death in infancy have occurred in siblings of CTX patients, including one child with jaundice from birth until his death at 13 months, suggesting that CYP27A pathogenic variants may be fatal in some patients [41].

Chronic infantile diarrhea, which is due to a defect in bile acid synthesis, is another early symptom of CTX. However, hepatitis of infancy and chronic diarrhea are rarely identified as symptoms of CTX until other manifestations of the disease appear. These symptom are present in approximately 20 to 55 percent of affected individuals [12,40,42].

Cataracts — Most patients (75 percent) present to medical attention in the first decade of life because of cataracts [2,43], and the overall incidence of cataracts is 60 to 70 percent [40,42], although it may be as high as 92 percent [44].

Xanthomas — Xanthomas develop in approximately 70 to 77 percent of patients with CTX [12,42,44]. They typically form in the second or third decade on the Achilles (figure 1), extensor elbow, extensor hand, patellar, and neck tendons. They begin as painless thickening of the tendon but as they grow, they can interfere with joint function [45,46]. Xanthomas can also develop in the brain, lungs, and bones.

Skeletal abnormalities — Although serum calcium is normal, patients with CTX have skeletal abnormalities due to impaired calcium absorption (demonstrated by impaired radiocalcium uptake) that leads to decreased bone density/osteopenia, osteoporosis, and fractures [45,47,48].

Cardiovascular — Atherosclerosis and cardiovascular disease have been associated with CTX, including reports of premature coronary atheroma, angina pectoris, myocardial infarction, aneurysmal coronary artery disease, mitral valve insufficiency, and lipomatous hypertrophy of the atrial septum [49-51]. The true prevalence of cardiac disease in CTX is unknown, but in one review of 144 patients with CTX, cardiac abnormalities were found in 15 patients (10 percent) [28]. In a series of seven patients who were studied with myocardial scintigram and coronary angiography, asymptomatic coronary artery disease was present in four [49].

The most likely mechanism of cardiac disease and atherosclerosis in CTX is the accumulation of cholesterol and cholestanol in various tissues [50]. However, this relationship is controversial, in part because patients with CTX are more likely to have what looks like an "antiatherogenic" lipid profile, with lower total cholesterol and low-density lipoprotein (LDL) levels and increased high-density lipoprotein (HDL) levels, than controls [49].

Other — Premature aging and hypothyroidism have also been reported in patients with CTX [2].

Neurologic — Although intellectual disability can present in infancy, most patients with CTX have borderline or normal intelligence until puberty. Intellectual functioning worsens with age, and over 50 percent of individuals with CTX have dementia and intellectual decline in their 20s [2]. Approximately 74 percent ultimately have neurocognitive deficits [12]. Cholestanol induces apoptosis of neurons, including cerebellar Purkinje cells [25,52-54].

●Neuropsychiatric manifestations of CTX include paranoid delusions, hallucinations, agitation, aggression, and depression. The latter may lead to suicide attempts.

●Many patients develop spasticity [55], which is especially prominent in spinal xanthomatosis. (See 'Spinal variant' below.)

●Seizures occur in approximately 50 percent of patients with CTX [2], and can be the presenting symptom [56,57].

●Extrapyramidal symptoms, such as parkinsonism, dystonia, myoclonus, and postural tremor, are observed in approximately 20 percent of patients [58-62].

●Both demyelinating and axonal neuropathies have been described [63], leading to distal muscle atrophy and pes cavus. Sensory symptoms are typically absent.

Neurologic symptoms are mostly secondary to a metabolic encephalopathy, not due to structural disease related to focal xanthomas [12].

Spinal variant — A rare spinal variant of CTX is characterized by a slowly progressive myelopathy and corticospinal and dorsal column demyelination [64-66]. In the largest series, with seven patients, the age at presentation ranged from 20 to 35 years old, and all had juvenile bilateral cataracts [64]. Other typical features of CTX, such as diarrhea, xanthomas, dementia, ataxia, and polyneuropathies, were less frequent than cataracts. Only two patients developed the classic symptoms; these were detected five to eight years after the onset of the myelopathy. In general, patients with spinal xanthomatosis have a milder clinical course than those with classic CTX [64].

Neuroimaging — Head computed tomography (CT) and magnetic resonance imaging (MRI) reveal diffuse atrophy, white matter signal alterations affecting cerebellum more than cerebrum, and bilateral focal cerebellar lesions [67].

On CT, white matter changes are hypodense, while cerebellar xanthomas are hyperdense.

In adults, hyperintense lesions on T2-weighted MRI are observed in the dentate nucleus (image 1), globus pallidus, substantia nigra, and inferior olive [68]. With disease progression, these lesions typically extend into adjacent white matter (image 2). On MRI, fluid-attenuated inversion recovery (FLAIR) sequences may be more sensitive than T2-weighted sequences, as suggested by a study of 12 patients with CTX that found bilateral hyperintensities in the dentate nuclei on T2 and FLAIR sequences in 9 and 12 patients, respectively [14]. As described above, cholestanol induces neuronal apoptosis; brain atrophy, particularly in the gray matter, is also evident on MRI [54,61,69].

Both dentate hyperintensity (common) and hypointensity (less common) on T2 MRI have been reported in CTX [68]. This discrepancy is explained by the presence of hemosiderin deposits and calcifications in the dentate, which lowers the T2 signal intensity.

The presence of bilateral focal cerebellar lesions and the predominance of cerebellar white matter involvement helps distinguish the radiographic features of CTX (image 2) from other leukodystrophies (algorithm 1) [67,70].

In a retrospective MRI study of 38 individuals with CTX, all had brain imaging abnormalities [70]. Among six patients with dentate nuclei hyperintense T2/FLAIR lesions and cerebellar vacuolation, five had progression of clinical disability and all six had worsening MRI scans; among six patients with dentate nuclei T2/FLAIR hyperintensity but without vacuolation, only one showed clinical worsening at follow-up, and MRI progression was absent or mild. The four patients without any dentate abnormalities on MRI remained clinically and neuroradiologically stable during follow-up.

In the spinal variant of CTX, abnormal signal on T2-weighted images was observed in the lateral and dorsal columns [68].

Laboratory — The disruption of bile acid synthesis in CTX results in a number of laboratory abnormalities. Serum and tissue levels of cholestanol are elevated, frequently 5 to 10 times normal levels, whereas serum cholesterol levels are normal or decreased. Plasma values of cholestanol are normally less than 4 to 5.2 mg/L. Values from 8.5 to 100.6 mg/L have been reported in CTX [12]. The formation of chenodeoxycholic acid is markedly decreased, and the bile, urine, and serum concentrations of bile alcohols and their glycoconjugates are increased.

Increased serum lactate is also seen, but this finding is nonspecific. Changes in the blood-brain barrier result in increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid.

While not routinely evaluated, the enzymatic activity of sterol 27-hydroxylase is markedly reduced in fibroblasts, liver, and leukocytes in patients with CTX.

Pathology — Sections of gross brain from patients with CTX reveal symmetric lesions in the cerebellar white matter, globus pallidus, midbrain, posterior part of the internal capsule, and dentate nuclei [68]. Granulomatous and xanthomatous lesions are seen in the cerebellar hemispheres, globus pallidus, and cerebellar peduncles [2].

Microscopic examination reveals extensive rarefaction, with severe neuronal loss, demyelination, hemosiderin deposits, lipid crystal clefts, fibrosis, infiltration of foamy macrophages, and reactive astrocytosis [68]. The cerebellar findings of lipid crystal clefts, xanthomatous lesions, fibrosis, and hemosiderin deposits, especially around the dentate nuclei, are pathognomonic for cerebrotendinous xanthomatosis [64,68]. In addition to the typical brain pathology, patients with significant spinal cord involvement have extensive demyelination, axonal loss, gliosis, and macrophagic infiltrates in the corticospinal tracts and gracile tracts.

Microscopically, xanthomas have shown birefringent crystalline storage material surrounded by multinucleated giant cells with foamy cytoplasm [71].

DIAGNOSIS — The diagnosis of cerebrotendinous xanthomatosis (CTX) is suggested when the typical symptoms are present. The presence of the hallmark clinical manifestations of CTX – chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction – should prompt further investigations [7]. Laboratory studies showing elevated levels of serum cholestanol and serum and urine bile alcohols are supportive of the diagnosis, and genetic testing can confirm the diagnosis. (See 'Clinical features' above.)

Suspicion for CTX is highest in patients with the following indicators [2,39,41]:

●Sibling with CTX

●Neonatal cholestatic jaundice

●Infantile diarrhea

●Noncongenital cataracts presenting in childhood

●Tendon xanthomas presenting during adolescence or early adulthood

●Progressive neurologic dysfunction beginning in late childhood or early adulthood

●Ataxia or spastic paraparesis

●Intellectual disability or psychiatric disturbances

●MRI evidence of dentate nuclei signal alterations

●Consanguineous parents

Thus, CTX should be considered if a child has prolonged neonatal jaundice or infantile diarrhea of unclear etiology, especially if there is a family history of similar symptoms or fetal demise. However, as noted earlier, hepatitis of infancy and chronic diarrhea are rarely identified as symptoms of CTX until other manifestations of the disease appear. In patients with intellectual disability who have a component of progressive neurologic disease, CTX deserves special consideration because of its response to treatment.

While CTX is suggested by the presence of xanthomas and cholesterol abnormalities, it may not be considered in patients lacking these systemic findings. However, this may lead to diagnostic error, as one review found that xanthomas were not present in 29 percent of patients with CTX [44]. In addition, children with early-stage CTX may present with bile disorders, diarrhea, or cataracts, but may lack overt neurologic symptoms or signs. In such cases, laboratory testing for serum cholestanol and serum and urine bile alcohols should be performed [71]. The strategy of screening for elevated urine bile alcohols has been successful in recognizing CTX even when it was not clinically suspected [72]; however, such screening is not routinely performed.

The presence of bilateral neuroimaging abnormalities in the dentate nuclei of the cerebellum strongly supports the diagnosis of CTX in patients who have clinical features that raise suspicion for the disorder.

Molecular genetic testing including sequence analysis can detect pathogenic CYP27A1 variants in up to 99 percent of affected individuals [2]. Genetic testing with sequence analysis is clinically available and is suggested to confirm the diagnosis.

Differential diagnosis — In patients with neurologic disease, myotonic dystrophy is the number one cause of early-onset cataracts, followed by CTX [73]. Distal myotonic dystrophy, as opposed to the proximal and neonatal forms, presents as early as adolescence with impaired muscle relaxation after contraction, facial and distal limb weakness, cataracts, frontal baldness, and endocrine abnormalities. The characteristic myotonia of myotonic dystrophy, which may be confirmed by clinical examination and/or by electromyography, should readily differentiate myotonic dystrophy from CTX. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

Tendon xanthomas are also present in sitosterolemia, an inherited sterol storage disease. However, neurologic signs and cataracts are absent [74]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

Similarly, xanthomas affecting the spinal cord may lead to spastic paraparesis in the absence of other features of CTX. While hypercholesterolemia and hyperlipidemia cause xanthomas, serum concentrations of cholestanol are normal.

A minority of patients with Langerhans cell histiocytosis have central nervous system involvement with ataxia, behavioral change, cognitive dysfunction, and bilateral symmetric lesions on brain MRI in the dentate nucleus of the cerebellum or in basal ganglia. The presentation may mimic CTX [75]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Central nervous system'.)

TREATMENT — The mainstay of treatment for cerebrotendinous xanthomatosis (CTX) is chenodeoxycholic acid. Although unproven, treatment with statins may be beneficial, but only when combined with chenodeoxycholic acid.

There are limited and conflicting data regarding the clinical benefit with low-density lipoprotein (LDL) apheresis [69,76-78].

Symptomatic therapies are also important.

Chenodeoxycholic acid — In 1975, chenodeoxycholic acid (CDCA) was shown to decrease cholesterol synthesis [18]. In the decades since, CDCA has remained the treatment of choice for CTX because it can stabilize or possibly reverse some of the associated symptoms.

We recommend treatment with CDCA for children and adults with CTX. The usual dose of CDCA is 250 mg three times a day for adults and 15 mg/kg per day in three divided doses for children; lower doses may be less effective [12]

In the first prospective (nonblinded) treatment study, 17 symptomatic patients with CTX were given CDCA, 750 mg daily [29]. After at least one year of treatment, the following observations were made:

●Dementia cleared in 10 of 13 patients

●Pyramidal tract and cerebellar signs disappeared in five

●Electroencephalographic abnormalities resolved in 5 of 10 patients

●Cerebral CT scans improved in seven patients, and one cerebellar xanthoma disappeared

●Mean serum cholestanol levels declined by a factor of three, and abnormal bile acid synthesis was suppressed

In a larger retrospective study of 43 patients with CTX, 31 were taking CDCA [12]. The patients were followed for a mean of 8 years. CDCA treatment was associated with improvement in symptoms in 57 percent, disease stabilization in 23 percent, and disease progression in 20 percent. All of the patients who worsened on CDCA were over 25 years of age and had significant neurologic symptoms at the time of diagnosis; some were treated with a lower dose of CDCA due to elevated liver enzymes or had an interruption in therapy due to drug availability. The mean pretreatment cholestanol level was 32 mg/L, and the post-treatment level was 6 mg/L, an 81 percent reduction on CDCA. The plasma cholestanol levels normalized in 63 percent of patients.

In adults with CTX, long-term treatment with CDCA (250 mg orally three times daily) corrects the defect of bile acid metabolism and normalizes the serum, urine, and cerebrospinal fluid lipid concentrations. Despite these data, the neurologic and psychiatric symptoms are often difficult to treat, and, if advanced, may not improve with CDCA [79-81]. CDCA may not reverse tendon xanthomas or cataracts [7,29,79].

Starting CDCA during childhood or young adulthood may be associated with greater benefit than starting treatment in older adults, when irreversible neurologic injury may be present [81-84].

●In a study of five symptomatic children (ages 7 to 20 years) treated with CDCA (15 mg/kg per day in three divided doses), diarrhea resolved immediately with the start of treatment, and biochemical abnormalities normalized [82]. At one year, no further motor development delays were observed, and the intelligence quotient improved in three children. At five years after the start of CDCA, the children were reported as in stable clinical condition.

●Another report described four patients with CTX within one family who were treated with CDCA for 14 years [83]. At the time treatment was started, two young sisters had minimal symptoms and two older brothers (uncles of the sisters) were already severely affected. After 14 years of follow-up, the two sisters remained free of symptoms, whereas the two uncles experienced only moderate improvement in symptoms.

Adverse effects — There are few data regarding adverse effects of CDCA in patients with CTX. However, in patients with gallstones who are treated with CDCA, dose-related diarrhea is seen in approximately 50 percent, and hypercholesterolemia and increased serum aminotransferases are observed in a substantial proportion. Since diarrhea is a common feature of CTX, it is not clear whether CDCA causes or exacerbates diarrhea in patients with CTX.

Plasma cholestanol levels may be monitored for drug efficacy (although it may take up to two years to normalize) and drug adherence [7]. Liver enzymes should be followed regularly and were elevated in 9 percent of adults on CDCA therapy in one study [12]. While elevated liver enzymes are often asymptomatic, the dose of CDCA may be reduced if signs of hepatotoxicity develop. One infant developed jaundice, pruritus, and hepatomegaly six weeks after initiation of therapy that resolved on a CDCA dose of 5 mg/kg/day [85]. For this patient, plasma cholestanol levels normalized on the lower dose.

Routine measurement of lipids and fat-soluble vitamins (given the diarrhea) is not necessary but rather should follow clinical guidelines and symptoms.

Pregnancy and CDCA — Observational studies have reported that women taking CDCA have conceived and delivered healthy children, while those not taking CDCA have had difficulty conceiving, pregnancies complicated by miscarriages or stillbirths, and children with intellectual disability [7,41,44,81,86].

Cholic acid — While cholic acid has been used a treatment for CTX in a few cases [87,88], high-quality data on long-term efficacy and safety are not available. Cholic acid is approved by the US Food and Drug Administration (FDA) for the treatment of bile acid disorders cause by single acid defects. The bile acids in CTX cannot be broken down to CDCA and cholic acid in the absence of CYP27A1; thus, exogenous administration of cholic acid is expected to result in decreased accumulation of cholestanol through feedback inhibition. Note that patients with CTX have relatively normal levels of cholic acid due a different enzymatic pathway [12].

Statins — Statins lower cholesterol and have been studied as a treatment for CTX [27,71]. However, statins deplete CoQ10 and thereby alter mitochondrial function, which is a theoretical concern because abnormal mitochondrial metabolism has been reported in CTX. (See 'Mitochondrial dysfunction' above.)

Although data are sparse, statin monotherapy appears to have little or no benefit for CTX. However, statins may be useful for lowering cholestanol levels when combined with CDCA, especially if CDCA treatment monotherapy is not effective in lowering cholestanol levels [17,78,89-91].

Symptomatic therapies — Management of CTX may require interventions for cataracts, epilepsy, parkinsonism, and spasticity. Patients often require cataract surgery before the age of 50 [2,43]. There is evidence from one small study that cerebellar ataxia may improve with piracetam (not available in the United States) [92]. Seizure frequency may improve with CDCA, allowing a decrease in the number of antiseizure medications or monotherapy dose [93].

Xanthomas that interfere with joint function may be surgically excised [45].

Management of seizures and epilepsy is discussed elsewhere. (See "Overview of the management of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

Levodopa/carbidopa has been used to treat the parkinsonian symptoms of CTX with variable success [94].

Prognosis and future directions — CTX is progressive without treatment, with possible survival into the fifth or sixth decades. Early treatment is critical in delaying or alleviating many of the symptoms. Thus, newborn screening programs have been piloted with success [52,95,96]. The implementation of such programs, especially in high-frequency populations, is likely to alter the morbidity and mortality of this disease.

SUMMARY AND RECOMMENDATIONS

●Cerebrotendinous xanthomatosis (CTX) is a rare disease caused by a genetic defect in the CYP27A1 gene, which results in a deficiency of sterol 27-hydroxylase, with accumulation of cholesterol and cholestanol in virtually all tissues. Cholestanol is thought to be responsible for the neurologic toxicity in CTX. (See 'Pathogenesis' above.)

●Systemic symptoms associated with CTX include intractable diarrhea, premature cataracts, tendon xanthomas, premature atherosclerosis, and cardiovascular disease. The systemic features typically present earlier than the neurologic manifestations. (See 'Clinical features' above.)

●Neurologic dysfunction, including intellectual disability, dementia, epilepsy, parkinsonism, myelopathy, and neuropathy, is usually apparent by late childhood or early adulthood, and progresses during adulthood. (See 'Neurologic' above.)

●Head computed tomography (CT) and brain magnetic resonance imaging (MRI) reveal diffuse atrophy, white matter signal alterations affecting cerebellum more than cerebrum, and bilateral focal cerebellar lesions. Hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI are observed in the dentate nucleus, globus pallidus, substantia nigra, and inferior olive. (See 'Neuroimaging' above.)

●Serum and tissue levels of cholestanol are elevated to 5 to 10 times normal levels, whereas serum cholesterol levels are normal or decreased. The formation of chenodeoxycholic acid is markedly decreased, and the bile, urine, and serum concentrations of bile alcohols and their glycoconjugates are increased. (See 'Laboratory' above.)

●The diagnosis of CTX is suggested by the typical constellation of CTX symptoms, which are seen in most patients with the disorder. These symptoms are:

•Neonatal cholestatic jaundice

•Infantile diarrhea

•Noncongential cataracts presenting in childhood

•Tendon xanthomas presenting during adolescence or early adulthood

•Progressive neurologic dysfunction beginning in late childhood or early adulthood

Elevated levels of serum cholestanol and serum and urine bile alcohols are supportive of the diagnosis, which can be confirmed with genetic testing. Laboratory testing for serum cholestanol and serum and urine bile alcohols should be performed for children with bile disorders, diarrhea, or cataracts. (See 'Diagnosis' above.)

●For children and adults with CTX, we recommend treatment with chenodeoxycholic acid (CDCA) (Grade 1B). The suggested dose of CDCA is 250 mg three times a day for adults, and 15 mg/kg per day in three divided doses for children. It is important to begin treatment before the onset of neurologic dysfunction in order to prevent irreversible neuronal injury; clinical improvement in established disease is uncommon. (See 'Chenodeoxycholic acid' above.)