Cerebrotendinous Xanthomatosis

A number sign (#) is used with this entry because cerebrotendinous xanthomatosis is caused by homozygous or compound heterozygous mutation in the CYP27A1 gene (606530), which encodes sterol 27-hydroxylase, on chromosome 2q35.

Description

Cerebrotendinous xanthomatosis is a rare inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients.

Dotti et al. (2001) examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed.

In a tabular presentation, Moghadasian et al. (2002) compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (143890) and sitosterolemia (210250).

Clinical Features

Van Bogaert et al. (1937) described affected cousins. Onset was at age 12 or 13 years. When examined in their 30s, the patients demonstrated cerebellopyramidal signs, myoclonus of the soft palate, mental debility, cataracts, xanthelasmata, and tendon xanthomata. At autopsy many deposits were found in the white matter of the cerebellum and the cerebral peduncles. Philippart and Van Bogaert (1969) gave follow-up on a member of the first family described by Van Bogaert et al. (1937). Menkes et al. (1968) described brother and sister, aged 60 and 57 years, respectively. The brother had slowly progressive ataxia in later years. Cataracts were removed in his 20s and he had enlarged Achilles tendons from childhood. Serum cholesterol was normal. He died of myocardial infarction. The cerebellar white matter was demyelinated and contained cholesterol deposits. The sister had had progressive enlargement of Achilles tendons, minimal mental retardation, and unsteadiness of gait. Bilateral cataracts were removed at age 24 years. Serum cholesterol was normal. Menkes et al. (1968) speculated that the defect concerns transport of cholesterol out of cells. Cholesterol can be synthesized in many tissues but oxidation is virtually limited to the liver. Whereas tendon xanthomata and cataracts may appear early, neurologic impairment may be a late development.

Harlan and Still (1968) described black brother and sister with multiple tendinous and tuberous xanthomas despite plasma lipids that were quantitatively and qualitatively normal. Evidence of xanthomatous involvement of the lungs was found in the male. The authors suggested that normolipemic xanthomatosis is a distinct entity inherited as an autosomal recessive and that it should be classified as a reticuloendotheliosis. Swanson (1968) suggested that normolipemic xanthomatosis is the same entity as cerebrotendinous xanthomatosis. Although neurologic manifestations were not evident, these may be late in appearing.

Cruysberg et al. (1991) suggested that bilateral juvenile cataract associated with chronic diarrhea may represent the earliest clinical manifestations of CTX. They described a 6-year-old girl, her 12-year-old brother, and another unrelated 12-year-old boy.

Dotti et al. (1994) described the CT and MR findings in brain and spinal cord of 10 patients with cerebrotendinous xanthomatosis. All patients were aged 35 years or older and had cerebral and/or cerebellar atrophy. The majority had focal lesions distributed through the cerebrum, cerebellum, brainstem, or basal nuclei. Some of these lesions appeared to be xanthomata.

Verrips et al. (1999) described 7 Dutch patients from 6 families with a slowly progressive, mainly spinal cord syndrome that existed for many years before the classic CTX symptomatology became manifest. The diagnoses were confirmed by biochemical and MRI findings and mutation assays of the CYP27A1 gene. The authors concluded that spinal xanthomatosis should be included in the differential diagnosis of chronic myelopathy. Early recognition of this myelopathy is important since effective therapy is available.

Sugama et al. (2001) reported a 44-year-old woman with progressive frontal lobe dementia and spastic paraplegia. Examination revealed increased serum levels of cholestanol with abnormal cholesterol metabolism and a heterozygous mutation (arg441 to gln; 606530.0005) of the sterol 27-hydroxylase gene. While biochemical findings were compatible with the diagnosis of cerebrotendinous xanthomatosis, the clinical manifestations were very dissimilar.

Clayton et al. (2002) reviewed the medical histories of a group of patients with CTX and found that prolonged neonatal cholestatic jaundice was common. The family histories also revealed fetal and neonatal deaths among sibs of CTX patients. Clayton et al. (2002) concluded that defective activity of cholesterol 27-hydroxylase can lead to neonatal cholestatic jaundice ('hepatitis of infancy'), which may be self-limiting. After a latent period, however, progressive accumulation of cholesterol and cholestanol can lead to the xanthomata, neurodegeneration, cataracts, and atherosclerosis that are typical of CTX.

Guyant-Marechal et al. (2005) reported a 53-year-old man with an unusual CTX phenotype, involving xanthomas since adolescence but no mental retardation, and development of a progressive neuropsychiatric disorder beginning at age 44 that was suggestive of frontotemporal dementia. He had no cataract or ataxia. Despite combination cholesterol-lowering therapy over a 3-year period, his cognitive function continued to decline, although no other signs of neurologic deterioration appeared.

Szlago et al. (2008) reported 2 Argentinian sibs with CTX confirmed by genetic analysis. Both had chronic diarrhea from birth, seizures, mild mental retardation, and developed cataracts in childhood. At 17 years of age, the boy showed palatal myoclonus, dystonic posture, distal tremor, uncoordinated gait, and hyperreflexia. The girl had distal tremor at age 14. Neither patient had tendon xanthomas. Both patients had high plasma levels of cholestanol. Szlago et al. (2008) noted the lack of tendon xanthomas but stated that xanthomas may manifest at a later date in these 2 young patients.

Biochemical Features

Setoguchi et al. (1974) found that bile acid production in CTX1 is subnormal, yet the activity of cholesterol 7-alpha-hydroxylase, the rate-determining enzyme of bile acid synthesis, is elevated. Oftebro et al. (1980) found that liver mitochondria in a CTX patient were completely devoid of 26-hydroxylase activity involved in oxidation of the side chain of 5-beta-cholestane-3 alpha,7 alpha,12 alpha-triol. The same mitochondrial fraction catalyzed 25-hydroxylation of vitamin D3. Thus, the major pathway in the biosynthesis of cholic acid in human liver involves a mitochondrial C27-steroid 26-hydroxylase. The substrate for 26-hydroxylation accumulated in the microsomal fraction to a level about 50 times normal. Shore et al. (1981) found that, in addition to the defect in bile acid synthesis (impaired oxidation of the cholesterol side chain in the formation of cholic acid), there is an abnormality of high density lipoproteins (HDL). Although morphologically normal by electron microscopy, HDL had a low cholesterol content. They postulated that HDL in CTX is deficient in the performance of its normal functions of modulating LDL-cholesterol uptake by cells and removing excess cholesterol from peripheral tissues. Bjorkhem et al. (1983) interpreted the results of in vivo studies as supporting their conclusion that CTX is due to lack of a hepatic mitochondrial C27-steroid 26-hydroxylase, involved in the normal biosynthesis of cholic acid and chenodeoxycholic acid (CDCA). Chenodeoxycholic acid is virtually absent from the bile in this disorder. In cultured skin fibroblasts, Skrede et al. (1986) demonstrated 26-hydroxylation of C27-steroids. The activities were normally about 5 to 10% of those found in liver homogenates. In fibroblasts from 3 patients with CTX, 26-hydroxylation proceeded at a rate only 0.2 to 2.5% that of healthy controls.

Koopman et al. (1988) reported biochemical findings in 20 patients in the Netherlands. Diagnosis was best based on determination of urinary bile alcohols, in particular 5-beta-cholestane-3-alpha,7-alpha,12-alpha,23,25-pentol, by means of capillary gas chromatography. Koopman et al. (1986) developed a test for biochemically identifying heterozygotes from normals. By subjecting individuals to oral administration of cholestyramine, a marked decrease in the bile acid pool is observed. The production of newly synthesized bile acids is increased to compensate for that loss. During the provocation test, heterozygotes, like homozygotes, produce raised quantities of the pentol, which is excreted in the urine. In contrast, noncarriers do not produce the unusual bile acid. Koopman et al. (1985) found that cholic acid, which produces reduction in bile acid synthesis by a negative feedback mechanism, could be used in the treatment of this disorder.

Population Genetics

Berginer and Abeliovich (1981) observed 6 patients from 3 Moroccan Sephardic Jewish families. In this particular group they estimated the gene frequency to be 1 in 108.

Clinical Management

Because of the differences in expression of CTX, Berginer and Abeliovich (1981) recommended serum cholestanol studies in cases of undiagnosed cataract or tendinous xanthomas in childhood or early adolescence. Treatment with cholic acid and chenodeoxycholic acid was promising. Berginer et al. (1984) treated 17 patients with CDCA. All were symptomatic before treatment: Achilles tendon xanthomas (in 15 of 17), cataracts (in 12 of 17), dementia (in 13 of 17), pyramidal-tract signs (in all 17), cerebellar dysfunction (in 13 of 17), EEG changes (in 10 of 13), and abnormal cerebral CT scans (in 10 of 12). After at least 1 year of treatment, dementia cleared in 10; pyramidal and cerebellar signs disappeared in 5 and improved in 8 others; peripheral neuropathy disappeared in 6 and the EEG became normal in 5 and improved in 3 others. The CT scan improved in 7, including 1 patient in whom a cerebellar xanthoma disappeared. Mean plasma cholestanol levels declined 3-fold. The rationale of treatment with CDCA is to compensate for the pronounced deficiency of CDCA in the intrahepatic pool. The treatment produces a substantial reduction in cholestanol synthesis and lowers the cholestanol levels. Salen et al. (1987) found that treatment reduced high levels of cholesterol and cholestanol in the cerebrospinal fluid. Furthermore, untreated patients showed increased levels of apolipoprotein B and albumin. These results suggested that increased cerebrospinal fluid sterols were derived from plasma lipoproteins by means of a defective blood-brain barrier and that treatment with CDCA reestablished selective permeability of this barrier. Kuriyama et al. (1994) treated 7 patients with cerebrotendinous xanthomatosis either with CDCA alone, pravastatin (another inhibitor of HMG-CoA reductase), or the 2 agents in combination. CDCA treatment alone reduced serum cholestanol, but the sera of the patients on this treatment became more 'atherogenic' with an increase in total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and a decrease in high-density lipoprotein cholesterol. In contrast, pravastatin made the sera markedly 'anti-atherogenic,' but only modestly reduced cholestanol and sitosterol levels. However, the combination of CDCA and pravastatin resulted in improvement of serum lipoprotein metabolism, suppression of cholesterol synthesis, and reduction of cholestanol and plant sterol levels. The progression of disease was arrested in all 7 patients, but no dramatic reversal of clinical manifestations was seen.

Molecular Genetics

The defect in cerebrotendinous xanthomatosis was shown by Cali et al. (1991) to reside in the CYP27A1 gene; see 606530.0001-606530.0002.

In a 53-year-old man with an unusual CTX phenotype involving no mental retardation but a progressive neuropsychiatric disorder beginning at age 44, Guyant-Marechal et al. (2005) identified compound heterozygosity for mutations in the CYP27A1 gene (606530.0013-606530.0014).