Induction Mechanism of Apoptosis in Cerebrotendinous Xanthomatosis

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Onset of CTX is usually in early teens and mental retardation is most frequently observed at this stage. Pyramidal sign and progressive cerebellar symptom appear at puberty together with atactic gait, lateral nystagmus or atactic dysphasia. Juvenile cataract also appears in late teens. Most characteristic symptom is xanthoma in brain, tendon, muscle and lung. Treatment is symptomatic therapy, and oral administration of chenodeoxycholic acid is effective to reduce the size of xan-thoma. By feeding experiments, we proved that the high concentration of cholestanol induced the accumulation of chole-stanol in cerebellum and caused the neurological disturbance. We formulated a hypothesis that cholestanol in serum of CTX patients might induce neuronal cell death in cerebellum and eventually cerebellar ataxia would occur. In the present study, we developed hypercholestanolemia rats and examined the effects of cholestanol on death of cerebellar neuronal cells, corneal endothelial and lens epith … More elial cells. Apoptosis was evident in cells cultured with cholestanol in these cells. As activities of interleukin-1β-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis. Our observation may explain the mechanism of cerebellar ataxia, cataract and corneal opacities of CTX patients. We studied a 44-year old woman with progressive frontal lobe dementia and spastic araplegia. Examination revealed increased serum levels of cholestanol and heterozygous mutation of the sterol 27-hydroxylase gene (CYP27), In genomic DNA, both the G and A were found at codon 441, indicating the heterozygous pattern of the mutation of CGG441Arg to CAG441Gln. Computed tomography and magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, which was marked in the frontal area. Cerebral MR images showed diffuse symmetric areas of hyperintensity in the white matter of the lateral ventricles in the optic radiation. Less