Pathophysiological investigation on cerebrotendinous xanthomatosis

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Cerebrotendinous xanthomatosis is a metabolic disease, characterized by neurologic dysfunction, tendon xanthomas and juvenile cataracts. CTX patients have an impaired capacity to convert cholesterol to bile acids, due to a defect of hepatic enzyme, which catalyzes the oxidation of side chains of sterol intermediates. The first case in Japan was reported by Shibasaki in 1969.We intended first to clarify the genetic mutations in CTX patients, and secondly to establish an experimental model animal of this disease.1. Genetic abnormalities in CTX patients : In collaboration with Ingemar Bjoerkhem, we (Seyama, Yonemoto, Hoshita and Kubota) analyzed the nucleotide sequence of cDNA encoding the sterol 27-hydroxylase. Direct sequencing of RT-PCR products revealed a mutation at the heme-ligand binding site in five CTX patients. Arginine at the 441 position was replaced by glutamine or tryptophan, and one base deletion was also found in one patient at the position encoding 445th amino acid. In pa … More tients with replacement of arginine by glutamine, a new restriction site with "Stu I" appeared. In patients with a replacement of arginine by tryptophan, "Hpa II" site disappeared. These findings suggest a possibility of genetic diagnosis using RFLP.2. Establishment of experimental model animal of CTX : In collaboration with Salen and Shefer, we (Seyama and Kasama) established an experimental model animal by feeding cholestanol diet. After feeding 1% cholestanol in the diet, gallstones developed in 20 % of the mice and were associated with gallbladder mucosal inflammation and serosal vessel wall thickening. Hepatic HMG-CoA reductase activity rose by 51 % In contrast cholesterol 7a-hydroxylase activity was severely depressed. Discontinuing cholestanol from the diet for 1 month, reduced the elevated serum and liver cholestanol concentrations, and restored hepatic HMG-CoA reductase and cholesterol 7a-hydroxylase to normal. The combination of increased cholesterol synthesis with decreased bile acid formation promotes gallstone formation in cholestanol fed mice. Less