Cerebrotendinous xanthomatosis in seven Hong Kong Chinese

Abstract

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease characterized by the accumulation of cholestanol and cholesterol, leading to xanthomas and neurological symptoms. Genetic defect in CYP27A1 leads to a deficiency in sterol 27-hydroxylase and reduced chenodeoxycholic acid (CDCA) formation from cholesterol. The lack of negative feedback of CDCA on bile acid synthesis leads to increased production of cholestanol. Cholesterol production is also increased in CTX, but the role of statin therapy in these subjects is unclear. SUBJECT AND METHODS: The records of all adult Chinese CTX patients managed at our center were retrieved from our computerized record system. Clinical and biochemical parameters and drug history were reviewed. RESULTS: Seven adult CTX patients (5 males, 2 females) from 4 unrelated, non-consanguineous families were identified. The mean age was 31.0+/-9.4 years at first symptoms, 36.0+/-10.9 years at diagnosis and 48.9+/-7.0 years at the time of study. Reported first symptoms were xanthomata (n=5) and motor abnormalities (n=2). At presentation, all patients had bilateral Achilles tendon xanthomata, 4 patients had cerebellar sign and 3 patients had subnormal intelligence. Pre-treatment cholestanol level was 147.9+/-70.5 umol/l (reference range <13.0 umol/l), low-density cholesterol (LDL) level was 2.2+/-0.3 mmol/l, high-density cholesterol (HDL) level was 1.4+/-0.3 mmol/l and triglyceride (TG) level was 1.1+/-0.4 mmol/l. CDCA, at 750mg daily in 3 divided doses, was started at diagnosis in 4 patients and at 4 years post-diagnosis in 3 patients. After 1 year of treatment, mean cholestanol level was reduced to 13.0+/-11.6 umol/l (p<0.05), while no significant changes were noted in LDL (2.8+/-0.5 mmol/l), HDL (1.4+/-0.2 mmol/l) or TG (1.2+/-0.7 mmol/l). Simvastatin 10mg nocte in addition to CDCA in 3 of the 7 patients at 3.3+/-2.2 years after diagnosis did not lead to any change in cholestanol, LDL, HDL or TG levels at 5 and 10 years post-treatment commencement. Six patients had stable intelligence and were engaged in meaningful employment. No improvement in demyelinating changes in the brain on MRI was observed with treatment (assessed serially in 3 patients). Xanthoma regressed partially in 3 patients, was excised with no recurrence in 2 patients and remained stable in 2 patients. CONCLUSION: Our series is one of the largest of Chinese CTX patients, and possibly one of the longest longitudinally followed series of CTX patients, reported in the literature. Our data suggests that CDCA is effective in lowering cholestanol starting in the first year of treatment. Simvastatin at 10mg nocte seems to have no effect on circulating levels of cholestanol, LDL, HDL or TG at 5 and 10 years of follow-up. Further follow-up assessment may help to ascertain whether the reduction in cholestanol is associated with any clinical benefits.