Watts G F, Mitchell W D, Bending J J, Reshef A, Leitersdorf E
University Department of Medicine, University of Western Australia, Perth.
QJM. 1996 Jan;89(1):55-63. doi: 10.1093/oxfordjournals.qjmed.a030138.
We examined the phenotypic characteristics, molecular genetics and optimal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband presented in adulthood with classical clinical characteristics of CTX, a greater than tenfold elevation in plasma cholestanol and combined hyperlipidaemia. His brother also had typical features of CTX without the presence of dyslipidaemia. Genotyping revealed that the two brothers were compound heterozygotes for a novel missense mutation in exon 2 (R94Q) and for a recently described nonsense mutation in exon 5, of the sterol 27-hydroxylase gene (CYP27). Analysis of all available family members revealed that hyperlipidaemia did not co-segregate with the presence of a CYP27 mutant allele. Trial of therapy showed that the lowest plasma sterol and triglyceride concentrations and cholestanol:cholesterol ratio were achieved with the combination of chenodeoxycholic acid (CDCA) 750 mg/day, a primary bile acid, and simvastatin 40 mg/day, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alone and simvastatin alone significantly lowered plasma cholestanol concentration, but the decrease was greater with the former. After 1 year there was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We conclude that CTX in this English pedigree is probably due to compound mutant alleles in CYP27, that combined hyperlipidaemia in this family is unrelated to CTX, and that this complicated condition responds optimally to the combination of CDCA and simvastatin.
我们研究了一个患有混合性高脂血症的英国家庭中脑腱性黄瘤病（CTX）的表型特征、分子遗传学及最佳药物治疗方法。先证者成年后出现CTX的典型临床特征，血浆胆甾烷醇升高超过10倍且伴有混合性高脂血症。他的兄弟也有CTX的典型特征，但无血脂异常。基因分型显示，这两兄弟是甾醇27 - 羟化酶基因（CYP27）外显子2的一个新错义突变（R94Q）和外显子5中一个最近描述的无义突变的复合杂合子。对所有可获得的家庭成员的分析表明，高脂血症与CYP27突变等位基因的存在不共分离。治疗试验表明，每天服用750毫克鹅去氧胆酸（CDCA，一种初级胆汁酸）和40毫克辛伐他汀（一种3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶抑制剂）的组合，可使血浆甾醇和甘油三酯浓度以及胆甾烷醇：胆固醇比值降至最低。单独使用CDCA和单独使用辛伐他汀均可显著降低血浆胆甾烷醇浓度，但前者降低幅度更大。1年后，认知和运动功能均有显著改善，计算机断层扫描显示肌腱黄瘤消退。我们得出结论，这个英国家系中的CTX可能是由于CYP27中的复合突变等位基因所致，该家族中的混合性高脂血症与CTX无关，并且这种复杂病症对CDCA和辛伐他汀的组合反应最佳。
