Clinical and biochemical features, molecular diagnosis and long-term management of a case of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease characterised clinically by juvenile bilateral cataracts, progressive neurological dysfunction, and formation of tendon xanthomata. We describe the clinical and biochemical features, molecular diagnosis and long-term management of the first reported Australasian case of CTX. Molecular analysis confirmed the diagnosis of CTX and demonstrated that the patient was homozygous for a G-->A transition in the splice donor site of intron 4 of the sterol 27-hydroxylase gene. Serum cholestanol concentrations were decreased with the HMG-CoA reductase inhibitor simvastatin alone and greater reductions were achieved after the addition of the bile acid chenodeoxycholic acid; suggesting a synergistic effect of this combination. Despite serum cholestanol concentrations remaining within the low-normal range, there has been no significant improvement in mental and physical abilities or in EEG abnormalities with 5 years of treatment. Metabolism of radiolabeled 7-ketocholesterol to aqueous soluble products was absent in CTX-derived macrophages. Consistent with this finding, plasma 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol concentrations were increased in the CTX subject compared with controls.     

Detection of carriers of cerebrotendinous xanthomatosis

Patients suffering from cerebrotendinous xanthomatosis (an autosomal recessive inborn error of metabolism) can easily be distinguished from patients not suffering from this disease, as the first excrete large amounts of the bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, in urine, whereas the second do not. In order to find out, whether carriers of cerebrotendinous xanthomatosis can be detected in a biochemical way, we compared known carriers with controls. The urinary excretions of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol of both groups were practically absent and no selection of carriers with cerebrotendinous xanthomatosis could be made on that basis. When, however, carriers and non-carriers were subjected to cholestyramine treatment, by which endogenous bile acid synthesis was stimulated, the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol in the carrier rose considerably, whereas this excretion remained essentially the same in the non-carriers. This test can be of value in the genetic counseling of carriers with cerebrotendinous xanthomatosis and helpful in the detection of newborn patients with cerebrotendinous xanthomatosis.     

Primary hyperlipoproteinemia in xanthomatosis.

Blood lipid values, clinical data and effects of therapy are reported on 74 patients with hyperlipidemia and xanthomatosis. A natural subdivision into two groups was observed on the basis of low density lipoprotein lipid values: one corresponding to Frederickson's type II, characterized by elevated low density lipoproteins, tendinous xanthomata, absence of eruptive xanthomata and a high incidence of cardiovascular diseases and the other resembling Frederickson's type III, with elevated very low density lipoproteins, eruptive xanthomata, xanthomata striata palmaria, elevated cholesterol/triglyceride ratios in the very low density lipoproteins and irregular appearance of floating beta lipoproteins. The latter group consisted of 32 patients in whom cardiovascular symptoms were relatively rare, despite mean cholesterol levels of 500 mg/dl.     

Atherogenic risk factors in cerebrotendinous xanthomatosis

In a study of coronary artery disease in patients with cerebrotendinous xanthomatosis (CTX), we documented the presence or absence of atherogenic risk factors and performed detailed analyses of serum lipid and lipoprotein profiles. Four of the seven patients examined had coronary arterial narrowing and/or obstruction, but multiple atherogenic risk factors were not found in any of these patients. Total cholesterol (T.ch) levels and low density lipoprotein-cholesterol (LDL-ch) levels were lower, and high density lipoprotein2-cholesterol (HDL2-ch) levels were higher in CTX patients than in controls. Triglyceride and very low density lipoprotein (VLDL) levels were significantly lower in the former. Indices correlating with the risk of atherosclerosis, such as the atherogenic index, and the ratios of apolipoprotein B/apolipoprotein AI, HDL2-ch/LDL-ch, HDL2-ch/HDL3-ch, indicated that CTX serum was, in fact, 'anti-atherogenic'. However, coronary artery disease is frequently seen in patients with CTX. This discrepancy suggests the existence of a unique mechanism by which atherosclerosis is induced in patients with CTX. We discuss a mechanism of disturbed lipoprotein metabolism which might be responsible for the deposition of sterols in the tissues of patients with CTX.     

A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis.

We examined the relationship between cholesterol biosynthesis and total and high affinity LDL binding in liver specimens from two sitosterolemic and 12 healthy control subjects who died unexpectedly and whose livers became available when no suitable recipient for transplantation was identified. Accelerated atherosclerosis, unrestricted intestinal sterol absorption, increased plasma and tissue plant sterol concentrations, and low cholesterol synthesis characterize this disease. Mean total microsomal HMG-CoA reductase (rate-control controlling enzyme for cholesterol biosynthesis) activity was sevenfold higher (98.1 +/- 28.8 vs. 15.0 +/- 2.0 pmol/mg protein per min) and microsomal enzyme protein mass was eightfold larger (1.43 +/- 0.41 vs. 0.18 +/- 0.04 relative densitometric U/mg protein) in 11 controls than the average for two sitosterolemic liver specimens. HMG-CoA reductase mRNA probed with pRED 227 and pHRED 102 was decreased to barely detectable levels in the sitosterolemic livers. In addition, there was a 50% decrease in the rate [2-14C]mevalonic acid was converted to cholesterol by sitosterolemic liver slices compared with controls (112 vs. 224 +/- 32 pmol/g liver per h). In contrast, average total LDL binding was 60% greater (326 vs. 204 +/- 10 ng/mg), and high affinity (receptor-mediated) binding 165% more active (253 vs. 95.1 +/- 8.2 ng/mg) in two sitosterolemic liver membrane specimens than the mean for 12 controls. Liver morphology was intact although sitosterolemic hepatocytes and microsomes contained 24 and 14% less cholesterol, respectively, and 10-100 times more plant sterols and 5 alpha-stanols than control specimens. We postulate that inadequate cholesterol biosynthesis is an inherited abnormality in sitosterolemia and may be offset by augmented receptor-mediated LDL catabolism to supply cellular sterols that cannot be formed.     

脑腱性黄色瘤病患者的护理

报告了1例脑腱性黄色瘤病患者的护理.重点做好患肢护理、安全护理,防止患者跌倒和坠床,做好依从性护理、饮食护理,使患者能够顺利接受手术.本例术后2周顺利出院.     

脑腱黄瘤病临床、影像学、病理和基因分析一家系报道并文献复习

目的 对一个脑腱黄瘤病家系进行临床、病理及基因的分析.方法 收集患者病史、家族史,进行影像学检查、神经肌肉活检.对患者及家族成员进行CYP27A1基因突变分析.结果 36岁女性患者,具有典型的脑腱黄瘤病临床表现,跟腱组织可见典型的胆固醇结晶,腓肠神经可见洋葱皮样髓鞘改变.CYP27AI基因新发现2种突变:1号外显子缺失一个鸟嘌呤(C.73delG),而2号外显子缺失一段7核苷酸序列(C.369-375delGTACCCA).家族成员为上述突变的单个突变携带者.结论 先证者可临床诊断脑腱黄瘤病,患者和无症状的家族成员均存在基因突变.