Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and & epsilon;1/lsquo;null genotype‡

A 60-year-old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl-1). The patient's apo E migrated in the apo E1 position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo epsilon 1 allele and another allele whose product did not appear in the plasma compartment ('null' allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endonuclease Taq I identified an adenosine for guanosine (G-->A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E1 isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo epsilon 1 allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol-enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a non-functional 'null' allele in addition to a probably dominant apo E1 (Gly127-->Asp, Arg158-->Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.     

“Essential” phospholipids versus nicotinic acid in the treatment of patients with type IIb hyperlipoproteinemia and ischemic heart disease

Summary In patients with moderate, dietary noncorrigible hyperlipoproteinemia type IIb and ischemic heart disease, treatment with nicotinic acid is limited by the side effects of the drug. In 100 patients, 6-month treatment with nicotinic acid (n=50) or essential phospholipids (EPL); Lipostabil^®, manufacturer: Rhône-Poulenc Rorer) (n=50) indicated comparable efficacy for both substances: Significant (p<.001) reductions of serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride values were similar in both groups, while nicotinic acid increased high-density lipoprotein (HDL) cholesterol significantly (p<.01) better than Lipostabil. A detailed analysis of ultracentrifugal lipoprotein profiles, hydroperoxide concentrations in LDL, and cholesterol-accepting properties of HDL in a small number of Lipostabil- and nicotinic acid-treated patients revealed favorable shifts in the lipoprotein profile, significant (p<.05) reductions of LDL hydroperoxides, and favorable increases of the most antiatherogenic HDL_2b subfraction only in the Lipostabil-treated group. Clinically, both medications reduced the intensity and number of angina pectoris attacks per week (p<.05), but only Lipostabil-treated patients significantly (p<.05) increased their working capacity in the veloergometric test. Since in the nicotinic acid-treated group dropouts (nine patients, eight related to the drug) and side effects [14] exceeded those in the Lipostabil-treated group (two dropouts not related to the drug, no side effects), it is suggested that Lipostabil is a preferable alternative in the treatment of patients with moderate, dietary noncorrigible hyperlipoproteinemia IIb and ischemic heart disease.     

Role of apolipoprotein E variants in lipoprotein glomerulopathy and other renal lipidoses

Lipoprotein glomerulopathy (LPG) is a new renal lipidosis entity, characterized by peculiar histology and abnormal lipoprotein profiles mimicking type III hyperlipoproteinemia. Recently, it has been clarified that LPG is associated with novel apolipoprotein E (apoE) mutations. In particular, ApoE-Sendai, which substitutes arginine 145 with proline, is observed in most Japanese patients with LPG, although isoelectric focusing polyacrylamide gel electrophoresis has shown that it is consistent with the apoE2 isoform. To confirm the etiological role of these apoE mutations, we established an animal model of LPG. The model was created by the introduction of recombinant adenovirus containing human apoE-Sendai into apoE knockout mice. Both clinical and experimental findings indicate that LPG is caused not only by hyperlipoproteinemia but also by an in situ interaction between apoE variants and glomerular elements. In addition, several studies suggest that the apoE2 mutation is responsible for the development of diabetic nephropathy and IgA nephropathy, as well as renal lipidosis with type III hyperlipoproteinemia. In this review, we present the clinical and histological features of LPG and its pathogenesis, and discuss the role of apoE abnormalities, especially apoE-Sendai and apoE2, in LPG and other renal lipidoses. Received: August 27, 2001 / Accepted: September 11, 2001     

儿童单纯性肥胖症综合干预前后内皮素及血脂的变化

目的探讨单纯性肥胖症儿童综合干预前后内皮素及血脂改变的特点。方法收集7～14岁单纯性肥胖症儿童30例(肥胖组),正常儿童30例(对照组)。肥胖组进行为期6个月的综合干预,包括行为干预、膳食调整、运动锻炼,测定其综合干预前、后的内皮素、血脂、体重等指标,测定对照组儿童的内皮素及血脂。结果肥胖组儿童的内皮素、血脂明显升高,与对照组比较,差异有显著性(P<0.01)。综合干预后肥胖组儿童自身比较体重下降(P<0.01),与干预前比较,差异有显著性(P<0.01)。结论单纯性肥胖症儿童内皮素及血脂增高,而综合干预能使其降低。     

Recognition of familial dyslipidemias in 5-year-old children using the lipid phenotypes of parents. The STRIP project

Adult dyslipidemias may reveal familial and, therefore, offspring dyslipidemias. We evaluated the prevalences of the adult-offspring dyslipidemias in 441 general population families composed of both parents and one 5-year-old child. Family members were classified using the 90th or 10th percentiles for hypercholesterolemia (IIA), hypertriglyceridemia (IV), combined hyperlipidemia (IIB), and low high density lipoprotein cholesterol concentration without hyperlipidemia (hypoHDL). In familial combined hyperlipidemia (FCHL), the IIB-phenotype was in one generation and one of the three hyperlipidemias in the other generation. Finally, the parental dyslipidemia phenotypes and elevated lipids (>80th percentile) that reveal offspring dyslipidemia were selected by stepwise logistic regression. Either the IIA-, IV- or hypoHDL phenotype was found in both generations in 2.8, 2.0 and 1.4% of the families, respectively. FCHL was seen in 1.8% of the families, which confirms the earlier views. The predictive values of the elevated parental cholesterol, type IV or hypoHDL parents to find type IIA, IV and hypoHDL children were low for systematic screening: 16, 13 and 15%, respectively. However, 44% of the children of IIB parents expressed hyperlipidemia (odds ratio 4.7, P=0.006). The IIB phenotype of the parent is a good predictor of the child's hyperlipidemia, and when encountered, it indicates that the lipids of the child should be studied. This would be as important as selective screening of familial hypercholesterolemia.     

TYPE 1 HYPERLIPOPROTEINEMIA PRESENTING AS SUDDEN DEATH IN INFANCY

A routine post-mortem investigating sudden death in an eight week old male infant revealed gross Type I hyperlipoproteinemia (triglyceride concentration 825 mmol/L). Death was attributed to generalized cerebral anoxia. Study of the family revealed the parents were first cousins both of whom had depressed postheparin lipolytic activity, as did five out of seven of the remainder of the family members tested. This family is a notable example of deficiency of extrahepatic lipoprotein lipase.     

国产诺衡治疗原发性高脂血症的疗效观察

本文报道了国产诺衡治疗35例原发性高脂血症的疗效,结果显示:降低血清甘油三脂(TG)显效为71％,降低总胆固醇(TC)显效为100％,升高高密度脂蛋白(HDL·C)显效为62％,降低TC·HDL·C/HDL·C显效为100％,并观察到升高HDL·C随治疗时间4周;8周;12周;有继续升高趋势,与对照组氯贝丁酯治疗23例原发性高脂血症比较,诺衡不仅降低低密度脂蛋白(LGL·C)和TG,而且升高HPL—C。该药是一种具有特色的血脂调节剂,且副作用较小,易于临床广泛应用。     

Type IV hyperlipoproteinemia and moderate instability of CAG triplet expansion in the androgen-receptor gene

Kennedy-Alter-Sung (KAS) disease is a hereditary lower motor neuron disease. In this study, we investigated 2 KAS patients presenting with progressive muscle weakness and wasting, action tremor, perioral fasciculation and gynecomastia. Three carriers and 5 healthy members from this 3–generation KAS Chinese family and 60 normal Chinese controls were included in this study. Hormone studies revealed normal serum level in thyrotropin, prolactin, testosterone, leuteinizing hormone, follicle stimulating hormone, and estradiol. Lipid study disclosed type IV hyperlipoproteinemia in 2 KAS patients and 3 healthy members. Molecular studies revealed that the number of CAG triplet repeats in the first exon of androgen receptor gene of the normal allele is in the range of 15–19 and 12–25 in this family and normal controls, respectively. However, the number of CAG repeat of androgen receptor gene were unstable in the mutant alleles with a range of 41–45 and increased from generation to generation (genomic anticipation) in the 2 KAS patients and 3 female carriers. We conclude that the CAG triplet repeats in mutant alleles were unstable in the family with the KAS disease. Furthermore, type IV hyperlipoproteinemia may be a co-transmitted syndrome in the family with KAS disease.     

耳穴贴压配合耳尖放血对高脂蛋白血症患者血脂的影响

目的研究耳穴贴压配合耳尖放血对高脂蛋白血症患者血脂的影响。方法将83例高血脂患者随机分为2组,治疗组41例进行耳穴贴压和耳尖放血,对照组42例口服普罗布考治疗,2组患者每日1次,疗程均为30d。结果治疗组总有效率92．7％,对照组总有效率95．2％,两组疗效比较差异无统计学意义（P〉0．05）。与对照组治疗后血清TC、TG、LDL-c比较差异无统计学意义（P〉0．05）,HDL-c与对照组治疗后比较差异有统计学意义（P〈0．05）。结论耳穴贴压配合耳尖放血对高脂蛋白血症疗效确切,操作简便、费用低廉,具有临床推广价值。     

Left main coronary angioplasty in a 10-year-old boy with homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia is a rare cause of premature coronary artery disease. A young boy with this disorder who underwent successful coronary angioplasty for left main stem stenosis is presented. © 1993 Wiley-Liss, Inc.