1/4. Two Italian kindreds carrying the Arg136-->Ser mutation of the Apo E gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele.BACKGROUND AND AIMS: Type III hyperlipoproteinemia, or dysbetalipoproteinemia, is commonly associated with apolipoprotein e2 homozygosity (Cys112, Cys158). Apo E2-Christchurch (Arg136-->Ser), a rare mutation of the Apo E gene, located in the receptor-binding domain of the protein, has been found to be associated in the vast majority of cases of dysbetalipoproteinemia. methods AND RESULTS: This is the first report of two Italian kindreds carrying the Arg136-->Ser mutation. One family is a four-generation kindred from Genoa (Liguria, italy) with a high rate of mortality due to coronary artery disease: the proband was a 51-year-old woman with previous myocardial infarction and residual angina, severe carotid atherosclerosis, peripheral arterial vascular disease and arterial hypertension. The other family was identified in Palermo (sicily, italy): the proband was an overweight 62-year-old man with a mixed form of hyperlipidemia. The mutation, which was identified by means of Apo E genotyping followed by direct sequencing, co-segregated with the same haplotype in the two families. CONCLUSIONS: The family histories and clinical examinations of these subjects clearly show that the Apo E Arg136-->Ser variant fully expresses a type III phenotype in association with a second allele coding for Apo E2, and only partially in association with a second allele coding for Apo E4.- - - - - - - - - - ranking = 1keywords = vascular disease (Clic here for more details about this article) |
2/4. Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/'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.- - - - - - - - - - ranking = 1keywords = vascular disease (Clic here for more details about this article) |
3/4. Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation.OBJECTIVE: To describe a patient with tuberous xanthomas and high levels of cholesterol and triglycerides, who was found to have type III hyperlipoproteinemia (HLP) and a rare apolipoprotein E (apoE) mutation. methods: We present a case report with extensive clinical, laboratory, and genetic documentation. RESULTS: A 33-year-old African American man presented for evaluation of hypertriglyceridemia. His medical history was remarkable for schizophrenia necessitating ongoing olanzapine therapy for the past 6 years. A few months after olanzapine treatment was begun, he noted the development of nontender, firm, papular skin lesions on his elbows and knees. His family history was negative for lipid disorders or premature vascular disease. physical examination revealed the presence of prominent tuberous xanthomas on both elbows and knees. Results of a lipid panel demonstrated a total cholesterol level of 374 mg/dL (9.7 mmol/L) and triglycerides of 828 mg/dL (9.3 mmol/L). A work-up for causes of secondary hyper-triglyceridemia was negative. Results of apoE genotyping by a commercial laboratory showed the E3/E3 genotype, based on gene sequencing at codons 112 and 158. Because the skin lesions were typical for type III HLP, his entire apoE gene was sequenced. This analysis revealed an apoE2/E2 (arginine 145 to cysteine) mutation, previously reported to be a rare cause of type III HLP in 5 patients of African descent. Triglyceride-lowering therapy with gem-fibrozil was initiated, in addition to lifestyle modification. At follow-up several months later, total cholesterol was 276 mg/dL (7.14 mmol/L) and triglycerides were 479 mg/dL (5.41 mmol/L). CONCLUSION: We speculate that olanzapine therapy, with its known metabolic side effects, exacerbated this patient's underlying lipoprotein metabolic abnormality. To our knowledge, this is the first report of an association between olanzapine therapy and tuberous xanthomas and the sixth report of this rare apoE2/E2 (arginine 145 to cysteine) mutation in the literature.- - - - - - - - - - ranking = 1keywords = vascular disease (Clic here for more details about this article) |
4/4. Familial apolipoprotein E deficiency.A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.- - - - - - - - - - ranking = 1keywords = vascular disease (Clic here for more details about this article) |