Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.

CONTEXT: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. OBJECTIVE: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. DESIGN: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. SETTING: The study was conducted in a general community. SUBJECTS: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community. MAIN OUTCOMES MEASURES: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. RESULTS: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P < 0.001). Heterozygotes had 42% reduction in Angptl3 level compared with noncarriers (P < 0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol. No differences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected. CONCLUSIONS: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

Low HDL levels and the risk of death, sepsis and malignancy.

BACKGROUND: High density lipoprotein (HDL) plays an important role as an anti-atherogenic molecule, but also possesses anti-inflammatory and anti-angiogenic properties. The effect of extremely low levels of HDL on the risk of sepsis and malignancy were therefore examined. METHODS: A retrospective analysis of patients hospitalized at the Edith Wolfson Medical center was conducted. Patients were divided into Group 1: 108 patients with serum HDL levels < or =20 mg/dl. Group 2: 96 patients with serum HDL levels > or =65 mg/dl. Medical history and laboratory data was recorded. RESULTS: The mean HDL levels in Group 1 were 16.1 +/- 33 mg/dl compared to 74.9 +/- 12.6 mg/dl in Group 2. Using a multivariate logistic regression analysis, low HDL was inversely associated with death (OR 0.96, 95% 0.93-0.99, P = 0.02), 3.98 fold increase in odds of fever (OR 3.98, 95% CI 1.3-11.8, P = 0.01), and 6.7-fold increase in the risk of cancer (OR 6.68, 95% CI 1.8-24.5, P = 0.004). HDL serum levels were inversely associated with sepsis. For each 1 mg/dl increase in HDL, a relative 11% decrease in odds of sepsis was observed (OR 0.886, 95% CI 0.8-0.976, P = 0.01). CONCLUSIONS: Extremely low serum HDL levels (< or =20 mg/dl) are associated with an increased risk of death, sepsis and malignancy.

Clinical inquiries: What is the dietary treatment for low HDL cholesterol?

Low-carbohydrate diets raise high-density lipoprotein (HDL) cholesterol levels by approximately 10%; soy protein with isoflavones raises HDL by 3% (strength of recommendation [SOR]: C, based on meta-analysis of physiologic parameters). The Dietary Approaches to Stop Hypertension (DASH) diet and multivitamin supplementation raise HDL 21% to 33% (SOR: C, based on single randomized trial each measuring physiologic parameters). No other dietary interventions studied raise HDL (SOR: C, based on meta-analysis of physiologic parameters).

Serum lipid levels in patients with dissociative disorder.

OBJECTIVE: There may be an association between a low serum cholesterol level and dissociative disorders. METHOD: The subjects of the study were 16 patients with dissociative disorder and 16 normal comparison subjects (two men and 14 women in each group). Total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein levels were compared. RESULTS: Patients with dissociative disorders had lower serum triglyceride, total cholesterol, low-density lipoprotein, and very low density lipoprotein levels than normal comparison subjects. CONCLUSIONS: Low serum lipid concentrations may be related to a high incidence of self-injurious behaviors and borderline features in patients with dissociative disorders.

Hypobetalipoproteinemia with an apparently recessive inheritance due to a "de novo" mutation of apolipoprotein B.

Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder either linked or not linked to apolipoprotein (apo) B gene. Abetalipoproteinemia (ABL) is a recessive disorder due to mutations of microsomal triglyceride transfer protein (MTP) gene. We investigated a patient with apparently recessive hypobetalipoproteinemia consistent with symptomatic heterozygous FHBL or a "mild" form of ABL. The proband had fatty liver associated with LDL-cholesterol (LDL-C) and apo B levels <5th percentile but no truncated apo B forms detectable in plasma. MTP gene sequence revealed that he was a carrier of the I128T polymorphism and an unreported amino acid substitution (V168I) unlikely to be the cause of hypobetalipoproteinemia. Apo B gene sequence showed that he was heterozygous for two single base substitutions in exon 9 and 22 resulting in a nonsense (Q294X) and a missense (R1101H) mutation, respectively. Neither of his parents carried the Q294X; his father and paternal grandmother carried the R1101H mutation. Analysis of polymorphic genetic markers excluded non-paternity. In conclusion, the proband has a "de novo" mutation of apo B gene resulting in a short truncated apo B form (apo B-6.46). Sporadic cases of FHBL with an apparently recessive transmission may be caused by "de novo" mutations of apo B gene.

Analysis of apolipoprotein A-I, lecithin:cholesterol acyltransferase and glucocerebrosidase genes in hypoalphalipoproteinemia.

Hypoalphalipoproteinemia (HALP) is a dyslipidemia characterized by low HDL-cholesterol (HDL-C) levels with important genetic contribution. However, no common genetic mutations have been found to be associated with this disorder. We screened the promoter and coding sequence of apolipoprotein (apo) A-I and lecithin:cholesterol acyltransferase (LCAT) genes and the 5' apo C-III region by SSCP and heteroduplex analysis, and DNA sequencing in 66 unrelated subjects with recurrent low HDL-C levels. We also analyzed the N370S and L444P variants, in the glucocerebrosidase (GBA) gene by restriction fragment analysis. Three mutations in the apo A-I gene (L144R, W108R, g.1833C>T) and 3 mutations in the LCAT gene (S208T, I178T, IVS3-23C>A) were detected, in six heterozygous subjects. In addition, a novel polymorphic site in LCAT gene (g.4886C>T) has been identified. Allelic frequencies of polymorphisms g.(-636)C>A, g.(-625)G>A, g.(-620)T>del, g.(-479C>T and g.(-452)T>C, located upstream of the apo C-III gene, were in normal range, and no other mutation was found in this region. Two HALP subjects were found to carry the N370S mutation at GBA locus. In conclusion, 12% of HALP subjects were found to carry mutations in apo A-I, LCAT, or GBA genes, which could explain this phenotype. Our results confirm the molecular, genetic and phenotypic heterogeneity of HALP.

Genetics of lipoprotein disorders.

The study of lipoprotein metabolism has led to major breakthroughs in the fields of cellular physiology, molecular genetics, and protein chemistry. These advances in basic science are reflected in medicine in the form of improved diagnostic methods and better therapeutic tools. Perhaps the greatest benefit is the improved ability to identify at an early stage patients who are at high risk for atherosclerosis, providing clinicians the opportunity to proceed swiftly with intensive lipid-lowering therapy for the prevention of cardiovascular complications. Recent clinical trials have shown that such an approach is not only cost-effective but saves lives while improving the quality of life. They also emphasize the important role physicians can have in prevention. More than half of patients with premature CAD have a familial form of dyslipoproteinemia. This review of the genetics of atherogenic lipoprotein disorders underscores the importance of identifying major genetic defects. It also stresses the need to take into account multifactorial etiologies and clustering of risk factors, as well as gene-gene and gene-environment interactions in assessing the atherogenic potential of a lipid transport disorder. Table 2 summarizes the key points in the diagnosis, clinical implications, and treatment of the major inherited atherogenic dyslipidemias.

Lipoproteína(a) y lípidos en insuficiencia renal crónica y en trasplante renal / Lipoprotein(a) and lipid abnormalities in chronic renal insufficiency and renal transplantation

Objetivo. Establecer la prevalencia de las anormalidades de lípidos y lipoproteína(a) en pacientes tratados con hemodiálisis y en trasplantados. Métodos. Se estudiaron 40 dializados, 64 trasplantados y un grupo de comparación de 77 sujetos de población abierta pareados por edad y género. Resultados. En el grupo de hemodiálisis la atención más prevalente fue la hipoalfalipoproteinemia seguida de exceso de Lp(a) y la de menor frecuencia fue la hipercolesterolemia. Contrariamente, los trasplantados tuvieron la prevalancia más baja de exceso de Lp(a), y una proporción de hipercolesterolemia más alta que la de pacientes hemodializados y semenjantes a los controles. Conclusión. Nuestros resultados confirman algunas observaciones de otros pero en nuestro estudio fue la hipoalfalipoproteinemia y no la hipertrigliceridemia la anormalidad predominante en los pacientes hemodializados

[How I study a patient with a low concentration of HDL cholesterol]. / Comment j'explore ... un sujet avec une concentration basse de cholestérol HDL.

A decrease in plasma HDL cholesterol concentration is considered as a major cardiovascular risk factor and is a prevalent lipid abnormality among patients with coronary heart disease. This condition is most often observed in the presence of hypertriglyceridaemia, generally linked to the insulin resistance syndrome, but may also be associated to elevated LDL cholesterol level or even be present alone (hypoalphalipoproteinaemia). The decision to treat a patient with low HDL level depends on the individual overall cardiovascular risk which should be evaluated as carefully as possible. The investigation should look for causes which may favour this metabolic condition, such as bad life habits or possible pharmacological interferences.

Analysis of familial hypoalphalipoproteinemia syndromes.

Familial hypoalphalipoproteinemias (HA) are a heterogenous group of disorders characterized by various degrees of HDL deficiency. Differential diagnosis involves clinical and biochemical evaluation after intervention designed to correct known secondary causes of low HDL. Two specific HAs are discussed in this report: 1. primary isolated HA (PIHA) is a poorly characterized entity with an apparent autosomal dominant transmission and distinct abnormalities in the structure and function of HDL. 2. Lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes are caused by a number of different genetic defects that lead to at least two distinct clinical presentations i.e. familial LCAT deficiency and fish eye disease. PIHA is an example of a genetic disorder whose diagnosis would greatly be improved by the availability of molecular diagnostic tests. Conversely, the effect of the genetic heterogeneity of LCAT deficiency syndromes on diagnosis is best overcome by utilizing existing biochemical measurement of LCAT activity and the plasma cholesterol esterification rate.

Acquired hypolipoproteinemia.

We present a six-year follow-up of a boy with a novel type of hypolipoproteinemia, with clinical and biochemical features distinct from classical hypoalphalipoproteinemias. There were abnormally low concentrations of total and high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) B, apo A-I, and apo A-II, and the phospholipids were decreased. The most striking abnormality was an extra fraction containing mainly phospholipids and apo A-I in the HDL3 subfraction. This fraction is reminiscent of concentric 20- to 50-nm-diameter lamellar phospholipid liposomes. Plasma lecithin:cholesterol acyltransferase activity was strongly decreased. We noted a persisting polyclonal hypergammaglobulinemia, hematological abnormalities (hemolytic anemia and thrombocytopenia), and a progressive splenomegaly. After the five-year follow-up, the patient had recurrent severe infections; moderate hematuria and proteinuria developed gradually. Treatment with corticosteroids and immunoglobulins improved thrombocytopenia and hypolipoproteinemia. These clinical and biochemical findings differ from those in the known primary and secondary hypo-alpha-lipoproteinemia syndromes. Although investigation of the relatives suggests a familial predisposition for hypo-alpha-lipoproteinemia, the subject's condition can be regarded as acquired.

[Early detection of dyslipidemias. Is the isolated determination of total cholesterol efficient?]. / Detección inicial de las dislipemias. Es eficaz la determinación aislada del colesterol total?

BACKGROUND: The aim of this study was to analyze the percentage of individuals with hypoalphalipoproteinemia and isolated hypertriglyceridemia which would not be detected if only total cholesterol were included in the initial detection of dyslipemia. METHODS: Five hundred forty-one individuals participating in a study concerning factors of cardiovascular risk were included in the present study which consisted in a survey on risk factors and a medical examination. The population studied was divided according to the concentration of total cholesterol (TC) in desirable concentrations (5.2 mmol/l), intermediate (5.2-6.2 mmol/l) and elevated (6.2 mmol/l). The concentrations of cholesterol bound to high density lipoproteins (cHDL) less than 0.9 mmol/l and of triglycerides (TG) greater than 2.3 mmol/l were considered as high risk. RESULTS: Hypoalphalipoproteinemia would not be detected in 2.9% of the population studied (IC 95%: 1.5%-4.3%) and isolated triglyceridemia in 2.4% (IC 95%: 1.1%-3.7%) if the cHDL and the TG were only determined in the individuals who had high or elevated CT concentrations and two or more cardiovascular risk factors. CONCLUSIONS: These data support the efficacy of CT as the only test for initial detection of dyslipemia and question the convenience of initial quantification of cHDL and triglycerides in all cases as some authors request.

Diagnosis and management of familial dyslipoproteinemia in children and adolescents.

CAD results from atherosclerosis, a chronic disease process that has its origin in childhood. Children and adolescents can be at higher risk for CAD by virtue of being from families with premature CAD or familial dyslipoproteinemias. The plasma lipid and lipoprotein levels result from a number of complex metabolic processes that are under the control of genetic and environmental (e.g., diet) influences. The normal ranges of plasma lipids and lipoproteins in children are known, and children and adolescents with dyslipoproteinemia are ordinarily defined as those having levels of plasma total, LDL, or triglyceride above the 95th percentile or with a low HDL cholesterol below the 5th percentile. Children of a parent with documented dyslipoproteinemia or with family history of premature CAD may be screened in the fasting state any time after 2 years of age. Following the exclusion of secondary causes of dyslipoproteinemia, the diagnosis of primary dyslipoproteinemia can be made. Lipoprotein patterns are not diagnostic for a given genotype. Efforts to determine further the biochemical defects responsible for a given phenotype have led to the investigation of gene coding for the apolipoproteins, the key enzymes in the lipoproteins pathways (LPL, HDL, and LCAT) and the receptors that process lipoproteins, such as the LDL receptor and the chylomicron remnant receptor. From a practical standpoint, the diagnosis of the kind of dyslipoproteinemia in a child will depend upon the nature and severity of the dyslipoproteinemia, both in the child (or adolescent) and in parents and siblings. Marked increases in plasma total and LDL cholesterol in the child and in at least one of the parents often reflect the presence of familial hypercholesterolemia, an inherited dominant condition due to a defect in the LDL receptor gene. The triglyceride levels are often normal. If the child has a different dyslipoproteinemia pattern from siblings and parents, then the diagnosis of familial combined hyperlipidemia or hyperapobetalipoproteinemia should be considered. Most children with mild or borderline elevations in total and LDL cholesterol will have polygenic hypercholesterolemia. Triglyceride problems in children and adolescents are relatively uncommon, particularly the more severe hypertriglyceridemia such as that found in lipoprotein lipase and apoC-II deficiency, dysbetalipoproteinemia, and type V hyperlipoproteinemia. High levels of Lp(a) lipoprotein, in isolation or in combination with other dyslipoproteinemia, accelerate risk for CAD. Low levels of HDL cholesterol in the absence of other abnormalities suggest the diagnosis of hypoalphalipoproteinemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Screening, diagnosis, and management of dyslipoproteinemia in children.

The authors provide an extensive and comprehensive review of dyslipoproteinemia in children. An effective program for CVD reduction in this population will include an accessible screening program to identify high-risk children, high-quality measurements of TC and LP-C, careful follow-up of screening results with multiple measurement to classify risk status and diagnose primary dyslipidemia, a key role for family and education, and consistent and long-term follow-up for diet and drug adherence, efficacy, and safety.

[The relationship between high-density lipoproteins, thromboxane B2 and arteriosclerosis in a case of primary hypoalphalipoproteinemia]. / Rapporto tra lipoproteine ad alta densità, trombossano B2 ed arteriosclerosi in un caso di ipoalfalipoproteinemia primitiva.

Data in the literature suggest that cases of hypoalphalipoproteinemia involve an increase in thromboxane B2 (TXB2) together with an increased risk of atherosclerosis. A recent detailed examination of a 32-year-old man revealed clinical and biochemical features strongly indicative of that pathology. The case presented several unusual features: marked infiltration of the skin and mesenteric lymph nodes by histiocytic lipids with sufficient hyperplasia to induce acute intestinal occlusion combined with an in vivo TXB2 generation curve, subsequently inhibited by aspirin, that was comparable to the curves of the control subjects. Furthermore there were no signs of early atherosclerotic damage so that it was possible to postulate the hypothesis that despite the 50% drop in alpha-lipoprotein levels, they were still sufficient to ensure normal turnover of the other lipoproteins so that, however complex the clinical condition, it was an incomplete expression of a phenotype.