Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia.

OBJECTIVE: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB (apolipoprotein B) and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P<0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia. CONCLUSIONS: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.

Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease.

PURPOSE OF REVIEW: Several mutations in the apolipoprotein (apo) B, proprotein convertase subtilisin kexin 9 (PCSK9) and microsomal triglyceride transfer protein genes result in low or absent levels of apoB and LDL cholesterol (LDL-C) in plasma which cause familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Mutations in the angiopoietin-like protein 3 ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). Clinical manifestations range from none-to-severe, debilitating and life-threatening disorders. This review summarizes recent genetic, metabolic and clinical findings and management strategies. RECENT FINDINGS: Fatty liver, cirrhosis and hepatocellular carcinoma have been reported in FHBL and ABL probably due to decreased triglyceride export from the liver. Loss of function mutations in PCSK-9 and ANGPTL3 cause FHBL but not hepatic steatosis. In 12 case-control studies with 57 973 individuals, an apoB truncation was associated with a 72% reduction in coronary heart disease (odds ratio, 0.28; 95% confidence interval, 0.12-0.64; P = 0.002). PCSK9 inhibitors lowered risk of cardiovascular events in large, randomized trials without apparent adverse sequelae. SUMMARY: Mutations causing low LDL-C and apoB have provided insight into lipid metabolism, disease associations and the basis for drug development to lower LDL-C in disorders causing high levels of cholesterol. Early diagnosis and treatment is necessary to prevent adverse sequelae from FHBL and ABL.

Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels.

BACKGROUND: Screening of variants, related to lipid metabolism in patients with extreme cholesterol levels, is a tool used to identify targets affecting cardiovascular outcomes. The aim of this study was to examine the prevalence and characteristics of rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol (LDL-C) levels. METHODS: Among 13,545 participants enrolled in a cardiovascular genome cohort, 22 subjects, whose LDL-C levels without lipid-lowering agents were ≤1 percentile (48 mg/dL) of Korean population, were analyzed. Two target genes, APOB and PCSK9, were sequenced by targeted next-generation sequencing. Prediction of functional effects was conducted using SIFT, PolyPhen-2, and Mutation Taster, and matched against a public database of variants. RESULTS: Eight rare variants of the two candidate genes (five in APOB and three in PCSK9) were found in nine subjects. Two subjects had more than two different rare variants of either gene (one subject in APOB and another subject in APOB/PCSK9). Conversely, 12 common variants (nine in APOB and three in PCSK9) were discovered in 21 subjects. Among all variants, six in APOB and three in PCSK9 were novel. Several variants previously reported functional, including c.C277T (p.R93C) and c.G2009A (p.G670E) of PCSK9, were found in our population. CONCLUSIONS: Rare variants of APOB or PCSK9 were identified in nine of the 22 study patients with extremely low LDL-C levels, whereas most of them had common variants of the two genes. The common novelty of variants suggested polymorphism of the two genes among them. Our results provide rare genetic information associated with this lipid phenotype in East Asian people.

Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins.

Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective: To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design: We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results: First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was <25% of normal (<60 ng/dL). Second, the very low-density lipoprotein particle concentration correlated strongly with plasma ANGPTL3 when the latter was <58% of normal. Third, both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9 and higher levels of its furin-cleaved form. Finally, LDL-bound PCSK9 is protected from cleavage by furin and binds to the LDL receptor more strongly than apoB-free PCSK9. Conclusions: Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.

Association between familial hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol-diabetes connection? A systematic review of literature.

Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB, PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980-2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.

Establishment of reference values of α-tocopherol in plasma, red blood cells and adipose tissue in healthy children to improve the management of chylomicron retention disease, a rare genetic hypocholesterolemia.

BACKGROUND: Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for α-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of α-tocopherol in patients with CMRD after oral treatment with vitamin E. METHODS: This prospective study included 166 healthy children (1 month - 18 years) and 4 patients with CMRD. Blood and AT were collected in healthy children during a scheduled surgery and in patients before and after a 4-month treatment with α-tocopherol acetate. RESULTS: The reference ranges for α-tocopherol were 11.9 - 30 µmol/L in plasma, 2.0 - 7.8 µmol/L packed cells in RBC and 60 - 573 nmol/g in AT. α-tocopherol levels in plasma correlated with those of RBC (r = 0.31; p < 0.01). In patients with CMRD after 4 months treatment, α-tocopherol concentrations remained less than 70 % of the control values in plasma, increased by 180 % to reach normal values in RBC, and remained stable in the normal range in AT. CONCLUSION: This study establishes pediatric reference intervals for α-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate α-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC α-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with α-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin E deficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.

Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects.

We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these patients, we identified two previously uncharacterized missense mutations in the microsomal triglyceride transfer protein (MTP) gene, R46G and D361Y, and studied their functional effects. We also characterized three missense mutations (H297Q, D384A, and G661A) reported earlier in a familial hypobetalipoproteinemia patient. R46G had no effect on MTP expression or function and supported apoB secretion. H297Q, D384A, and G661A mutants also supported apoB secretion similarly to WT MTP. Contrary to these four missense mutations, D361Y was unable to support apoB secretion. Functional analysis revealed that this mutant was unable to bind protein disulfide isomerase (PDI) or transfer lipids. The negative charge at residue 361 was critical for MTP function as D361E was able to support apoB secretion and transfer lipids. D361Y most likely disrupts the tightly packed middle α-helical region of MTP, mitigates PDI binding, abolishes lipid transfer activity, and causes ABL. On the other hand, the hypolipidemia in the other two patients was not due to MTP dysfunction. Thus, in this study of five missense mutations spread throughout MTP's three structural domains found in three hypolipidemic patients, we found that four of the mutations did not affect MTP function. Thus, novel mutations that cause severe hypolipidemia probably exist in other genes in these patients, and their recognition may identify novel proteins involved in the synthesis and/or catabolism of plasma lipoproteins.

The relation of fibrosis stage with nutritional deficiencies and bioelectrical impedance analysis of body composition in patients with chronic hepatitis C.

UNLABELLED:  Background. Nutritional deficiencies may aggravate the course of chronic hepatitis C (CHC). Our aim has been to perform a comprehensive analysis of body composition and nutritional deficiencies in CHC patients in non-cirrhotic and compensated cirrhotic stages to correlate the detected deficiencies with the fibrosis stage. MATERIAL AND METHODS: Body multifrequency bioimpedance analysis (BIA) and a wide and simultaneous analytical profile were prospectively performed in 74 CHC patients (36 male) with known METAVIR fibrosis stage established with liver biopsy or transient elastography. Results were analyzed to identify deviations from the normal range and variations according to the fibrosis stage. RESULTS: Body fat compartment was greater in women. Body composition did not change among the 4 stages of liver fibrosis. Low levels (< 30 µg/L) of vitamin D were detected in 74.3% of patients irrespective of the fibrosis stage. Most analytical results remained into the normal range with the exceptions of thrombocytopenia and vitamin A deficiency, that were limited to the stage 4 of fibrosis, and low Zn and LDL-cholesterol values, that were frequently found in patients with advanced (F3 and F4) fibrosis stage. CONCLUSION: Body composition and most biochemical parameters, including cyanocobalamin, folic acid and vitamin E, are well preserved in compensated patients with CHC, with the exception of generalized vitamin D insufficiency and of deficiencies of vitamin A and zinc that are restricted to the more advanced, although still compensated, stages of the disease.

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism.

The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. We studied 7 homozygous (undetectable circulating ANGPTL3 levels) and 31 heterozygous (50% of circulating ANGPTL3 levels) subjects with familial combined hypolipidemia (FHBL2) due to inactivating ANGPTL3 mutations in comparison with 35 controls. All subjects were evaluated at fasting and during 6 h after a high fat meal. Postprandial lipid and lipoprotein changes were quantified by calculating the areas under the curve (AUCs) using the 6 h concentration data. Plasma changes of ß-hydroxybutyric acid (ß-HBA) were measured as marker of hepatic oxidation of fatty acids. Compared with controls, homozygotes showed lower incremental AUCs (iAUCs) of total TG (-69%, P < 0.001), TG-rich lipoproteins (-90%, P < 0.001), apoB-48 (-78%, P = 0.032), and larger absolute increase of FFA (128%, P < 00.1). Also, heterozygotes displayed attenuated postprandial lipemia, but the difference was significant only for the iAUC of apoB-48 (-28%; P < 0.05). During the postprandial period, homozygotes, but not heterozygotes, showed a lower increase of ß-HBA. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietary-derived fatty acids into the liver. These results add information on mechanisms underlying hypolipidemia in FHBL2.

Lipoprotein metabolism in an apoB-80 familial hypobetalipoproteinemia heterozygote.

OBJECTIVE: Familial hypobetalipoproteinemia (FHBL) is characterized by mutations in APOB, the majority of these causing protein truncations, and low plasma levels of apolipoprotein (apo) B. The hypobetalipoproteinemia may be due to enhanced clearance and possibly reduced production of apoB-containing lipoproteins; the mechanism may depend on the length of the apoB truncation. We studied fasting lipoprotein metabolism in an FHBL subject heterozygous for a mutation causing a truncated apoB, apoB-80. DESIGN AND METHODS: Very low density lipoprotein (VLDL)-, intermediate density lipoprotein (IDL)-, and low density lipoprotein (LDL)-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. RESULTS: Compared with lean normolipidemic controls the apoB-80 FHBL subject had an elevated VLDL-apoB fractional catabolic rate and lower LDL production. ApoB production rates and IDL- and LDL-apoB fractional catabolic rates were not different. CONCLUSION: FHBL subjects heterozygous for a mutation truncating apoB to 80% of full-length are able to produce VLDL-apoB normally, but have rapid clearance of these particles, resulting in low levels of circulating apoB.

Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS: ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.

Diagnostico de hipobetalipoproteinemia en un nino de 8 años? / Diagnosis of hypobetalipoproteinemia in an 8-year-old child? / Diagnostico hipobetalipoproteinemia numa crianca de 8 anos?

La hipobetalipoproteinemia familiar es un trastorno hereditario autosomico dominante que afecta a las lipoproteinas que contienen Apo B, una proteina indispensable para el transporte de los quilomicrones en el intestino y que ademas participa en la sintesis y transporte de las VLDL en el higado. La concentracion de Apo B se usa junto con otras pruebas lipidicas para establecer el riesgo individual de un paciente de desarrollar enfermedad cardiovascular. Presentacion del caso: Paciente de 8 anos, varon, que acude a la consulta de Pediatria del Hospital Universitario Virgen Macarena de Sevilla con sintomas de dolor abdominal, deposiciones blandas y diarreicas, sobrepeso y unas quebradizas. El paciente fue derivado al laboratorio para su estudio con sospecha de hipobetalipoproteinemia. Se le solicito un hemograma, frotis sanguineo, pruebas de coagulacion, bioquimica general y estudio de riesgo vascular. Los datos del estudio bioquimico descartaron la celiaquia (IgA 174 mg/dL [100- 400 mg/dL] y antitransglutaminasa 5 U/mL [< 20]). Las determinaciones incluidas en el perfil de riesgo cardiovascular (RCV) fueron: colesterol total 83 mg/dL (45 mg/dL), c-LDL 32 mg/dL (< 160 mg/dL), colesterol no HDL 35 mg/dL, c-VLDL 3 mg/dL (< 40 mg/dL), trigliceridos 28 mg/dL, Apo-A1 112 mg/dL (119-240 mg/dL), Apo B-100 25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (< 3 mg/dL), Lp (a) 2 mg/dL (< 30 mg/ dL), homocisteina 5,8 µmol/L (< 15 µmol/L), vitamina A 42 µg/dL (50-200 µg/ dL), vitamina E 1051 µg/dL (50-180 µg/dL) y 25-(OH) D 48,9 ng/mL (30-54 ng/mL) en intervalos de normalidad. El HLA-27 fue negativo. Tras encontrar hallazgos bioquimicos de bajas concentraciones de lipoproteinas con Apo B, se le solicito al paciente una prueba de saliva para realizacion de estudio genetico de LipochipR para mutaciones en el gen de Apo B y PCSK9. Se concluye que el paciente presento una disminucion de la concentracion de las lipoproteinas que contienen Apo B y trigliceridos. La sintomatologia de dolor abdominal y heces pastosas apoyaron el diagnostico clinico. La inexistencia de deficit vitaminico, retraso mental, acantocitosis y demas sintomatologia asociada, hizo pensar en una herencia heterocigota, que con las herramientas disponibles no se pudo describir geneticamente ya que LipochipR no detecta positividad para este paciente para una mutacion de cambio de aminoacidos en el gen y exon de Apo 26, PCSK9-7, PCSK9-4, PCSK9-10.

Familial hypobetalipoproteinemia is a dominant autosomal inherited disorder that affects lipoproteins containing Apo B. It is an essential protein for the transport of chylomicrons in the intestine and it is involved in the synthesis and transport of VLDL in the liver. This concentration is used along with other lipid tests to establish a patient's individual risk of developing cardiovascular disease. This is the case of an 8 year-old male patient who presented at the University Hospital Virgen Macarena in Seville with symptoms of abdominal pain, loose stools and diarrhea, overweight and broken nails. The patient was referred to the laboratory for examination with suspected hypobetalipoproteinemia. He was requested a complete blood count, blood smear, coagulation, biochemistry and vascular risk study. Biochemical data discarded celiac disease (IgA 174 mg/dL [100-400 mg/dL] y antitransglutaminase antibody 5 U/mL [< 20]). Determinations were RCV's profile: Total cholesterol 83 mg/dL (45 mg/dL), c-LDL 32 mg/dL (< 160 mg/dL), non-HDL cholesterol 35 mg/dL, c-VLDL 3 mg/dL (< 40 mg/dL), triglycerides 28 mg/dL, Apo-A1 112 mg/dL (119-240 mg/dL), Apo B-100 25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (< 3 mg/dL), Lp (a) 2 mg/dL (< 30 mg/dL), Homocysteine 5,8 µmol/L (< 15 µmol/L), Vitamin A 42 µg/dL (50-200 µg/dL), Vitamine E 1051 µg/dL (50-180 µg/dL) and 25-(OH) D 48,9 ng/mL (30-54 ng/mL) in normal ranges. HLA-27 Negative. After biochemical findings of low concentrations of lipoproteins with Apo B100, the patient was requested a saliva test for genetic study conducting LipochipR for mutations of Apo B and PCSK9. It can be concluded that the patient had a decreased concentration of lipoproteins containing Apo-B and triglycerides. The symptoms of abdominal pain and tarry stools supported the clinical diagnosis. The lack of vitamin deficiency, mental retardation, acanthocytosis and other associated sintomatology, made it possible to consider it an heterozygous inheritance. which could not be genetically described with the tools available since LipochipR does not detect in this patient positivity for a mutation to the amino acid change in the gene and exon 26 of Apo, Apo 26, PCSK9-7, PCSK9- 4, PCSK9-10.

Hypobetalipoproteinemia familiar e um disturbio autossomico hereditario dominante que afeta as lipoproteinas contendo Apo--B, uma proteina essencial para o transporte de quilomicrons no intestino e esta envolvido na sintese e transporte de VLDL no figado. A concentracao de Apo-B e utilizada, juntamente com outros testes lipidicos, para estabelecer o risco individual de um paciente de desenvolver doencas cardiovasculares. O caso e o de um paciente de 8 anos, do sexo masculino, que se apresenta para consulta de Pediatria do Hospital Universitario Virgen Macarena, em Sevilha, com sintomas de dor abdominal, fezes brandas e diarreia, sobrepeso e unhas quebradicas. O paciente foi derivado ao laboratorio para exame com suspeita de hypobetalipoproteinemia. Foi pedido um hemograma completo, esfregaco de sangue, coagulacao, bioquimica geral e estudo de risco vascular. Os dados do estudo bioquimico descartaram a doenca celiaca (IgA 174 mg/dL [100-400 mg/dL] e Antitrasglutaminase 5 U/mL [<20]). As determinacoes incluidas no perfil de risco cardiovascular (RCV) foram colesterol total 83 mg/dL (45 mg/dL), LDL-C 32 mg/ dL (<160 mg/dL), colesterol nao-HDL de 35 mg/dL, VLDL-C 3 mg/dL (<40 mg/dL), triglicerideos de 28 mg/dL, Apo-A1 112 mg/ dL (119-240 mg/dL), Apo B-100-25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (<3 mg/dL) de Lp (a) 2 mg/dL (<30 mg/dL), homocisteina de 5,8 µmol/L (<15 µmol/L), a vitamina A 42 µg/dL (50-200 µg/dL), vitamina E 1051 µg/dL (50-180 µg/dL) e 25- (OH) D 48,9 ng/mL (30-54 ng/mL) em intervalos de normalidade. O HLA-27 foi negativo. Depois de encontrar achados bioquimicos de baixas concentracoes de lipoproteinas com apo-B, foi solicitado ao paciente um teste de saliva para estudo genetico de LipochipR para mutacoes no gene de Apo-B e PCSK9. Conclui-se que o paciente apresentou uma diminuicao na concentracao das lipoproteinas contendo Apo-B e triglicerideos. Os sintomas de dor abdominal e fezes pastosas apoiaram o diagnostico clinico. A inexistencia de deficit vitaminico, retardo mental, acantocitose e outros sintomas associados fez pensar numa heranca heterozigotica, que com as ferramentas disponiveis nao se pode descrever geneticamente ja que LipochipR nao detecta positividade para este paciente para uma mutacao de mudanca de aminoacidos no gene e exon de Apo 26, PCSK9-7, PCSK9- 4, PCSK9-10.

Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.

Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation.

A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia.

OBJECTIVE: In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. APPROACH AND RESULTS: The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation. CONCLUSIONS: We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.

Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids.

OBJECTIVE: Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. APPROACH AND RESULTS: We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. CONCLUSIONS: These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism.

Recent developments in the genetics of LDL deficiency.

PURPOSE OF REVIEW: Inherited diseases of lipoprotein metabolism may give rise to marked hypocholesterolemia with low or absent levels of LDL, depending on the gene involved and mode of inheritance of the condition, together with the severity of the mutation or mutations present. In this review, we discuss the recent developments in the genetics of LDL deficiency. RECENT FINDINGS: Carriers of a single loss-of-function variant in ANGPTL3 have reduced LDL-cholesterol and triglyceride concentrations, whereas homozygotes have markedly reduced LDL-cholesterol, triglyceride and HDL-cholesterol concentrations, a recessive form of hypocholesterolemia designated as familial combined hypolipidemia. SUMMARY: The identification of loss-of-function ANGPTL3 mutations as a cause of familial combined hypolipidemia suggests a new mechanism for the regulation of LDL metabolism in humans, thereby making ANGPTL3 an attractive protein to target for therapeutics.

Low rate of production of apolipoproteins B100 and AI in 2 patients with Anderson disease (chylomicron retention disease).

OBJECTIVE: Anderson disease is a rare inherited lipid malabsorption syndrome associated with hypocholesterolemia and linked to SAR1B mutations. The aim of this article was to analyze the mechanisms responsible for the low plasma apolipoprotein Apo-B100 and Apo-AI in 2 patients with Anderson disease. METHODS AND RESULTS: A primed constant infusion of (13)C-leucine was administered for 14 hours to determine the kinetics of lipoproteins. In the 2 patients, total cholesterol (77 and 85 mg/dL versus 155±32 mg/dL), triglycerides (36 and 59 versus 82±24 mg/dL), Apo-B100 (48 and 43 versus 71±5 mg/dL), and Apo-AI (47 and 62 versus 130±7 mg/dL) were lower compared with 6 healthy individuals. Very-low-density lipoprotein-B100 production rate of the patients was lower (4.08 and 5.52 mg/kg/day versus 12.96±2.88 mg/kg/day) as was the fractional catabolic rate (5.04 and 4.32 day(-1) versus 12.24±3.84 day(-1)). No difference was observed in intermediate-density lipoprotein-B100 and LDL-B100 kinetic data. The production rate of high-density lipoprotein Apo-AI was lower in the patients (7.92 and 8.64 versus 11.96±1.92 mg/kg/day) and the fractional catabolic rate was higher (0.38 and 0.29 versus 0.22±0.01 day(-1)). CONCLUSIONS: The low plasma Apo-B100 and Apo-AI concentrations in the patients with Anderson disease were mainly related to low rates of production.