Did you mean: hypolipoproteinemias
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Journal of Clinical Lipidology 2022The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited... (Review)
Review
The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.
Topics: Humans; Abetalipoproteinemia; Hypobetalipoproteinemias; Lipid Metabolism Disorders; Homozygote; Vitamins
PubMed: 36243606
DOI: 10.1016/j.jacl.2022.08.009 -
Current Opinion in Lipidology Jun 2014Several mutations in the apoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and MTP genes result in low or absent levels of apoB and LDL-cholesterol in plasma,... (Review)
Review
PURPOSE OF REVIEW
Several mutations in the apoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and MTP genes result in low or absent levels of apoB and LDL-cholesterol in plasma, which cause familial hypobetalipoproteinemia and abetalipoproteinemia. Mutations in the ANGPTL3 gene cause familial combined hypolipidemia. Clinical manifestations range from none to severe, debilitating, and life-threatening disorders. This review summarizes recent genetic, metabolic, and clinical findings and presents an update on management strategies.
RECENT FINDINGS
Cases of cirrhosis and hepatocellular carcinoma have now been identified in heterozygous familial hypobetalipoproteinemia probably because of decreased triglyceride transport capacity from the liver. ANGPTL3 mutations cause low levels of LDL-cholesterol and low HDL-cholesterol in compound heterozygotes and homozygous individuals, decrease reverse cholesterol transport, and lower glucose levels. The effect on atherosclerosis is unknown; however, severe fatty liver has been identified. Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae. Phase III clinical trials are now underway examining the effect of PCSK9 inhibitors on cardiovascular events in combination with statin drugs.
SUMMARY
Mutations causing low LDL-cholesterol and apoB have provided insight into lipid metabolism, disease associations, and the basis for drug development to lower LDL-cholesterol in disorders causing high levels of cholesterol. Early diagnosis and treatment are necessary to prevent adverse sequelae from familial hypobetalipoproteinemia and abetalipoproteinemia.
Topics: Abetalipoproteinemia; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Apolipoproteins B; Biological Transport, Active; Carcinoma, Hepatocellular; Cholesterol, LDL; Coronary Artery Disease; Humans; Hypobetalipoproteinemia, Familial, Apolipoprotein B; Lipid Metabolism; Liver Cirrhosis; Liver Neoplasms; Mutation; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases; Triglycerides
PubMed: 24751931
DOI: 10.1097/MOL.0000000000000072 -
Orphanet Journal of Rare Diseases Oct 2011Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive... (Review)
Review
Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington's disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.
Topics: Abetalipoproteinemia; Adult; Basal Ganglia; Child; Cognition Disorders; Female; Humans; Hypobetalipoproteinemias; Male; Movement Disorders; Neuroacanthocytosis; Syndrome
PubMed: 22027213
DOI: 10.1186/1750-1172-6-68 -
Journal of Atherosclerosis and... Oct 2021Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride... (Review)
Review
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) <15 mg/dL and apoB <15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.
Topics: Abetalipoproteinemia; Apolipoproteins B; Cholesterol, LDL; Cost of Illness; Disease Management; Humans; Prognosis
PubMed: 33994405
DOI: 10.5551/jat.RV17056 -
Blood Sep 2006
Topics: Abetalipoproteinemia; Acanthocytes; Humans; Liver Diseases; Splenectomy
PubMed: 16955552
DOI: No ID Found -
Neurologia Mar 2020
Topics: Abetalipoproteinemia; Adult; Chorea; Creatine Kinase; Humans; Male; Mutation; Vesicular Transport Proteins
PubMed: 29752031
DOI: 10.1016/j.nrl.2018.03.012 -
Biomedicine & Pharmacotherapy =... Mar 2022Lecithin: cholesterol acyltransferase (LCAT) is the only enzyme in plasma which is able to esterify cholesterol and boost cholesterol esterify with phospholipid-derived... (Review)
Review
Lecithin: cholesterol acyltransferase (LCAT) is the only enzyme in plasma which is able to esterify cholesterol and boost cholesterol esterify with phospholipid-derived acyl chains. In order to better understand the progress of LCAT research, it is always inescapable that it is linked to high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). Because LCAT plays a central role in HDL metabolism and RCT, many animal studies and clinical studies are currently aimed at improving plasma lipid metabolism by increasing LCAT activity in order to find better treatment options for familial LCAT deficiency (FLD), fish eye disease (FED), and cardiovascular disease. Recombinant human LCAT (rhLCAT) injections, cells and gene therapy, and small molecule activators have been carried out with promising results. Recently rhLCAT therapies have entered clinical phase II trials with good prospects. In this review, we discuss the diseases associated with LCAT and therapies that use LCAT as a target hoping to find out whether LCAT can be an effective therapeutic target for coronary heart disease and atherosclerosis. Also, probing the mechanism of action of LCAT may help better understand the heterogeneity of HDL and the action mechanism of dynamic lipoprotein particles.
Topics: Animals; Atherosclerosis; Cholesterol; Coronary Artery Disease; Genetic Therapy; HIV Infections; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Lipoproteins, HDL; Phosphatidylcholine-Sterol O-Acyltransferase; Recombinant Proteins; Renal Insufficiency, Chronic
PubMed: 35121343
DOI: 10.1016/j.biopha.2022.112677 -
BioFactors (Oxford, England) 2014ABCA1 mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein... (Review)
Review
ABCA1 mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). Thus, ABCA1 is a key molecule in cholesterol homeostasis. Functional studies of certain Tangier disease mutations demonstrate that ABCA1 has multiple activities, including plasma membrane remodeling and apoAI binding to cell surface, which participate in nascent HDL biogenesis. Recent advances in our understanding of ABCA1 have demonstrated that ABCA1also mediates unfolding the N terminus of apoAI on the cell surface, followed by lipidation of apoAI and release of nascent HDL. Although ABCA1-mediated cholesterol efflux to apoAI can occur on the plasma membrane, the role of apoAI retroendocytosis during cholesterol efflux may play a role in macrophage foam cells that store cholesterol esters in cytoplasmic lipid droplets.
Topics: ATP Binding Cassette Transporter 1; Animals; Apolipoprotein A-I; Atherosclerosis; Biological Transport; Cell Membrane; Cholesterol Esters; Gene Expression Regulation; Homeostasis; Humans; Lipid Droplets; Lipid Metabolism; Lipoproteins, HDL; Signal Transduction; Tangier Disease
PubMed: 25359426
DOI: 10.1002/biof.1187 -
The New England Journal of Medicine Mar 2006A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in... (Comparative Study)
Comparative Study
BACKGROUND
A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.
METHODS
We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.
RESULTS
Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).
CONCLUSIONS
These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
Topics: Black People; Carotid Arteries; Cholesterol, LDL; Codon, Nonsense; Cohort Studies; Coronary Disease; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Hypolipoproteinemias; Incidence; Male; Middle Aged; Proportional Hazards Models; Proprotein Convertase 9; Proprotein Convertases; Risk; Serine Endopeptidases; United States; White People
PubMed: 16554528
DOI: 10.1056/NEJMoa054013 -
Current Atherosclerosis Reports Jul 2014"Primary hypobetalipoproteinemia" refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density... (Review)
Review
"Primary hypobetalipoproteinemia" refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.
Topics: Abetalipoproteinemia; Avitaminosis; Diet, Fat-Restricted; Humans; Hypobetalipoproteinemia, Familial, Apolipoprotein B; Hypobetalipoproteinemias; Vitamin A; Vitamin E; Vitamins
PubMed: 24781598
DOI: 10.1007/s11883-014-0423-3