Diagnosis Of Homozygous Familial Hypercholesterolemia Research Articles

Evinacumab (Evkeeza)


 CADTH recommends that Evkeeza be reimbursed by public drug plans as an adjunct to diet and other low-density lipoprotein cholesterol (LDL-C)–lowering therapies for the treatment of adult and pediatric patients aged 5 years and older with homozygous familial hypercholesterolemia (HoFH) if certain conditions are met.
 Evkeeza should only be covered to treat patients aged 5 years and older with a diagnosis of HoFH and extremely high levels of LDL-C (sometimes referred to as bad cholesterol) despite receiving other cholesterol-lowering treatments.
 Evkeeza should only be reimbursed if prescribed by specialists with experience in managing HoFH and if the cost of Evkeeza is reduced. Evkeeza may only be prescribed for 24 weeks the first time it is used. To continue treatment with Evkeeza longer than 6 months, the treating physician must provide proof that the patient is responding to treatment, defined as reduction in LDL-C levels.

The efficacy of double filtration plasmapheresis in the treatment of homozygous familial hypercholesterolemia: A single-center experience

IntroductionDifferent modalities of low-density lipoprotein (LDL) apheresis are used to treat patients with familial hypercholesterolemia (FH). The aim of this study was to describe the efficacy of the Double Filtration Plasmapheresis (DFPP) method for FH cases in our hands and to compare with other LDL apheresis techniques. Materials and methodsThis retrospective study was conducted between January 2016 and January 2018 in the University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Adult Hematology Clinic and Therapeutic Apheresis Unit. The study included 5 patients with a diagnosis of homozygous FH. A total of 288 DFFP procedures were performed twice a month (every 15 days) for 2 years. ResultsThe percentage reductions in Lipoprotein A, total cholesterol, Low Density Lipoprotein-C, High Density Lipoprotein-C and triglyceride levels were found to be 84%, 69.2%, 69.8%, 58.8% and 50.1% respectively (5 cases, n = 288). No cardiac event occurred after the initiation of LA with DFPP. ConclusionDFPP is an effective and safe LA method that can be used in the treatment of homozygous FH patients who do not respond to diet and statin therapy.

The rationale and design of the national familial hypercholesterolemia registries in Turkey: A-HIT1 and A-HIT2 studies.

Familial hypercholesterolemia (FH) is a genetic disease characterized by extremely high levels of cholesterol, leading to premature atherosclerosis. Although many countries have already addressed the burden of FH by means of national registries, Turkey has no national FH registry or national screening program to detect FH. Creation of a series of FH registries is planned as part of Turkish FH Initiative endorsed by the Turkish Society of Cardiology to meet this need. This article provides detailed information on the rationale and design of the first 2 FH registries (A-HIT1 and A-HIT2). A-HIT1 is a nationwide survey of adult homozygous FH (HoFH) patients undergoing low-density lipoprotein (LDL) apheresis (LA) in Turkey. A-HIT1 will provide insight into the clinical status of HoFH patients undergoing LA. Primary objective of this cross-sectional study is to identify how HoFH patients on LA are managed. Inclusion criteria are age >12 years, diagnosis of HoFH, and regular LA treatment. All available apheresis centers were electronically invited to participate in the study. The principal physicians of each center will respond to a questionnaire regarding their attitude toward LA. For each patient, another questionnaire will be used to collect data on clinical status, medication use, and disease data. In addition, patients will be asked to complete self-report questionnaires that provide information on quality of life, disease-related anxiety, and depression. A-HIT2 is a registry of adult FH patients presenting at outpatient clinics. At least 1000 FH patients will be recruited from 30 outpatient clinics representing the 12 statistical regions in Turkey based on the EU NUTS classification. Sites specializing in cardiology, internal medicine, and endocrinology were invited to participate. The primary objective of this cross-sectional study is to determine clinical status and management of patients in Turkey diagnosed with FH. Eligibility for screening was defined as having LDL-cholesterol level >160 mg/dL. Inclusion criteria are age >18 years and diagnosis as possible FH (total score of >2 according to Dutch Lipid Clinic Network criteria). In addition to measuring clinical status of patients, a short survey to assess patient level of disease awareness will also be administered. A-HIT1 and A-HIT2 are the first nationwide FH registries in Turkey and will provide important information on the management of Turkish FH patients. In addition, it is planned that they will guide establishment of a national policy for the diagnosis and treatment of FH in Turkey.

Familial hypercholesterolemia/autosomal dominant hypercholesterolemia: Molecular defects, the LDL-C continuum, and gradients of phenotypic severity

Familial hypercholesterolemia (FH) is a common inherited disorder in which the severity of atherosclerosis is generally proportional to the extent and duration of elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. Homozygous FH (HoFH) is generally considered the most severe condition and results in very high LDL-C levels that respond only partially to statin therapy. The diagnosis of HoFH is complicated by its presentation as a phenotypic spectrum involving multiple genes. The objective here is to review the genetics, continuum of LDL-C concentrations, and phenotypic severity of FH. Multiple PubMed searches were conducted as described in the main text of this article. Traditionally, FH has been considered an autosomal co-dominant disorder whereby both heterozygotes (HeFH) and homozygotes are affected. Recently, additional genes and loci for monogenic FH have been characterized that allow for the identification of double mutations in the known genes and loci and the description of novel forms of double heterozygous FH. Phenotypic expression and clinical severity of untreated HeFH, double HeFH, compound HeFH, and HoFH vary with some overlap both between and within the genotypes. In addition, there is overlap in LDL-C levels of treated HeFH and treated HoFH. These discoveries raise the possibility that new combinations of molecular defects could modulate the severity of hypercholesterolemia. These defects are unlikely to represent true homozygosity. However, they are likely to result in a phenotype consistent with HoFH or severe HeFH, which will be important as new therapies become available with indications specifically for HoFH.

Challenges in the Diagnosis and Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic disorder characterized by an absence or impairment of low-density lipoprotein receptor (LDLR) function resulting in significantly elevated low-density lipoprotein cholesterol (LDL-C) levels. The cholesterol exposure burden beginning in utero greatly increases the risk for atherosclerotic cardiovascular disease (ASCVD) and premature death. The genetic heterogeneity of HoFH results in a wide range of LDL-C levels among both untreated and treated patients. Diagnosis of HoFH should, therefore, be based on a comprehensive evaluation of clinical criteria and not exclusively LDL-C levels. As treatment goals, the European Atherosclerosis Society and International FH Foundation suggest target LDL-C levels of <100 mg/dL (<2.5 mmol/L) in adults or <70 mg/dL (<1.8 mmol/L) in adults with clinical coronary artery disease or diabetes. The National Lipid Association (NLA) recommends that LDL-C levels be reduced to <100 mg/dL (<2.5 mmol/L) or by at least ≥50 % from pretreatment levels. Conventional therapy combinations that lower atherogenic lipoproteins levels in the blood, such as statins, ezetimibe, bile acid sequestrants and niacin, as well as lipoprotein apheresis, are usually unable to reduce LDL-C levels to recommended targets. Two recently approved agents that reduce lipoprotein synthesis and secretion by the liver are lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen, an apolipoprotein B antisense oligonucleotide. The newly approved inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), evolocumab, also shows promise for the management of FH. Because of the extremely high risk for ASCVD, HoFH patients should be identified early.

Use of 18F-FDG PET and MPI with 99mTc-MIBI in a patient with delayed diagnosis of homozygous familial hypercholesterolemia

a Beijing Anzhen Hospital, Capital Medical University, Department of Nuclear Medicine, 2 Anzhen Road, ChaoYang District, Beijing 100029, China b Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, 2 Anzhen Road, ChaoYang District, Beijing 100029, China

Homozygous Familial Hypercholesterolemia: Case report and Review of Literature

Familial hypercholesterolemia (FH) is a genetic disease presented by high levels of serum low density lipoprotein (LDL), xanthomas and early coronary artery disease (CAD). The diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) is based on a family history of elevated cholesterol, persistent high LDL levels despite maximum medical treatment and the development of xanthomas and early atherosclerotic cardiac lesions such as aortic stenosis. Management of HoFH patients requires lifestyle modifications and medical therapy

&#x0D; Acute Myocardial Infarction in an 8-Year Old Male Child with Homozygous Familiar Hypercholesterolemia: Laboratory Findings and Response to Lipid-Lowering Drugs

Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited metabolic disease, caused by low-density lipoprotein (LDL) receptor abnormality, consequently leading to an increase of serum levels of LDL cholesterol (LDL-C). Clinically, this disease is characterized by the deposition of LDL-C in skin, tendons, and arterial wall. Children with HoFH develop significant coronary artery disease (CAD) in the first decade of life and frequently die of myocardial infarction (MI) before 20 years of age. An 8-year-old boy with a diagnosis of acute MI on January 15, 2012 was admitted to our hospital for further evaluation of the potential cause and treatment. He had severe hypercholesterolemia for the past several years and showed typical signs of FH. Laboratory work-up excluded secondary causes of hypercholesterolemia and a diagnosis of HoFH was made after assessing the lipid profiles of his parents and his relatives. After careful consideration, he was prescribed a combination regime of lipid-lowering therapy. The plasma pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels were also evaluated for him and his family members. His total cholesterol (TC) was 18.96 mmol/L and both parents had hypercholesterolemia (TC of mother: 7.46 mmol/L and father: 8.74 mmol/L). The plasma level of PCSK9 of the patient was significantly higher than his parents and his uncles and this pattern was similar with the level of their lipid profile. Importantly but not surprisingly, his serum lipid profile was not significantly improved by concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg daily for one month, even a double dose of rosuvastatin and ezetimibe 10 mg daily for another month. The present case may have an important clinical implication for future investigation regarding the relation of HoFH to statin and PCSK9.

Homozygous familial hypercholesterolemia: development and a case illustration

Familial hypercholesterolemia (FH) is a genetic disease caused by a mutation of the gene encoding for the low density lipoproteins (LDL) membrane receptor. The mutation is transmitted in an autosomal dominant mode and is manifested by permanent elevation of the plasma LDL-cholesterol concentration; such elevation is responsible for the early onset of cardiovascular complications. The other clinical manifestation is the existence of extravascular cholesterol deposits: xanthomas and corneal arcus. There are two forms of familial hypercholesterolemia: homozygous FH and heterozygous FH which is generally less severe biologically and clinically. We report in this work, a case of FH diagnosed at the laboratory of clinical chemistry of Rabat children's hospital. The lipid profile revealed a dramatic LDL-cholesterol elevation (24 mmol/L) with normal triglycerides concentration (0.84 mmol/L). The physical examination revealed cutaneous xanthomas. The diagnosis of homozygous FH was strongly suggested by family study.

Lipid apheresis applications in childhood: Experience in the University Hospital of Gazi

The most commonly encountered complications in familial hypercholesterolemia (FH) are mainly cardiovascular in origin and the majority of cases unfortunately die due to this problem. LDL-apheresis is a proven therapeutic method in lowering this mortal risk. In this study we aimed to demonstrate the efficiency of LDL-apheresis performed by DALI or Cascade filtration on four pediatric patients with the diagnosis of homozygous FH. Applied LDL-apheresis techniques, side effects, laboratory results and cardiovascular follow-up are discussed in the light of current literature. Our study has shown once again that lipid apheresis treatment in children with homozygous FH is the most effective treatment. The number of childhood subjects in whom lipid apheresis is performed is quite insufficient. There are no studies that compare DALI with cascade filtration in childhood subjects in our knowledge. The view of this aspect, this study will contribute to literature.

Gene mutations in low-density lipoprotein receptor in one Chinese padigree with homozygous familial hypercholesterolemia

Objective To investigate low density lipoprotein receptor (LDLR)gene mutation in familial hypercholesterolemia (FH) patients. Methods The proband was given clinical diagnosis of homozygous FH based on marked features and blood lipid tests results. After apoB100R3500Q mutation was excluded, the promoter region and all of the 18 exons of LDLR gene were amplified by touch-downpolymerase chain reaction (PCR). The PCR products were analyzed by single-strand conformationalpolymorphism (SSCP). The PCR products with abnormal single strands were sequenced directly. Thesecondary structures of the mutational and wild type proteins were analyzed and compared byANTHEPROT5.0, and then the tertiary structures of the mutant and wild type LDLR were predicted atSWISS MODEL homepage online. Results A homozygous mutation A606T at exon 13 of the patients wasfound by SSCP and confirmed by DNA sequencing. GOR Ⅰ method in ANTHEPROT5.0 indicates that therandom coils and turns would replace some helixes at the mutation site. The online prediction from theSWISS MODEL homepage indicates the backbone structure of the mutant LDLR has no difference from thewild type one. Conclusion The results suggest the A606T mutation of LDLR gene is the cause of the FH inthis pedigree. Key words: Hypercholesterolemia,familial; Receptors,LDL; Homozygote; Mutation

Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene

Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.—Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene. J. Lipid Res. 1999. 40: 213–220.

Two novel point mutations causing receptor-negative familial hypercholesterolemia in a South African Indian homozygote

Two novel point mutations have been identified in the low density lipoprotein receptor (LDLR) gene of a South African Indian patient with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The patient is a compound heterozygote, whose paternally-inherited allele has a single base substitution of A to T at position + 1. This conversion of the initiation codon ATG (methionine) to TTG (leucine) would abolish initiation of translation at the normal site, and consequently the synthesis of any normal LDLR molecules. The second mutation identified is a C to A base change at nucleotide position 1176 in exon 8, which creates a stop codon at cysteine-371. Except for previously-described polymorphisms in specific regions of the LDLR gene, the mutations identified in exons 1 and 8 were the only variants observed by screening enzymatically amplified genomic DNA comprising the entire coding and promoter region of the LDLR gene by combined heteroduplex-single-strand conformation polymorphism analysis and by direct sequencing. Cultured cells from the proband expressed no functional LDLR activity and contained no receptor protein that could be detected by antibody binding. These findings are consistent with the nature of the two base changes identified and provide evidence that the mutations cause FH in the proband and his affected family members. The mutations, designated M-21L and C371X, were absent in 17 apparently unrelated Indian hypercholesterolemics and 200 normal chromosomes screened.

Characterization of two new point mutations in the low density lipoprotein receptor genes of an English patient with homozygous familial hypercholesterolemia.

Two new point mutations have been detected in the low density lipoprotein (LDL) receptor gene of a patient with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The patient is a compound heterozygote, in whom the mutant allele inherited from his English father has a single base substitution of A for G in exon 3, changing the codon for residue 80 in the mature protein from glutamic acid to lysine. The mutant allele inherited from his mother, who is of Irish origin, has a single base pair deletion in the codon for residue 743 in exon 15 that causes a frameshift and introduces a new stop codon in the adjacent position. The glu80 to lys mutation results in a transport-defective phenotype and a mature protein that migrates abnormally slowly on nonreduced SDS-PAGE, but normally under reducing conditions; this was confirmed by site-directed mutagenesis and expression in vitro. The deletion in exon 15 results in a null phenotype in which the putative truncated receptor protein cannot be detected in cultured skin fibroblasts and the amount of mRNA derived from the allele is reduced. The glu80 to lys mutation was found in a further five unrelated individuals in a sample of 200 FH patients from the London area and in 11 from a sample of 77 FH patients from Manchester. Haplotype analysis suggested that all the patients had inherited this allele from a common ancestor. The deletion in exon 15 was not found in the London sample, nor in any unrelated individuals in the Manchester sample.

Liver transplantation for treatment of cardiovascular disease: Comparison with medication and plasma exchange in homozygous familial hypercholesterolemia

Liver transplantation for treatment of cardiovascular disease: Comparison with medication and plasma exchange in homozygous familial hypercholesterolemia

The LDL receptor locus in familial hypercholesterolemia: Multiple mutations disrupt transport and processing of a membrane receptor

The receptor for low-density lipoprotein (LDL) is synthesized as a 120 kd precursor that undergoes a 40 kd posttranslational increase in apparent molecular weight en route to the cell surface. We describe seven mutations that disrupt synthesis, processing and transport of the receptor in fibroblasts from 77 subjects with the clinical diagnosis of homozygous familial hypercholesterolemia. One mutation obliterates synthesis of immunoprecipitable precursor. Three mutations specify precursors (100, 120 and 135 kd) that fail to undergo normal processing and fail to reach the cell surface. The other three mutations specify precursors (100, 120, and 170 kd) that undergo a normal 40 kd increase in molecular weight and reach the surface, but do not bind LDL normally. Pedigree studies show that each mutation segregates as an allele at the LDL receptor locus. These data imply that signals for transport of receptors from endoplasmic reticulum to the cell surface are contained within the amino acid sequences of the receptors, and that mutations affecting these sequences can disrupt receptor transport.

Prenatal diagnosis of homozygous familial hypercholesterolemia: Investigation of a case at risk

Cultivated amnion cells obtained from a pregnancy at risk for the homozygous form of familial hypercholesterolemia were analyzed, as were fibroblasts from normal, heterozygous and homozygous controls. Three different methods were employed in order to compare their diagnostic value: i. Acetate incorporation into the cellular 3beta-OH-sterol fraction; ii. LDL-binding to the cell surface receptor; and iii. Oleate incorporation into the cholesterylester pool of the cells after addition of LDL to lipoprotein-deficient growth medium. The best discrimination between normal, heterozygous and homozygous cells was achieved using the third technique. On the basis of the acetate incorporation analysis, we concluded that the child is not homozygous, but probably completely unaffected. This diagnosis was confirmed by repeated determinations of plasma cholesterol levels during the first 11 months of life. Our investigations further substantiate the specularion that prenatal diagnosis of this disorder is possible.