Homozygous Familial Hypercholesterolemia Patients Research Articles

Familial hypercholesterolemia: A complex genetic disease with variable phenotypes.

Familial hypercholesterolemia (FH) is the most frequent genetic disease and is characterized by elevation of LDL-cholesterol that accumulates in tissues leading to premature atherosclerosis and sometime tendon xanthomas. Main causes of FH are pathogenic variants in the genes encoding the LDL receptor (LDLR), its ligand - the apolipoprotein B (APOB) - or Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Rarer causes include variants in genes encoding apolipoprotein E (APOE) and the signal-transducing adaptor family member 1 (STAP1). Genetics of FH is extremely complicated by 1. high heterogeneity, 2. presence of variant clusters and 3. phenotypic variability. In fact, a great variability was observed among patients with the same genetic status: an overlap of LDL-cholesterol levels was observed between heterozygous patients (HeFH) and homozygous FH patients, as well as some HeFH showed a normal lipid profile. A correct pathogenicity evaluation is the first step to correctly define the genetic status helping to identify the variants which really cause the FH. Several phenotypic differences were observed among HeFH patients carrying different variant types (null or defective) or variants in different affected genes. Patients with a null variant in LDLR gene showed higher LDL-cholesterol levels and higher risk for coronary artery disease than patients with a defective variant. Pathogenic variants in several lipid-related genes causing different dyslipidemias were found among FH patients acting as both modifying factors (worsening the phenotype) and confounding factors (needing a differential diagnosis to be discriminated from FH). This review aims at depicting the complex genetic basis of FH.

P5365Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolemia phenotype

Abstract Introduction The majority of patients with homozygous familial hypercholesterolemia (HoFH) phenotype are treated additionally to lipid lowering (LL) drugs (statin + ezetimibe ± colesevelam) with lipoprotein apheresis (LA) sessions. The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in HoFH patients. Patients and methods In 12 HoFH patients treated with LL drugs ± biweekly LA sessions (9 patients) the 5–40 mg daily of lomitapide was added. Lipid profile [total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C)] before (LL drugs ± LA) and after lomitapide treatment were evaluated. Results The follow-up period of lomitapide treatment for 12 patients was 3–24 months (13.8±7.9). The median baseline LDL-C levels was 1000 mg/dL (339–1150). During LL drug therapy, patients showed a median LDL-C level of 383.5 mg/dL (Range: 214–866 mg/dL) and with LL drugs + Time-averaged levels (CAVG) the median was 288.1 mg/dL (Range: 183.69–716.65 mg/dL). The addition of lomitapide at the average dosage of 21.4 mg/day lowered LDL-C levels by 56.8% comparing to LL drugs alone therapy [mean reduction 262.12, 95% CI (105.53, 418.71), p=0.005] and by 54% [mean reduction −182.89, 95% CI (−342.35, −23.43), p=0.031] comparing to LL drugs + LA (CAVG). The CAVG of LDL-C in LL drugs + LA patients compared with LL drugs + lomitapide was 54% in favour of lomitapide (p=0.031). After lomitapide administration to LL drugs + LA treatment, 78% patients discontinued LA and 2 patients reduced their LA frequency by 50%. During follow-up, 2 patients (16.6%) reported side effects (transient diarrhea, 1 patient had liver transaminase >5× ULN and had to decrease dose of lomitapide). Two patients stopped lomitapide due to diet and alcohol restrictions. Median and ranges of lipid and lipoprotein values before any intervention, after LL drugs, LL drugs plus LA, LL drugs plus LA (CAVG) and LL drugs plus lomitapide Total Cholesterol LDL-C HDL-C Triglycerides Before any intervention 1000 (339–1150) 900 (245–1070) 34.5 (25–50) 125 (87–314) After LL drugs 434 (278–915) 383.5 (214–866) 36 (27–51) 113 (62–198) LL drugs + LA (CAVG) 336.13 (248.57–784.16) 288.07 (183.69–716.65) 42.81 (25.84–46.68) 105.09 (55.79–166.68) LL drugs + Lomitapide 228.5 (118–554) 173.5 (74–515) 37.5 (29–50) 83.5 (23–316) LDL graph Conclusions Treatment with lomitapide in HoFH patients has beneficial effect with constant decrease of LDL-C by 57% compared with classical LL therapy and by 54% compared with classical LL therapy and CAVG and seems to be with good safety profile. Although, in some cases the hybrid (all availably drug treatment and LA) therapy may be needed.

Usefulness of Gemcabene in Homozygous Familial Hypercholesterolemia (from COBALT-1)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was -26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.

Homozygous familial hypercholesterolaemia in childhood – The first case report in Southeast Europe

Homozygous familial hypercholesterolaemia (HoFH) is the rare, severe, but treatable disease characterised by exceedingly high levels of low-density lipoprotein cholesterol (LDL-C) and subsequent premature coronary heart disease. Of note, HoFH detection rate and patient access to healthcare and treatment modalities still differ considerably across EU countries. To our current knowledge, there are still no published reports describing HoFH in the paediatric population of Southeastern Europe.In this case report, a few important topics on obstacles in getting adequate health care service and management of HoFH children from Southeastern Europe are tackled.

Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolaemia.

The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia. In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7), p = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23), p = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide (p = 0.031). Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

Liver Transplantation In A Patient With Homozygous Familial Hypercholesterolemia – Long-Term Follow Up And Literature Review

Background and Aims: Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder, leading to severe atherosclerosis and early cardiovascular death if untreated. Since medications do not reduce cholesterol levels satisfactorily, LDL-apheresis is a mainstay of management of HoFH patients but also very burdensome and suboptimally effective. Liver transplantation (LT) is shown to be a possible alternative.

Inclisiran Durably Lowers Ldl-C And Pcsk9 Expression In Subjects With Homozygous Familial Hypercholesterolaemia: The Orion-2 Pilot Study

Background and Aims: Homozygous familial hypercholesterolaemia (HoFH) is a genetic disorder characterised by severely elevated plasma LDL cholesterol (LDL-C) levels and development of premature atherosclerotic cardiovascular disease. Robust and durable LDL-C lowering is essential, but additional reductions beyond what can be achieved with statins and ezetimibe are required. We evaluated the LDL-C–lowering effect and safety of inclisiran in an open-label, single-arm, multicentre pilot study in HoFH patients receiving high-intensity statin plus ezetimibe.

Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters.

Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.

Lomitapide: a review of its clinical use, efficacy, and tolerability.

Lomitapide is an inhibitor of MTP, an enzyme located in the endoplasmic reticulum of hepatocytes and enterocytes. This enzyme is responsible for the synthesis of very low-density lipoproteins in the liver and chylomicrons in the intestine. Lomitapide has been approved by the US Food and Drug Administration, European Medicines Agency, and other regulatory agencies for the treatment of hypercholesterolemia in adult patients with homozygous familial hypercholesterolemia. Clinical trials have shown that lomitapide reduces low-density-lipoprotein cholesterol levels by around 40% in homozygous familial hypercholesterolemia patients on treatment with statins with or without low-density-lipoprotein apheresis, with an acceptable safety and tolerance profile. The most common adverse events are gastrointestinal symptoms that decrease in frequency with long-term treatment, and the increase in liver fat remains stable. This review analyzes the clinical use, efficacy, and tolerability of lomitapide.

Familial Hypercholesterolemia and Lipoprotein Apheresis.

Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.

Function and Immunogenicity of Gene-corrected iPSC-derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia

Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient’s iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient’s peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH.

Therapeutic Options for Homozygous Familial Hypercholesterolemia: The Role of Lomitapide.

Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine. The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH. The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from "real life" clinical practice. Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment. Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.

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.

Clinical, demographic and genetic characteristics of homozygous familial hypercholesterolemia patients worldwide: Interim results from the hofh international clinical collaborators (HICC) registry

Clinical, demographic and genetic characteristics of homozygous familial hypercholesterolemia patients worldwide: Interim results from the hofh international clinical collaborators (HICC) registry

Features of radionuclide myocardial perfusion imaging in patients with homozygous familial hypercholesterolemia

Objective To evaluate the features of myocardial perfusion imaging (MPI) in patients with homozygous familial hypercholesterolemia (HoFH) and its influence factors. Methods Forty-two consecutive HoFH patients (21 males, 21 females; average age: (14.8±8.4) years) were retrospectively enrolled in this study from June 2010 to November 2016. Diagnosis was proved by clinical and chromosome tests, and all patients underwent ATP stress and rest 99Tcm-methoxyisobutylisonitrile (MIBI) SPECT MPI with a two-day protocol. Summed stress score (SSS) and summed rest score (SRS) were acquired, and summed difference score (SDS; SSS-SRS) was calculated. Relations between SSS, SRS, SDS and age, lipid profile were analyzed. Two-sample t test, χ2 test, multiple linear regression analysis and multivariate logistic regression were used to analyze the data. Results There were 24 patients with positive MPI results (SSS≥1), and females (76.2%, 16/21) showed more positive MPI results than males (38.1%, 8/21; χ2=6.22, P 0.05). Positive electrocardiograph (ECG) in ATP stress test was observed in 9 females (42.9%, 9/21) and 3 males (14.3%, 3/21; χ2=4.20, P<0.05). Sixty-three (8.8%, 63/714) abnormal myocardial perfusion segments (SSS≥1) were found, which was mainly (60.3%, 38/63) distributed in myocardial regions supplied by left anterior descending branch (LAD). SSS was positively correlated with age and high density lipoprotein cholesterol (HDLC). SRS, SDS were positively correlated with HDLC and age respectively. Multivariate logistic regression analysis indicated that the female was the only independent risk factor to predict positive MPI (odds ratio=5.2, 95% CI: 1.363-19.774). Conclusions In HoFH patients, abnormal myocardial perfusion had a rising trend with age increasing. Female patients are more likely to have abnormal MPI. Abnormal myocardial perfusion segments are mainly located in myocardial regions supplied by LAD. Age and gender are influence factors of abnormal MPI in HoFH patients. Key words: Hyperlipoproteinemia type Ⅱ; Homozygote; Myocardial perfusion imaging; Tomography, emission-computed, single-photon; Technetium Tc 99m sestamibi

Dietary Intake during 56 Weeks of a Low-Fat Diet for Lomitapide Treatment in Japanese Patients with Homozygous Familial Hypercholesterolemia.

Aim: Lomitapide is an oral inhibitor of the microsomal triglyceride transfer protein used to treat homozygous familial hypercholesterolemia (HoFH); patients require a low-fat diet to minimize gastrointestinal adverse effects and dietary supplements to prevent nutrient deficiencies. We investigated the diet and nutritional status during lomitapide treatment.Methods: Japanese patients with HoFH, who were in a phase 3 trial of lomitapide, were instructed to start low-fat diets with supplements of vitamin E and essential fatty acids 6 weeks before starting lomitapide treatment. Dietary education was conducted by registered dietitians 16 times during the study period, which included a pretreatment run-in phase (Weeks −6-0), a lomitapide treatment efficacy phase (Weeks 0–26) and a safety phase (Weeks 26–56). Two-day dietary records were collected at each dietary counseling session. Anthropometric and biochemical parameters were measured at Weeks 0, 26 and 56.Results: Eight patients completed the 56 weeks of lomitapide treatment. Their median energy intakes derived from lipids were 19.2% and 17.9% during the efficacy and safety phases, respectively. “Fats and oils” intakes, and “Fatty meat and poultry” intakes in two patients, were successfully reduced to achieve low-fat diets. Although intakes of energy, fatty acids and fat-soluble vitamins did not differ significantly among phases, body weight, serum fatty acid levels and vitamin E concentrations were decreased at Week 26 as compared with Week 0.Conclusion: HoFH patients can adhere to low-fat diets with ongoing dietary counseling. Instructions about intakes of energy, fatty acids and fat-soluble vitamins, as well as periodic evaluations of nutritional status, are necessary.

The Pharmacologic Role and Clinical Utility of PCSK9 Inhibitors for the Treatment of Hypercholesterolemia

In addition to monoclonal antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9), vaccines against PCSK9 and smaller molecule inhibitors as well as RNA inhibitors of PCSK9 production have been created. The monoclonal antibodies against PCSK9 and the PCSK9 RNA inhibitors can reduce low-density lipoproteins (LDLs) by over 50%, non-high-density lipoprotein (HDL) cholesterol and triglycerides, and increasing HDL. Although effective in several homozygous familial hypercholesterolemia patient types, PCSK9 inhibitors does not work in all patient types. Outcome trials show no effects on mortality but do show reductions in atherosclerotic events such as myocardial infarctions, strokes, and need for coronary revascularization. PCSK9 inhibitors have a very attractive safety profile with no significant elevations in measures of muscle or liver damage. The current and more advanced experimental agents all require subcutaneous dosing, and injection site reactions are among the most common adverse events. Therapy for the Food and Drug Administration(FDA) approved agents is markedly expensive, and this is the primary barrier to utilization. However, it is possible to identify patients with a number needed to treat to prevent an atherosclerotic event low enough to render it cost-effective and one such factor is whether or not you require a 50% reduction in LDL in order to achieve your LDL goal.

Lomitapide in homozygous familial hypercholesterolemia: cardiology perspective from a single-center experience.

Homozygous familial hypercholesterolemia (HoFH) is a genetic dyslipidemia characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Frequently, traditional lipid-lowering therapy is ineffective in these patients, and lipoprotein apheresis is required. Lomitapide has been recently approved for HoFH. We reported our experience in HoFH patients treated with lomitapide, evaluating its efficacy and safety profile. Probands suspected for familial hypercholesterolemia were extrapolated from the registry of patients admitted to our cardiology department. Dutch Lipid Clinic Network (DLCN) criteria were adopted to diagnose familial hypercholesterolemia clinically. Individuals receiving a definite or probable diagnosis of familial hypercholesterolemia underwent family cascade screening and genetic test. Patients with a genetic diagnosis of HoFH were treated with lomitapide and monitored with serial follow-up visits. Within 1 year of screening, from a population of 3250 patients admitted to our cardiology department, seven probands were selected with a DLCN score greater than 5. A total of two patients resulted genetically homozygotes for familial hypercholesterolemia and started lomitapide. A marked reduction in LDL-C occurred in both patients on lomitapide (78% reduction in patient 1 and 86% in patient 2 already on lipoprotein apheresis, compared with baseline LDL-C), allowing the apheresis treatment to be stopped in the second case. Lomitapide was well tolerated, and both patients experienced only mild gastrointestinal events. Lomitapide is an effective and well tolerated cholesterol-lowering drug approved for the treatment of HoFH patients. It would be useful to administer it early in these patients to reduce LDL-C and avoid the development of fatal cardiovascular complications.

Screening of LDLR and APOB gene mutations in Mexican patients with homozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes accumulation of serum low-density lipoprotein cholesterol and premature cardiovascular disease. It is mainly related to mutations in the LDLR gene. Homozygous FH (HoFH) patients have the most severe form of the disease accounting for a worldwide prevalence of 1:1,000,000. In Mexico, at least 5 cases of HoFH have been reported. The aim of this study was to describe the clinical, biochemical, and molecular data observed in patients with HoFH phenotype. We included 13 patients, belonging to 11 families, with clinical and biochemical diagnoses suggestive of HoFH. Molecular analyses of the LDLR and APOB genes were performed by means of polymerase chain reaction followed by Sanger sequencing. The causal mutation of HoFH was found in 8 of 11 unrelated patients. Excepting 1, all were true homozygotes. Six different variants in LDLR were identified: c.-139delCTCCCCCTGC, p.Glu140Lys, p.Asp360His, p.Asn405Lys, p.Ala755Glyfs*7, and p.Leu759Serfs*6. Of these, p.Asp360His and p.Asn405Lys were detected for the first time in Mexico; p.Leu759Serfs*6 showed to be the most frequent (43.7% of the alleles 7/16), and c.-139delCTCCCCCTGC is a new variant located in the promoter region. This work increases knowledge of biochemical and genetic features in Mexican patients with HoFH. A novel mutation in the LDLR gene promoter was detected: c.-139delCTCCCCCTGC, which possibly inhibits its expression.

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels (usually 4–5-fold normal) and appearance of xanthomas, aggressive atherosclerotic cardiovascular as well as aortic and supra-aortic valve diseases, before the age of 20 years.1 The severity of the HoFH phenotype and its ominous consequences correlate with LDL-C levels. The latter are influenced primarily by the type of familial hypercholesterolemia (FH)-causing molecular defect. The gravest phenotypes result from homozygous or compound heterozygous mutations in the LDLR gene (low-density lipoprotein receptor) encoding null or negative alleles that are associated with <2% of LDLR activity. Less severe forms are encountered in homozygotes or compound heterozygotes for LDLR -defective alleles encoding LDLRs with 2% to 25% activity, or variants in other genes, such as APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin kexin type 9), or rarely LDLRAP1 (LDL receptor adaptor protein-1).2 See accompanying article on page 592 HoFH patients have been treated mainly with statins, ezetimibe, and, when available, lipoprotein apheresis.2 Unfortunately, despite best efforts with these traditional therapies, individuals with HoFH remain severely undertreated and seldom achieve target or even acceptable LDL-C levels. The residual LDLR expression and consequent function certainly play a role in LDL-C reduction induced by statins.3 For instance, Stein et al3 encountered significantly greater LDL-C–lowering effects of rosuvastatin in HoFH patients who had receptor-defective alleles in comparison to those with receptor-negative ones, namely, 23% and 14% lowering, respectively. On the contrary, despite effectiveness of ezetimibe in reducing LDL-C in HoFH, it is uncertain whether this is …