Homozygous Familial Hypercholesterolemia Patients Research Articles

Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia.

Patients with familial hypercholesterolemia (FH) are at high or very high risk for cardiovascular disease. Those with heterozygous FH (HeFH) often do not reach low-density lipoprotein cholesterol (LDL-C) targets with statin and ezetimibe therapy, and those with homozygous FH (HoFH) usually require additional lipid-modifying therapies. Drugs that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) offer a novel approach to reduce LDL-C. The monoclonal antibodies, alirocumab and evolocumab, given by subcutaneous injection every 2 or 4 weeks produce reductions in LDL-C of 50% to 60% in patients with HeFH, allowing many of them to achieve their LDL-C goals. Patients with HoFH show a reduced and more variable LDL-C response, which appears to depend on residual LDL receptor activity, and those with receptor-negative mutations may show no response. Inclisiran is a long-acting small interfering RNA therapeutic agent that inhibits the synthesis of PCSK9. Subcutaneous doses of 300 mg can reduce LDL-C by more than 50% for at least 6 months and the responses in HeFH and HoFH patients are similar to those achieved with monoclonal antibodies. These PCSK9 inhibitors are generally well tolerated and they provide a new opportunity for effective treatment for the majority of patients with FH.

Monitoring of up to 15\xa0years effects of lipoprotein apheresis on lipids, biomarkers of inflammation, and soluble endoglin in familial hypercholesterolemia patients

BackgroundLipoprotein apheresis (LA) is considered as an add-on therapy for patients with familial hypercholesterolemia (FH). We aimed to analyze the data collected in the last 15 years from FH patients treated with LA, to elucidate the benefit of this procedure with respect to plasma lipids, biomarkers of inflammation, and endothelial dysfunction and soluble endoglin.Results14 patients (10 heterozygous FH patients (HeFH), 4 homozygous FH patients (HoFH)) were treated by long-term lipoprotein apheresis. Lipid levels were examined, and ELISA detected biomarkers of inflammation and soluble endoglin. Paired tests were used for intergroup comparisons, and a linear regression model served to estimate the influence of the number of days patients were treated with LA on the studied parameters. LA treatment was associated with a significant decrease of total cholesterol (TC), LDL-C, HDL-C, and apoB, in both HeFH and HoFH patients, after single apheresis and in a long-term period during the monitored interval of 15 years. Biomarkers of inflammation and endothelial dysfunction were reduced for soluble endoglin, hsCRP, and MCP-1, and sP-selectin after each procedure in some HeFH and HoFH patients.ConclusionsLA treatment up to 15 years, reduced cholesterol levels, levels of biomarkers related to endothelial dysfunction, and inflammation not only after each procedure but also in the long-term evaluation in FH patients. We propose that long-term LA treatment improves lipid profile and endothelial dysfunction in familial hypercholesterolemia patients, suggesting a promising improvement in cardiovascular prognosis in most FH patients.

Supravalvular Aortic Stenosis and the Risk of Premature Death Among Patients With Homozygous Familial Hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (HoFH) have a high risk for premature death. Supravalvular aortic stenosis (SVAS) is a common and the feature lesion of the aortic root in HoFH. The relation between SVAS and the risk of premature death in patients with HoFH has not been fully investigated. The present study analysis included 97 HoFH patients with mean age of 14.7 (years) from the Genetic and Imaging of Familial Hypercholesterolemia in Han Nationality Study. During the median (±SD) follow-up 4.0 (±4.0) years, 40 (41.2%) participants had SVAS and 17 (17.5%) participants experienced death. The proportion of premature death in the non-SVAS and SVAS group was 7.0% and 32.5%, respectively. Compared with the non-SVAS group, SVAS group cumulative survival was lower in the HoFH (log-rank test, p <0.001). This result was further confirmed in the multivariable Cox regression models. After adjusting for age, sex, low density lipoprotein cholesterol (LDL_C)-year-score, lipid-lowering drugs, cardiovascular disease, and carotid artery plaque, SVAS was an independent risk factor of premature death in HoFH on the multivariate analysis (hazard ratio 4.45; 95% confidence interval, 1.10 to 18.12; p = 0.037). In conclusion, a significantly increased risk of premature death was observed in HoFH patients with SVAS. Our study emphasized the importance of careful and aggressive management in these patients when appropriate.

Endoplasmic reticulum stress induced by class 2 LDLR variants

Background and Aims: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the gene encoding the low-density lipoprotein receptor (LDLR). The majority of LDLR pathogenic variants are completely or partily retained in the endoplasmatic reticulum (ER). If these variants are not correctly processed for their elimination, the homeostasis of the ER can be altered by a sustained LDLR accumulation. This situation could lead to ER stress, a condition that contribute to hepatic injury. The aim of the present work has been to asses if c.97C>T, c.971delG and c.892delA LDLR variants, previously described in homozygous FH patients, induce ER estress.

Evaluating the effect of lipid-apheresis on evinacumab and angiopoietin-like 3 (ANGPTL3) levels

Background and Aims: Patients with homozygous familial hypercholesterolemia (HoFH) have severely elevated LDL-C levels despite the use of multiple pharmacologic lipid-lowering therapies and often require lipid-apheresis. Evinacumab, an ANGPTL3 inhibitor with LDLR-independent activity, has been shown to reduce LDL-C in HoFH patients. To ascertain the impact of lipid-apheresis on circulating drug levels, we conducted an ex-vivo study evaluating the effect of lipid-apheresis on the recovery of evinacumab and ANGPTL3.

Prognostic meaning of coronary flow reserve on the left anterior descending artery in homozygous familial hypercholesterolaemia: A case report

Background and Aims: Homozygous familial hypercholesterolemia (HoFH) is a rare disease that complicates with severe cardiovascular disease since childhood. HoFH patients need to be followed by cardiovascular imaging through their entire life span facing the risk of excessive radiological/ nuclear exposure.

The efficacy and safety of evinacumab in homozygous familial hypercholesterolaemia (HoFH) patients with little to no low-density lipoprotein receptor (LDLR) activity

The efficacy and safety of evinacumab in homozygous familial hypercholesterolaemia (HoFH) patients with little to no low-density lipoprotein receptor (LDLR) activity

Abstract 14270: The Effect of Evinacumab on Apheresis Eligibility in Patients With Homozygous Familial Hypercholesterolemia

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Evinacumab, a fully human monoclonal antibody against angiopoietin-like protein 3, has demonstrated approximately 50% reductions in LDL-C in HoFH patients when added to maximally tolerated lipid-lowering therapies. Objective: In this post-hoc analysis, we assessed the effect of evinacumab on the eligibility for apheresis using predefined US and EU apheresis criteria. Methods: This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to evinacumab 15 mg/kg intravenously every 4 weeks (Q4W; n=43) or placebo (n=22). We assessed the proportion of patients who met per protocol US apheresis criteria (LDL-C ≥300 mg/dL), newer US criteria for FH (LDL-C ≥300 mg/dL or LDL-C ≥160 mg/dL with coronary heart disease or peripheral artery disease) and per protocol EU apheresis criteria (LDL-C &gt;160 mg/dL [primary prevention] or &gt;120 mg/dL [secondary prevention]) at baseline and week 24. Results: Under the newer US criteria (2018), 62.8% (n=27) of evinacumab-treated patients and 54.5% (n=12) placebo-treated patients qualified for apheresis at baseline (Table). Following 24 weeks of treatment, 48.8% of all evinacumab versus 9.1% of all placebo patients no longer qualified for apheresis. Similar results were observed using EU apheresis criteria, where 46.5% of evinacumab-treated patients shifted from qualifying for apheresis at baseline to not qualifying at week 24, compared with 4.5% of placebo-treated patients. The majority of evinacumab (65.1%) and placebo (68.2%) patients did not qualify for per protocol US apheresis at baseline, however a shift of 27.9% and 9.1% was observed, respectively. Conclusions: Evinacumab has the potential to reduce the need for apheresis in patients with HoFH.

Abstract 16078: Risk Classification of Familial Hypercholesterolemia Through Screening of the Electronic Health Record Within a Large Healthcare System

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high low-density lipoprotein cholesterol (LDL-c) levels. The heterogeneity of clinical risk within FH may lead to differential treatment, management, and outcomes. Screening the electronic health record (EHR) permits risk classification within FH at scale. We leveraged the Georgetown/MedStar Health System (MHS) EHR to perform risk classification while describing other characteristics of suspected FH patients. Methods: The Dutch Lipid Clinical Network (DLCN) remains a common scoring algorithm for FH risk classification. Applying the DLCN algorithm to the EHR of MHS enabled risk classification of approximately 1.6 million patients. The classifiers included ‘definite,’ ‘probable,’ and ‘possible’ heterozygous FH (HeFH). ‘Possible’ homozygous FH (HoFH) was determined by LDL-c &gt; 500 mg/dL. Of these suspected FH patients, current age, gender, and race as well as abnormal lipid profile data (high-density lipoprotein cholesterol (HDL-c) cholesterol &lt; 20 mg/dL, triglyceride (TG) &gt; 300 mg/dL) were descriptively described. Results: Of 1.6 million patients, the number of definite, probable, and possible HeFH patients were 83 (1:19722), 690 (1:2318), and 5945 (1:266), respectively. The number of possible HoFH patients was 8 (1:200000). The highest reported median LDL-C (IQR) for the three HeFH subpopulations was 377 (346, 430 mg/dL), 262 (251, 282 mg/dL), and 203 (mg/dL), and the majority of all subpopulations were female and non-white. Definite HeFH patients were more likely to present with very low HDL-c and approximately 1:10 suspected HeFH patients presented with very high triglycerides. Conclusion: The application of DLCN to the EHR demonstrates risk classification for FH in a large healthcare system. The implications of stratifying suspected FH patients by classifier within the EHR may optimize clinical care as well as registry management.

Abstract 14267: Evinacumab Lowers LDL-C in Patients With Homozygous Familial Hypercholesterolemia Irrespective of Background Lipid-lowering Medication

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by very premature atherosclerotic cardiovascular disease due to profoundly elevated levels of LDL-C. Attempts to lower LDL-C in patients with HoFH often require multiple lipid-lowering medications (LLMs). Evinacumab, an angiopoietin-like protein 3 inhibitor, has been shown to reduce LDL-C in patients with HoFH by approximately 50% when added to maximally tolerated background LLMs. Objective: In this post-hoc analysis we assessed efficacy of evinacumab in patients with HoFH according to background LLM type. Methods: This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to receive intravenous (IV) evinacumab 15 mg/kg (n=43) or IV placebo (n=22) every 4 weeks. The effect of background LLMs on the efficacy of evinacumab to lower LDL-C was assessed for the following subgroups: high intensity-statin, low-intensity statins, lomitapide, triple therapy (ezetimibe + PCSK9 inhibitor + statin), and quadruple therapy (triple therapy + lomitapide). Primary endpoint was % LDL-C reduction from baseline to week 24. Results: At baseline, 55.4% (evinacumab, 58.1%; placebo, 50.0%) of HoFH patients were on triple therapy. Overall, 93.8% were on statins (76.9% on high intensity statins). Across LLM subgroups, mean baseline LDL-C levels ranged from 166.8 mg/dL to 281.8 mg/dL (Table). From baseline to week 24, marked reductions in LDL-C occurred with evinacumab treatment, which were observed in all groups: quadruple therapy (66.8%), triple therapy (56.0%), lomitapide (49.6%), high-intensity statins (48.6%) and low-intensity statins (41.0%). Evinacumab was generally well-tolerated. Conclusions: Evinacumab substantially lowers LDL-C levels in patients with HoFH irrespective of background LLM.

Abstract 14407: The Longer-term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by markedly elevated LDL-C and premature ASCVD. For HoFH patients (pts) with complete loss of low-density lipoprotein receptor (LDLR) function in both copies of the LDLR gene (null mutations) and some other HoFH pts, statins and PCSK9 inhibitors have limited to no efficacy, presenting a great unmet medical need. The efficacy and safety of evinacumab (EVIN; an angiopoietin-like protein 3 inhibitor) in HoFH pts was assessed during the double-blind treatment period (DBTP) of a phase 3 trial (NCT03399786). Objective: To examine longer-term efficacy and safety of EVIN in pts with HoFH who participated in the subsequent open-label treatment period (OLTP) of this phase 3 study. Methods: Patients with HoFH on stable lipid-lowering therapies (± lipoprotein apheresis) and screening LDL-C ≥70 mg/dL who completed the 24-week DBTP entered the 24-week OLTP and received IV EVIN 15 mg/kg every 4 weeks. Results: In total, 64 pts completed the DBTP and received open-label EVIN. Mean (standard deviation [SD]) baseline LDL-C at DBTP entry was 250.5 (162.3) mg/dL. From baseline to Week 48, EVIN reduced mean LDL-C by 46.3% (mean [SD] reduction of 134.3 [117.3] mg/dL). At Week 48, mean LDL-C reductions with open-label EVIN were 42.7% and 55.8% for pts who received EVIN (n=44) vs placebo (n=20) during the DBTP, respectively ( Figure ). LDL-C reduction observed at Week 48 was similar for pts with null/null mutations (n=19; 47.2%) versus non-null/null mutations (n=39; 45.9%). Adverse events (AEs) occurred in 47 pts (73.4%) during the OLTP; the most common were nasopharyngitis (9.4%) and headache (9.4%). During the OLTP, serious AEs occurred in 7 pts (10.9%; all pts received EVIN during the DBTP); none were considered related to study treatment. Conclusions: In pts with HoFH, EVIN showed substantial and sustained LDL-C reduction regardless of LDLR function and was generally well tolerated.

Familial Hypercholesterolaemia: An Updated Overall Management

Familial hypercholesterolaemia (FH), the commonest and serious but potentially treatable form of inherited dyslipidaemias, is characterised by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C) level, which subsequently leads to premature coronary artery disease (pCAD). Effectiveness of FH early detection and treatment is supported by the outcome of several international cohort studies. Optimal FH management relies on prescription of statins either alone or together with other lipid-lowering therapies (LLT). Intensive lifestyle intervention is required in parallel with LLT, which should be commenced at diagnosis in adults and childhood. Treatment with high intensity statin should be started as soon as possible. Combination with ezetimibe and/or bile acid sequestrants is indicated if target LDL-C is not achieved. For FH patients in the very-high risk category, if their LDL-C targets are not achieved, despite being on maximally tolerated statin dose and ezetimibe, proprotein convertase subtilisin/kexin type1 inhibitor (PCSK9i) is recommended. In statin intolerance, ezetimibe alone, or in combination with PCSK9i may be considered. Clinical evaluation of response to treatment and safety are recommended to be done about 4-6 weeks following initiation of treatment. Homozygous FH (HoFH) patients should be treated with maximally tolerated intensive LLT and, when available, with lipoprotein apheresis. This review highlights the overall management, and optimal treatment combinations in FH in adults and children, newer LLT including PCSK9i, microsomal transfer protein inhibitor, allele-specific oligonucleotide to ApoB100 and PCSK9 mRNA. Family cascade screening and/or screening of high-risk individuals, is the most cost-effective way of identifying FH cases and initiating early and adequate LLT.

Genetic and Clinical Characteristics of Patients With Homozygous and Compound Heterozygous Familial Hypercholesterolemia From Three Different Populations: Case Series.

Homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia (cHeFH) are rare disorders generated by disease-causing variants in both alleles of the LDLR or other familial hypercholesterolemia (FH)-related genes. HoFH and cHeFH are characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C), frequently leading to early cardiovascular disease. We investigated the genetic and clinical characteristics of HoFH and cHeFH patients from the Slovenian FH registry and/or those who were previously diagnosed or managed at our institution (Slovenian, Pakhtun and Albanian ethnicity), where genetic testing is not available. Our study includes seven patients. Their median age at the time of clinical diagnosis was 6.3 years (2.9–12.9 years); 2/7 were females. Two patients were diagnosed through the universal FH screening and five patients were diagnosed due to the presence of xanthomas. All the mutations are present in LDLR gene: 7 different genotypes for HoFH (p.Cys167Leu, p.Asp178Asn, p.Cys243Tyr, p.Gly549Asp, p.Cys27Trp, p.Ile585Thr and p.Val797Met) and p.Gly549Asp/p.Gln384Pro genotype for cHeFH patient. The median initial level of LDL-C was 17.0 mmol/L [655 mg/dL] (range 7.6–21.6 mmol/L). The HoFH/cHeFH patients are clinically and genetically very diverse. The clinical criteria (as Simon Broome criteria) might be applicable already in children to raise suspicion of FH but in some cases fail to distinguish heterozygous FH and HoFH/cHeFH patients. However, genetic testing is helpful in confirming the diagnosis, also for a prompt awareness, better compliance to treatment and family screening.

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives.

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia,” “diagnosis,” “management,” “guideline,” “consensus,” “genetics,” “screening,” “lipid lowering agents.” The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Genetics, Screening, and Treatment of Familial Hypercholesterolemia: Experience Gained From the Implementation of the Vietnam Familial Hypercholesterolemia Registry.

Familial hypercholesterolemia (FH) is underdiagnosed and undertreated in a majority of the low- and middle-income countries. FH registries could prove useful in bridging the knowledge gaps, supporting genetic and clinical research, and improving health-care planning and patient care. Here, we report the first usage experience of the Vietnam FH (VINAFH) Registry. The VINAFH Registry was established in 2016 as a long-term database for prospective cohorts. FH patients were detected based on the opportunistic and cascade screening. Diagnosis of FH was assessed using the Dutch Lipid Clinic Network criteria, plasma levels of low-density lipoprotein (LDL) cholesterol, and genetic testing. To date, a total of 130 patients with FH have been registered, with 48 index cases and 82 relatives. Of the 130 patients, 8 were homozygous FH patients and 38 were children. Of FH individuals, 46.7% was confirmed by genetic testing: 61 patients (96.8%) carried the LDLR mutation (c.681C > G, c.1427C > G, c.1187-?_2140 ± ?del, c.2529_2530delinsA), and two patients (3.2%) carried the PCSK9 (protein convertase subtilisin/kexin type 9) mutation (c.42_43insTG). The c.2529_2530delinsA mutation detected in this study is novel and reported only in the Vietnamese population. However, only 53.8% of FH patients were followed up post diagnosis, and only 15.3% of these were approved for lipid-lowering therapy and specialized care. Notably, factors such as knowledge about FH in patients and/or guardians of FH children and support of primary care physicians affected patient participation with respect to treatment strategies and follow-up. Genetic identification, screening, and treatment of FH were feasible in Vietnam. The VINAFH Registry significantly contributed to the formation of the government agencies legislative acts that established the importance of FH as a socially and medically important disease requiring appropriate management strategies. Other low- and middle-income countries could, thus, use the VINAFH Registry model as a reference to establish programs for FH management according to the current status.

The Efficacy and Safety of Evinacumab in Homozygous Familial Hypercholesterolemia Patients with Little to No Low-Density Lipoprotein Receptor Activity

Robert Rosenson has received honoraria from Amgen, Kowa, Pfizer, and Regeneron; consultancy/advisory board fees from Amgen, C5, Corvidia, CVS Caremark, Medicines Company, and Regeneron; and research funding from Akcea, Amgen, AstraZeneca, Medicines Compan.

Homozygous familial hypercholesterolemia: what treatments are on the horizon?

Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy. Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development. LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.

Cholestane-3β, 5α, 6β-triol: Further insights into the performance of this oxysterol in diagnosis of Niemann-Pick disease type C

In recent years the oxysterol species cholestane-3β, 5α, 6β-triol (C-triol) has found application as a diagnostic biomarker for Niemann-Pick disease type C. Other studies have described increased C-triol in patients with Niemann-Pick disease type A/B and milder increases in lysosomal acid lipase deficiency (LALD), whereas they note normal C-triol levels in Smith-Lemli-Opitz syndrome (SLOS) and familial hypercholesterolaemia (FH) patients. Herein, we review data collected in our laboratory during method evaluation along with 5 years of routine analysis and present findings which differ from those reported by other groups with respect to LALD, SLOS and FH in particular, whilst providing further evidence regarding the clinical sensitivity and specificity of this biomarker, which are difficult to accurately assess.All of our Wolman disease (severe LALD) patients have demonstrated gross elevations of C-triol at diagnosis, with reduction to normal levels after induction of enzyme replacement therapy. In diagnostic specimens from SLOS patients we observed very low or undetectable C-triol levels whereas in post-therapeutic SLOS patients demonstrated normalised levels; we also describe a homozygous FH patient in which C-triol is significantly elevated. Upon investigation, we found that C-triol was formed artefactually from cholesterol during our sample preparation, i.e. this is a false positive of analytical origin; at present it is unclear whether similar effects occur during sample preparation in other laboratories. Our data demonstrates clinical sensitivity of 100% during routine application to diagnostic specimens; this is in keeping with other estimates, yet in a small proportion of patients diagnosed prior to C-triol measurement, either by Filipin staining of fibroblasts or molecular genetics, we have observed normal C-triol concentrations. Clinical specificity of C-triol alone is 93.4% and 95.3% when performed in conjunction with lysosomal enzymology. These performance statistics are very similar to those achieved with Filipin staining of cultured fibroblasts in the 5 years preceding introduction of C-triol to routine use in our laboratory. It is increasingly apparent to us that although this analyte is a very useful addition to the diagnostic tools available for NPC, with considerable advantages over more invasive and time-consuming methods, the interpretation of results is complex and should be undertaken only in light of clinical details and results of other analyses including enzymology for lysosomal acid lipase and acid sphingomyelinase.

Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners.

Background:Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients.Methods:Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing.Results:We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the LDLR alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the LDLR variant, two possibly damaging APOB variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in APOC3, PON2 and LPL genes respectively were identified. The PON2 gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA).Conclusions:The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.

A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH), the severest form of familial hypercholesterolemia (FH), is characterized by very high LDL-cholesterol levels and a high frequency of coronary heart disease. The disease is caused by the presence of either a pathogenic variant at homozygous status or of two pathogenic variants at compound heterozygous status in the LDLR, APOB, PCSK9 genes. We retrospectively analyzed data of 23 HoFH patients (four children and 19 adults) identified during the genetic screening of 724 FH patients. Genetic screening was performed by sequencing FH causative genes and identifying large rearrangements of LDLR. Among the HoFH patients, four out of 23 (17.4%) were true homozygotes, whereas 19 out of 23 (82.6%) were compound heterozygotes for variants in the LDLR gene. Basal LDL-cholesterol was 12.9 ± 2.9 mmol/L. LDL-cholesterol levels decreased to 7.2 ± 1.8 mmol/L when treated with statin/ezetimibe and to 5.1 ± 3.1 mmol/L with anti-PCSK9 antibodies. Homozygous patients showed higher basal LDL-cholesterol and a poorer response to therapy compared with compound heterozygotes. Since 19 unrelated patients were identified in the Campania region (6,000,000 inhabitants) in southern Italy, the regional prevalence of HoFH was estimated to be at least 1:320,000. In conclusion, our results revealed a worse phenotype for homozygotes compared with compound heterozygotes, thereby highlighting the role of genetic screening in differentiating one genetic status from the other.