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Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose. • Medical therapy alone can achieve target low-density lipoprotein cholesterol in children with homozygous familial hypercholesterolemia without apheresis. • Genetics clarifies the functional severity and explains the low-density lipoprotein cholesterol responses to therapy. • Evolocumab 140 mg biweekly had similar effect to 420 mg monthly, lowering costs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with ‘severe heterozygous FH (HeFH)’. However, no uniform definition of ‘severe HeFH’ exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients. Methods and results: We analysed a cohort of 14,283 patients with molecularly defined HeFH, identified by the national FH screening programme in the Netherlands. Age and gender specific percentiles of untreated LDL-C were determined. The percentile corresponding to an LDL-C level of 8 mmol/L (309 mg/dL) in men aged 36–40 years (90th percentile) was selected as the cut-off value for severe HeFH. By applying this percentile-criterion to the whole cohort, 11% of the HeFH patients could be considered as having severe HeFH. Combined with an estimated HeFH prevalence of 1:300 in the Netherlands, this would translate into a prevalence of approximately 1:3,000 for severe HeFH. CVD risk was significantly increased in severe HeFH patients compared to non-severe HeFH patients (adjusted hazard ratio: 1.25 [95% CI: 1.05–1.51], p = 0.015). In line, male gender, increased age, increased BMI, smoking, hypertension, diabetes, high LDL-C and low high-density lipoprotein cholesterol were independent CVD risk factors in HeFH per se. Conclusions: We changed the commonly used static LDL-C level of 8 mmol/L for the identification of severe HeFH into an age and gender corrected percentile. This definition would theoretically result in a prevalence of 1:3,000 for severe HeFH. Patients with severe HeFH are at increased CVD risk compared to non-severe HeFH patients, which underscores the need for more aggressive LDL-C lowering these patients. [Copyright &y& Elsevier]

Background: Severe familial hypercholesterolemia (FH) individuals, refractory to conventional lipidlowering medications are at exceptionally high risk of cardiovascular events. The established therapeutic option of last choice is lipoprotein apheresis (LA). Herein, it was sought to investigate the clinical usefulness of LA in a highly selected group of severe heterozygous FH (HeFH), as recently described by the International Atherosclerosis Society (IAS), for their efficacy in lipid reduction and safety., Methods: Efficacy and safety of LA were investigated in 318 sessions of 7 severe HeFH females with cardiovascular disease, over a mean period of 26.9 ± 6.5 months. Relative reduction of low density lipoprotein cholesterol (LDL-C) ≥ 60%, clinical complications and vascular access problems were evaluated and compared between the direct adsorption of lipoproteins (DALI) and lipoprotein filtration (Membrane Filtration Optimized Novel Extracorporeal Treatment [MONET]). Additionally, lipoprotein (a) [Lp(a)], total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fibrinogen concentrations were investigated., Results: The relative reduction of LDL-C, TC, TG and Lp(a) were 69.4 ± 12.9%, 59.7 ± 9.1, 51.5 ± ± 14.2% and 71.3 ± 14.4%, respectively. A similar efficacy was found in both systems in LDL-C removal. DALI system led to larger depletions of Lp(a) (80.0 [76-83]% vs. 73.0 [64.7-78.8]%; p < 0.001). The frequency of clinical side effects and vascular access problems were low (8.5%)., Conclusions: Long-term LA in severe HeFH individuals is safe and efficiently reduces LDL-C and Lp(a). Higher efficacy of the DALI system than MONET in Lp(a) removal may indicate the need for individualized application of the LA system in severe HeFH individuals.

Background: Reverse cascade screening is not commonly employed to detect new cases of familial hypercholesterolemia (FH). We aimed to assess the outcome of this screening strategy in families in which the probands were children with severe FH., Hypothesis: Reverse cascade screening is an effective method to detect new patients with FH., Methods: Reverse cascade screening was undertaken starting from 47 index children with severe hypercholesterolemia; 39 were homozygous/compound heterozygous FH and 8 were heterozygous FH. Available parents, siblings, and second-degree relatives were contacted and screened., Results: From the 39 cases of homozygous/compound heterozygous FH, 80 first-degree family members were available for screening; 70 were parents and 10 were siblings. All first-degree relatives screened were genetically diagnosed with FH. None of the parents had been treated with statins at the time of diagnosis, and 10 (12.7%) had premature coronary artery disease. Additionally, 46 second-degree relatives were screened, of which 41 (89%) were diagnosed with FH. From the 8 heterozygous FH children, 17 first- and second-degree relatives were screened and 12 new cases of FH were also diagnosed. Hence, the overall diagnostic yield of screening was 2.8 new cases of FH per index case., Conclusions: Reverse cascade screening is a highly effective method for diagnosing new cases of FH in parents, siblings, and second-degree relatives of index children with severe FH., (© 2017 Wiley Periodicals, Inc.)