[TREATMENT OF HOMOZYGOTES OF FAMILIAL HYPERCHOLESTEROLEMIA: RECOMMENDATIONS OF THE ISRAELI SOCIETY OF ATHEROSCLEROSIS].

INTRODUCTION: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder caused by mutations affecting the function of the LDL receptor. In the Israeli population, the carrier heterozygote state is quite common, with the prevalence of 1:250, and the estimated prevalence of homozygote (hoFH) patients is 1:500,000. The life span of untreated hoFH patients is significantly shortened due to premature atherosclerosis and cardiovascular mortality. The basis of the appropriate treatment for hoFH is aggressive lipid lowering therapy from an early age and therefore, our approach is intensive LDL-C lowering as soon as the diagnosis is made. We recommend referring patients with hoFH to lipid-specialist clinics .We recommend genetic evaluation to confirm the diagnosis and cascade screening of family members for heterozygosity. Lipid goals are as recommended by the European Atherosclerosis Society. Aggressive and low as possible LDL-C targets (at least 50% reduction) are recommended. The initial treatment is high-dose potent statin and additional ezetimibe10 mg daily. PCSK9 inhibitor - Evolocumab is a novel additional option for hoFH with residual LDL receptor activity. The most effective method of reduction of plasma LDL levels is LDL-C apheresis. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that should be added to reduce the frequency of the apheresis procedures.

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family.

We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, microsomal triglyceride transfer protein (MTTP) R634C, into COS-7 cells to test enzymatic activity. The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/ml) compared with the WT allele (185.8 nmol/ml) (P = 0.0012) and was marginally associated with reduced LDLc in FH patients (P = 0.05). Phenotypic variability in a FH pedigree can only partially be explained by a combination of common SNPs and a rare mutation and a rare variant in the MTTP gene. LDLc variability in FH patients may have nongenetic causes.

[Statins and muscle pain].

Statins are used for the prevention and treatment of cardiovascular disease. The treatment is quite safe but not free of side effects, particularly muscle pain. Fear of pain may prevent patients from carrying out exercise or diminish their motivation to return and engage in it, even though both the statins and the exercise have a proven benefit in both treatment and prevention, and a synergistic effect enhances this benefit. Prevalence of muscular pain ranges from 1-30%. Pain usually appears at the beginning of treatment, but can occur even after months and under any of the existing agents. The creatine phosphokinase (CPK) enzyme level may rise, but not necessarily. Increases to exceptional values (10 times the upper normal level) are relatively rare and rhabdomyolysis is extremely rare. The risk increases with age, co-morbidities and especially when taken concurrently with drugs that are metabolized in a similar pathway. Pain usually passes within a month after discontinuing treatment, but may persist for six months or more. Studies have examined the effect of statin therapy on the ability to perform physical activity, but results are inconsistent. The increased rise of CPK was observed under statin therapy, a tendency that increased with age. However, it was not accompanied by an increased incidence of muscle pain or rhabdomyolysis. Considering the above we recommend encouraging patients to exercise. However, patients should be instructed to report new or worsening muscular pains. Discontinuation, lowering dose or replacement should be considered when pain is suspected to be related with treatment.

Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia.

OBJECTIVE: Evaluate the efficacy and safety of colesevelam hydrochloride in children with heterozygous familial hypercholesterolemia (heFH). STUDY DESIGN: This was a randomized, double-blind, 41-site study in 194 children aged 10 to 17 years (inclusive) with heFH (statin-naïve or on a stable statin regimen). After a 4-week stabilization period (period I), subjects were randomized 1:1:1 to placebo, colesevelam 1.875 g/d, or colesevelam 3.75 g/d for 8 weeks (period II). All then received open-label colesevelam 3.75 g/d for 18 weeks (period III), with follow-up 2 weeks later. The primary endpoint was percent change in low-density lipoprotein (LDL)-cholesterol from baseline to week 8. Secondary endpoints included percent change in other lipoprotein variables, including non-high-density lipoprotein (non-HDL)-cholesterol. Adverse events were also evaluated. RESULTS: At week 8, a significant difference from baseline in LDL-cholesterol was reported with colesevelam 1.875 g/d (-6.3%; P = .031) and colesevelam 3.75 g/d (-12.5%; P < .001) compared with placebo. Significant treatment effects were also reported for total cholesterol (-7.4%), non-HDL-cholesterol (-10.9%), HDL-cholesterol (+6.1%), apolipoprotein A-I (+6.9%), and apolipoprotein B (-8.3%) and a nonsignificant effect for triglycerides (+5.1%) with colesevelam 3.75 g/d compared with placebo at week 8. These treatment effects were maintained during period III. CONCLUSIONS: Colesevelam significantly lowered LDL-cholesterol levels in children with heFH.

Long-term plasma exchange for severe refractory hypertriglyceridemia: a decade of experience demonstrates safety and efficacy.

Hypertriglyceridemia (hyperTG) is a common form of dyslipidemia and is frequently associated with premature coronary disease, and when severe, recurrent events of pancreatitis may occur. The management of hyperTG is generally medical (life style modification, medications). Plasma exchange (PE) has been reported to be useful in emergency situations particularly when acute pancreatitis results from extreme hyperTG. To our knowledge, there is only one report on long-term use of PE for hyperTG. We here report our results of long-term treatment of hyperTG in 6 patients with Frederickson Type V hyperlipidemia who had recurrent attacks of pancreatitis due to hyperTG refractory to medical therapy. PE was performed from one to eight times a month, mostly using a Cobe Spectra apparatus. In total, our center has performed a total of 1,593 PE sessions for hyperTG. There were no safety issues associated with PE for hyperTG other than occasional access problems (clotted fistula, IV access problems). Determination of plasma TG levels before and after PE demonstrated high efficiency of TG removal (42% to 58% reduction). There was marked clinical improvement in recurrent pancreatitis; patients had a major decrease in episodes (39% to 100%) while on regular PE, as long as they adhered to the treatment schedule. We conclude that long-term PE for hyperTG, while costly, is feasible and safe and may reduce recurrent attacks of pancreatitis.

Molecular genetics of familial hypercholesterolemia in Israel-revisited.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel. METHODS: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes was done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping. RESULTS: Mean serum cholesterol was 7.48 ± 1.89 mmol/L and the mean serum LDL-C was 5.99 ± 1.89 mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q), in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C > A. The c.2479G > A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C, but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a "mild" FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p = 0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy. CONCLUSIONS: The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.

Pre-placement screening in international adoption.

BACKGROUND: The number of child adoptions from abroad is increasing, but the adverse living conditions of these children prior to the adoption raise questions on their medical and neurodevelopmental status, particularly since there are no guidelines for pre- or post-adoption medical evaluation. OBJECTIVES: To describe the condition of a cohort of young children who were candidates for adoption in East European orphanages and foster homes, and to determine those attributes associated with a family's decision to adopt or refuse a particular child. METHODS: Eighty-two young children, median age 11 months, were evaluated by Israeli pediatricians in Eastern Europe between 3 weeks and 6 months prior to their adoption. The evaluation consisted of comprehensive medical and neurodevelopmental testing on site using a battery of standardized assessment tools, and observation of free play and social interactive behaviors recorded on videotape. Laboratory tests included complete blood count, chemistries, serology screening, and metabolic and genetic testing. RESULTS: The children were growth-retarded. Medical problems were classified as resolved (pneumonia and diarrhea) in 32.8%; or ongoing, such as hepatitis B and C, failure to thrive, organomegaly, and visual and hearing disorders, in 14.8%. Neuromotor status was grossly abnormal in 13.4%. Twenty-two percent of the children were rejected for adoption by families in Israel. Factors associated with the adoption decision were performance skills on developmental testing (P = 0.0001), present medical status (P = 0.002), and weight (P = 0.016). CONCLUSIONS: Pre-placement comprehensive screening of children eligible for foreign adoption, which includes developmental screening, helps to identify a wide variety of strengths and impairments in a child's background before the adoption procedure is finalized. A family's decision to adopt or not was associated with the child's performance on Bayley Scales, weight, and current medical status, but not with language delays, serious past medical history or suspect family background.

One year experience with a low density lipoprotein apheresis system.

BACKGROUND: Low density lipoprotein apheresis is used as a complementary method for treating hypercholesterolemic patients who cannot reach target LDL-cholesterol levels on conventional dietary and drug treatment. The DALI system (direct absorption of lipoproteins) is the only extracorporeal LDL-removing system compatible with whole blood. OBJECTIVE: To describe our one year experience using the DALI system. METHODS: LDL apheresis was used in 13 patients due to inability to reach target LDL-C levels on conventional treatment. They included seven patients with familial hypercholesterolemia, three who had adverse reactions to statins, and three patients with ischemic heart disease who did not reach LDL-C target level on medical treatment. RESULTS: The average triglyceride, total cholesterol, high density lipoprotein-C and LDL-C levels before and after treatment in all patients were: 170 +/- 113 vs. 124 +/- 91, 269 +/- 74 vs. 132 +/- 48, 42 +/- 8 vs. 37 +/- 7.9, and 196 +/- 77 vs. 80 +/- 52 mg/dl, respectively. Comparing the results of a subgroup of seven patients who had previously been treated with plasma exchange, it is noteworthy that while the reduction in triglyceride, total cholesterol and LDL-C are comparable, the effect on HDL-C concentration was less apparent: from an average of 39.7 +/- 8.7 and 23 +/- 5.7 mg/dl before and after plasma exchange to an average of 43.9 +/- 8.1 and 38.4 +/- 7 mg/dl before and after LDL apheresis, respectively. Five patients developed treatment-related adverse events: three experienced allergic reactions manifested as shortness of breath, urticaria and facial flushing; one patient developed rhabdomyolysis, an adverse reaction that was not reported previously as a result of LDL apheresis; and one patient had myopathy with back pain. All untoward effects occurred during the first few treatment sessions. CONCLUSIONS: LDL apheresis using the DALI system is highly efficacious for the treatment of hypercholesterolemia. It is associated with a significant number of side effects occurring during the first treatment sessions. In patients not experiencing adverse effects in the early treatment period, it is well tolerated and can provide remarkable clinical benefit even after short-term therapy.