BACKGROUND:Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation. METHODS AND RESULTS:The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (P=0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (P=0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (P=0.05). CONCLUSIONS:In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.

Aim : To assess the quality of life, anxiety and concerns among statin-treated children with familial hypercholesterolaemia (FH) and their parents. Methods : 69 FH children on statin therapy and 87 parents (51 families) participated in this study. Quality of life of the children, and anxiety levels of both the children and their parents, were investigated using self-report questionnaires. In addition, a questionnaire was designed to evaluate FH-specific concerns of these children and their parents on six different topics: 1, knowledge about FH; 2, experience of the disease; 3, family communication; 4, screening; 5, diet; and 6, experience of medication therapy. Results : FH children and their parents reported no problems with regard to quality of life and anxiety. In contrast, the FH survey showed specific FH-related concerns. One-third of the children thought that FH can be cured, and 44% of the children suffered from the fact they have FH, but taking medication makes them feel safer (62%). The majority of the children kept a low cholesterol diet and more than 50% took care not to eat too much fat. Almost 38% of the parents experienced FH as a burden to their family and 79% suffered because their child had FH. Conclusion : These findings show that statin-treated children with FH and their parents did not report affected psychosocial functioning, but did show specific FH-related concerns.

Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 ± 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 ± 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one ε4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the ε4 allele explained 72.4% of the variance of HDL cholesterol levels (−0.15 mmol/L, 95% confidence interval −0.24 to −0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the ε4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5–12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2 %± 3.4% versus 10.1%±4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% ± 3.4% versus plant sterols: 7.7% ± 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children.

Aim: To assess the quality of life, anxiety and concerns among statin-treated children with familial hypercholesterolaemia (FH) and their parents. Methods: 69 FH children on statin therapy and 87 parents (51 families) participated in this study. Quality of life of the children, and anxiety levels of both the children and their parents, were investigated using self-report questionnaires. In addition, a questionnaire was designed to evaluate FH-specific concerns of these children and their parents on six different topics: 1, knowledge about FH; 2, experience of the disease; 3, family communication; 4, screening; 5, diet; and 6, experience of medication therapy. Results: FH children and their parents reported no problems with regard to quality of life and anxiety. In contrast, the FH survey showed specific FH-related concerns. One-third of the children thought that FH can be cured, and 44% of the children suffered from the fact they have FH, but taking medication makes them feel safer (62%). The majority of the children kept a low cholesterol diet and more than 50% took care not to eat too much fat. Almost 38% of the parents experienced FH as a burden to their family and 79% suffered because their child had FH.Conclusion: These findings show that statin-treated children with FH and their parents did not report affected psychosocial functioning, but did show specific FH-related concerns.

BACKGROUND Atherosclerotic complications are the main cause of death in adult patients with renal failure. Endothelial dysfunction is a hallmark of early atherosclerotic changes. The numerous risk factors for endothelial dysfunction present in adults are present in children with renal failure, as well. In addition to this, increased stiffness of the arterial tree conveys an increased risk for cardiovascular mortality. The aim of this study is to investigate whether pediatric kidney recipients already show endothelial dysfunction and have increased arterial stiffness. METHODS We investigated 20 pediatric kidney recipients with stable graft function and 20 healthy children. Endothelial function was studied noninvasively with ultrasound and digital signal analysis equipment as the percentage of post-ischemic flow-mediated dilatation (FMD) of the brachial artery. Parameters of arterial distensibility were calculated from distension of the brachial artery during the cardiac cycle, pulse pressure, and baseline diameter. RESULTS FMD was significantly less in patients (7.7% +/- 5.4%) than controls (15.0% +/- 7.1%; P < 0.001), indicating endothelial dysfunction in pediatric kidney recipients. Impairment of FMD was found predominantly in patients being treated for hypertension. Arterial distensibility was diminished in patients (3.4 +/- 2.8 versus 5.7 +/- 3.3 10(-3)/mm Hg; P < 0.02), indicating increased stiffness of the arterial tree. Patients had a greater baseline diameter of the brachial artery adjusted for height than healthy controls at equal blood pressure. CONCLUSION These findings suggest arterial wall changes in pediatric renal transplant recipients. They are already at risk for premature development of atherosclerotic complications and cardiovascular mortality.

OBJECTIVES:This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH). BACKGROUND:Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD. METHODS:The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment. RESULTS:At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05). CONCLUSIONS:Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.

Background— A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol–lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). Methods and Results— A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (−41%), total cholesterol (−31%), apolipoprotein B (−34%), VLDL cholesterol (−21%), and triglyceride (−9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. Conclusions— Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

Objectives: in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history. Study design: 50 FH children, 10–18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh+) and 19 children had no events in the family (fh−). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery. Results: baseline characteristics were comparable for fh+, fh− and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7±4.4 vs. 15.6±6.8%, P<0.03). In addition, FMD was significantly lower in fh+ compared to fh− (10.7±9.9 vs. 13.3±4.6%, P<0.05). Conclusion: In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease.

Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH).

Journal of Inherited Metabolic DiseaseVolume 22, Issue 6 p. 754-755 Article Spontaneous pregnancy in a patient with classical galactosaemia S. de Jongh, S. de Jongh Emma Children's Hospital, Amsterdam, The NetherlandsSearch for more papers by this authorP. Vreken, P. Vreken Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorL. IJlst, L. IJlst Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorR. J. A. Wanders, R. J. A. Wanders Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorC. Jakobs, C. Jakobs Department of Clinical Chemistry, Free University Hospital Amsterdam, The NetherlandsSearch for more papers by this authorH. D. Bakker, H. D. Bakker Emma Children's Hospital, Amsterdam, The NetherlandsSearch for more papers by this author S. de Jongh, S. de Jongh Emma Children's Hospital, Amsterdam, The NetherlandsSearch for more papers by this authorP. Vreken, P. Vreken Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorL. IJlst, L. IJlst Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorR. J. A. Wanders, R. J. A. Wanders Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorC. Jakobs, C. Jakobs Department of Clinical Chemistry, Free University Hospital Amsterdam, The NetherlandsSearch for more papers by this authorH. D. Bakker, H. D. Bakker Emma Children's Hospital, Amsterdam, The NetherlandsSearch for more papers by this author First published: 01 August 1999 https://doi.org/10.1023/A:1005504403173Citations: 16AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1Jakobs C, Kleyer WJ, Bakker HD, vanGennip AH, Przyrembel H, Niermeyer MF (1988) Dietary restriction of maternal lactose intake does not prevent accumulation of galactitol in the amniotic fluid of foetuses affected with galactosemia. Prenat Diagn, 8: 641– 645. 2Segal S (1998) Galactosaemia today: the enigma and the challenge. J Inher Metab Dis, 21: 455– 471. 3Segal S, Berry GT, Scriver CR, Beaudet AL, Sly WS, Valle D (1995) Disorder of galactose metabolism. In: The Metabolic and Molecular Bases of Inherited Disease, 7th edn.. New York: McGraw-Hill, 967– 1000. 4Waggoner DD, Buist NRM, Donnell GN (1990) Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inher Metab Dis, 13: 802– 818. Citing Literature Volume22, Issue6August 1999Pages 754-755 ReferencesRelatedInformation

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