Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.

Background And Aims: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8-10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece.

Statins for children with familial hypercholesterolemia.

Background: Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

Background: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency.

Statins for children with familial hypercholesterolemia.

Background: Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250.

A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia.

Background: The efficacy and safety of atorvastatin in children/adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed.

Objective: To characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6-15 years with HeFH.

Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward.

Familial hypercholesterolemia (FH) is a leading cause of premature atherosclerosis. Genetic defects in the LDLR, APOB and PCSK9 genes cause FH, and confirmation of a gene defect is essential for an indisputable diagnosis of the disease. FH is underdiagnosed and we aimed to revise the genetic defects that have been characterized in FH patients of Greek origin and define an effective, future strategy for genetic studies.

Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. These fully human monoclonal antibodies selectively block PCSK9, thus permitting the low-density lipoprotein (LDL) receptor to effectively recycle to the surface of liver cells. The administration of these antibodies leads to robust LDL cholesterol (LDL-C) lowering by 50-60% on top of maximum hypolipidemic treatment.

Efficacy and Safety of Pitavastatin in Children and Adolescents at High Future Cardiovascular Risk.

Objectives: To assess the safety and efficacy of pitavastatin in children and adolescents with hyperlipidemia.

Study Design: A total of 106 children and adolescents with hyperlipidemia, ages 6 to 17 years, were enrolled in a 12-week randomized, double-blind, placebo-controlled study and randomly assigned to pitavastatin 1 mg, 2 mg, 4 mg, or placebo. During a 52-week extension period, subjects were up-titrated from 1 mg pitavastatin to a maximum dose of 4 mg in an effort to achieve an optimum low-density lipoprotein cholesterol (LDL-C) treatment target of <110 mg/dL (2.

First on-line survey of an international multidisciplinary working group (MightyMedic) on current practice in diagnosis, therapy and follow-up of dyslipidemias.

The MightyMedic (Multidisciplinary International Group for Hemapheresis TherapY and MEtabolic DIsturbances Contrast) Working Group has been founded in 2013. The leading idea was to establish an international network of interdisciplinary nature aimed at working to cross national borders research projects, clinical trials, educational initiatives (meetings, workshops, summer schools) in the field of metabolic diseases, namely hyperlipidemias, and diabetes, preventive cardiology, and atherosclerosis. Therapeutic apheresis, its indications and techniques, is a parallel field of investigation.

POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia.

Background: In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin.

Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum.

Objective: Familial Hypercholesterolemia (FH) is a common lipid metabolism disease, resulting in premature atherosclerosis, even from childhood. We aimed to define the genetic basis of FH in children and their families, to refine the spectrum of Low-Density Lipoprotein Receptor gene (LDLR) mutations and identify genotype-to-phenotype correlations in patients of Greek origin.

Methods: LDLR was analyzed in 561 patients from 262 families, by whole-gene sequencing.

Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.

Background: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples.

Statins for children with familial hypercholesterolemia.

Background: Familial hypercholesterolemia is one of the most common inherited metabolic diseases; the average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500. Diagnosis of familial hypercholesterolemia in children is based on highly elevated low-density lipoprotein (LDL) cholesterol level or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old.

Novel LDLR variants in patients with familial hypercholesterolemia: in silico analysis as a tool to predict pathogenic variants in children and their families.

Familial hypercholesterolemia (FH) is an autosomal dominant disease with a frequency of 1:500 in its heterozygous form. To date, mutations in the low-density lipoprotein receptor gene (LDLR) are the only identified causes of FH in the Greek population, causing high levels of low-density lipoprotein (LDL) and total cholesterol and premature atherosclerosis. The Greek FH population is genetically homogeneous, but most previous studies screened for the most common mutations only.

Development of a universal chemiluminometric genotyping method for high-throughput detection of 7 LDLR gene mutations in Greek population.

Objectives: Familial hypercholesterolemia (FH) is caused by mutations in the LDL receptor (LDLR) gene. We report the application of a universal method with high allele discrimination properties to the simultaneous genotyping of 7 LDLR mutations in Greeks, in dry-reagent format.

Design And Methods: We genotyped mutations C858A, C939A, G1285A, T1352C, G1646A, G1775A, C/T81G.

Analysis of LDLR mutations in familial hypercholesterolemia patients in Greece by use of the NanoChip microelectronic array technology.

Background: Three mutations in the low density lipoprotein receptor (LDLR) gene account for 49% of familial hypercholesterolemia (FH) cases in Greece.

Methods: We used the microelectronic array technology of the NanoChip Molecular Biology Workstation to develop a multiplex method to analyze these single-nucleotide polymorphisms (SNPs). Primer pairs amplified the region encompassing each SNP.

A new mitochondrial DNA mutation in ND3 gene causing severe Leigh syndrome with early lethality.

We describe a new mitochondrial DNA mutation in a male infant who presented clinical and magnetic resonance imaging features of Leigh syndrome and died at the age of 9 mo. The patient's development was reportedly normal in the first months of life. At the age of 5 mo, he presented severe generalized hypotonia, nystagmus, and absent eye contact.

Analysis of low density lipoprotein receptor gene mutations and microsatellite haplotypes in Greek FH heterozygous children: six independent ancestors account for 60% of probands.

This study reports the characterization of 60% of low density lipoprotein receptor (LDLR) gene mutations in 150 unrelated Greek familial hypercholesterolaemia (FH) heterozygous children by the analysis of six LDLR gene mutations. The linkage disequilibrium of two polymorphic microsatellites (D19S394 and D19S221) flanking the LDLR gene on chromosome 19 to the four most common mutations strongly suggests that each mutation is identical-by-descent in the probands included in this study (this is also supported by the geographical distribution of FH families with these mutations throughout Greece) and permits an estimation of the number of generations from a common ancestor for each mutation. The characterization of 60% of LDLR mutations in a representative sample of Greek FH heterozygotes provides a basis for the diagnosis of FH through DNA analysis in Greece, by using single-strand conformation polymorphism analysis followed by allele-specific oligonucleotide hybridization (exon 6 mutations) or restriction endonuclease analysis (C152R, V408M).

Oral manifestations in glycogen storage disease type 1b.

Glycogen storage disease type 1b is a rare metabolic disorder which affects the transport system of glucose-6-phosphatase metabolism. As a result, hepatomegaly, failure to thrive, renal dysfunction and recurrent infections occur in affected patients. In this paper, the oral complications in three children with glycogen storage disease type 1b are discussed.

Late onset ornithine carbamoyl transferase deficiency in males.

Six boys with ornithine carbamoyl transferase deficiency presenting in infancy or later childhood are described. There was wide variation in both the time of presentation and the symptoms, which may initially suggest a neurological, behavioural, or gastroenterological problem. Two patients died, as did two male siblings who were probably affected, but with early recognition of the hyperammonaemia the outlook is good.

Timing of strict diet in relation to fetal damage in maternal phenylketonuria. An international collaborative study by the MRC/DHSS Phenylketonuria Register.

64 infants born to women with phenylketonuria (PKU) were grouped according to the mother's dietary treatment in pregnancy. 17 infants, whose mothers were receiving a strict low phenylalanine diet and had blood phenylalanine concentrations below 600 mumol/l at the time of conception, had normal birthweights and head circumferences and no malformations. In the 29 infants whose mothers were receiving either a relaxed diet or a normal diet at conception but who started a strict diet at some time during pregnancy, birthweights and head circumferences were below those in healthy infants and there was an excess of malformations; the findings closely resembled those for the 18 infants whose mothers received no treatment during pregnancy.