23 research outputs found
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. Methods: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations
Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study
Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life
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. A
literature search was performed in MEDLINE and EMBASE on genetic studies
with FH patients of Greek origin. To date, no APOB and PCSK9 mutations
have been found in the Greek population. It must be noted however, that
only a small number of patients has been screened for PCSK9 mutations.
In total, 41 LDLR defects have been characterized, with 6 common
mutations c.1646G>A (p.Gly546Asp), c.858C>A (p.Ser286Arg), c.81C>G
(p.Cys27Trp), c.1285G>A (p.Va1429Met), c.517T>C (p.Cys173Arg), and
c.1775G>A (p.Gly592G1u) that account for >80% of all mutations. Due to
geographic isolation, founder mutations exist in a subpopulation in
North West Greece and the Greek Cypriot population but not in the
general population. Genetic testing should focus primarily on LDLR, and
subsequently on PCSK9 and APOB. The Greek population is genetically
homogeneous, which allows for a quick molecular diagnosis of the
disease. Cascade screening is feasible and will certainly facilitate the
identification of additional patients. (C) 2016 National Lipid
Association. All rights reserved
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. The study aimed to
characterize and assess novel LDLR variants. LDLR was examined by
whole-gene DNA sequencing in 561 FH patients from 262 families of Greek
origin. Novel LDLR variants were analyzed in silico using various
software predicting pathogenicity and changes in protein stability.
Twelve novel LDLR variants were identified, six of which are putative
disease-causing variants: c.977C>G in exon 7, c.1124A>C in exon 8,
c.1381G>T in exon 10, c.628\_643dup\{636del\}, c.661-673dup in exon 4,
and 13 c.1987+1\_+33del in intron 13. All six putative variants were
confirmed in the hypercholesterolemic members of the family. The results
show that in silico analysis is a valuable tool to predict potential
pathogenicity of novel variants, especially for populations that have
not been extensively studied. The identification of novel pathogenic
variants will facilitate the molecular diagnosis of FH from early
childhood.
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. Results:
Children with identified LDLR mutations showed higher lipid levels
compared to non-carriers. Molecular analysis identified a mutation in
53.4% of index cases. Twenty six LDLR mutations were identified,
including 19 point mutations, 2 nonsense mutations, 3 splice site
mutations and 2 small insertions. Amongst patients with common
mutations, carriers of c.1646G > A and c.1285G > A showed higher lipid
levels, whereas carriers of c.858C > A and c.81C > G showed a milder
phenotype. Conclusions: The spectrum of LDLR mutations in Greece is
refined and expanded, with more patients analyzed by whole-gene
sequencing. Although a quick screening method is feasible for the Greek
population, whole-gene sequencing is essential to identify rare
variants. Children with border line lipid levels and a family history of
hypercholesterolemia should be considered for molecular diagnosis, since
carriers of certain mutations show milder phenotypes and may be missed
during clinical diagnosis. (C) 2014 Elsevier Ireland Ltd. All rights
reserved
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.
METHODS: A total of 272 subjects aged 6-15 years with HeFH and
low-density lipoprotein cholesterol (LDL-C) mmol/L (154 mg/dL) were
enrolled in a 3-year study (NCT00827606). Subjects were initiated on
atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based
on LDL-C levels.
RESULTS: Mean percentage reductions from baseline in LDL-C at 36
months/early termination were 43.8% for subjects at Tanner stage (TS) 1
and 39.9% for TS There was no evidence of variations in the
lipid-lowering efficacy of atorvastatin between the TS groups analyzed
(1 vs >= 2) or in subjects aged <10 vs years, and the treatment had no
adverse effect on growth or maturation. Atorvastatin had a favorable
safety and tolerability profile, and only 6 (2.2%) subjects
discontinued because of adverse events.
CONCLUSIONS: Atorvastatin over 3 years was efficacious, had no impact on
growth/maturation, and was well tolerated in children and adolescents
with HeFH aged 6-15 years. (C) 2016 National Lipid Association.
Published by Elsevier Inc