Clinical Features of Familial Hypercholesterolemia in Children and Adults in EAS-FHSC Regional Center for Rare Diseases in Poland

Background: Familial hypercholesterolemia (FH) is a genetic autosomal co-dominant metabolic disorder leading to elevated circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Early development of atherosclerotic cardiovascular disease (ASCVD) is common in affected patients. We aimed to evaluate the characteristics and differences in the diagnosis and therapy of FH children and adults. Methods: All consecutive patients who were diagnosed with FH, both phenotypically and with genetic tests, were included in this analysis. All patients are a part of the European Atherosclerosis Society FH-Study Collaboration (FHSC) regional center for rare diseases at the Polish Mother’s Memorial Hospital Research Institute (PMMHRI) in Lodz, Poland. Results: Of 103 patients with FH, there were 16 children (15.5%) at mean age of 9 ± 3 years and 87 adults aged 41 ± 16; 59% were female. Children presented higher mean levels of total cholesterol, LDL-C, and high-density lipoprotein cholesterol (HDL-C) measured at the baseline visit (TC 313 vs. 259 mg/dL (8.0 vs. 6.6 mmol/L), p = 0.04; LDL 247 vs. 192 mg/dL (6.3 vs. 4.9 mmol/L), p = 0.02, HDL 53 vs. 48 mg/dL (1.3 vs. 1.2 mmol/L), p = 0.009). Overall, 70% of adult patients and 56% of children were prescribed statins (rosuvastatin or atorvastatin) on admission. Combination therapy (dual or triple) was administered for 24% of adult patients. Furthermore, 13.6% of adult patients and 19% of children reported side effects of statin therapy; most of them complained of muscle pain. Only 50% of adult patients on combination therapy achieved their treatment goals. None of children achieved the treatment goal. Conclusions: Despite a younger age of FH diagnosis, children presented with higher mean levels of LDL-C than adults. There are still urgent unmet needs concerning effective lipid-lowering therapy in FH patients, especially the need for greater use of combination therapy, which may allow LDL-C targets to be met in most of the patients

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region

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

Difficulties in maintaining diet in patients with phenylketonuria

Phenylketonuria is the most common inborn error of amino acid metabolism. The defect is due to mutations in genes encoding enzymatic proteins, which result in deficient or impaired activity of phenylalanine hydroxylase, an enzyme responsible for converting phenylalanine into tyrosine. The therapy is based on an individually selected and appropriately balanced normal-protein, low-phenylalanine diet. The aim of the study was to identify and evaluate the most common difficulties in the maintenance of strict diet and to assess the objective measurable parameters indicating compliance with the low-phenylalanine diet. The study included 63 patients with phenylketonuria aged between 3 months and 44 years (mean age 12.65 ± 10.41 years), attending the Outpatient Metabolic Clinic in the Polish Mother’s Memorial Hospital Research Institute in Lodz. All patients were asked to complete an original questionnaire. The analyses showed that high costs of a lowprotein diet, poor taste of phenylalanine-free dietary supplements as well as reduced appetite due to the use of restrictive diet are the major problems faced by patients. A total of 68% of adult and 16% of adolescent patients failed to comply with the diet, as confirmed by increased serum phenylalanine levels. Young patients and their parents are more aware of the demand for phenylalanine than adult patients.Fenyloketonuria jest najczęściej występującym wrodzonym zaburzeniem metabolizmu aminokwasów. U podłoża tej choroby leżą mutacje genów kodujących białka enzymatyczne, co skutkuje brakiem lub zaburzeniem aktywności enzymu hydroksylazy fenyloalaninowej, która odpowiada za przekształcenie fenyloalaniny w tyrozynę. Podstawą terapii jest indywidualnie dobrana i odpowiednio zbilansowana dieta normobiałkowa, ubogofenyloalaninowa. Cele niniejszej pracy obejmują poznanie i analizę najczęstszych problemów związanych z realizacją restrykcyjnej diety oraz ocenę obiektywnych parametrów mierzalnych świadczących o przestrzeganiu diety niskofenyloalaninowej. Badaniami objęto 63 osoby chore na fenyloketonurię w wieku od 3 miesięcy do 44 lat (średnia 12,65 ± 10,41 roku), pozostające pod opieką Poradni Metabolicznej Instytutu Centrum Zdrowia Matki Polki w Łodzi. U wszystkich badanych przeprowadzono autorską ankietę. Wyniki analiz wykazały, że największy problem dla chorych na fenyloketonurię stanowią wysokie koszty żywności niskobiałkowej, niedobry smak preparatów bezfenyloalaninowych, a także spadek apetytu spowodowany stosowaniem restrykcyjnej diety. Zaleceń dietetycznych nie stosuje 68% chorych dorosłych i 16% młodzieży, co odzwierciedlają podwyższone wyniki stężenia fenyloalaniny we krwi. Pacjenci młodociani oraz ich rodzice orientują się w zapotrzebowaniu na fenyloalaninę znacznie lepiej niż pacjenci dorośli

Human milk – facts and myths

Breast milk is the most suitable nourishment for a newborn. After birth, the mammary glands produce colostrum, which is rich in proteins (including immunoglobulins). At later stages of lactation, the breast milk matures and changes its composition. Such changes are crucial to provide a young child with optimal conditions for proper development. Human milk contains lipids, proteins and carbohydrates as well as vitamins and minerals. Lipids are involved in the development of the entire nervous system, while proteins are essential for normal gastrointestinal and immunological function. Carbohydrates are responsible for the growth of intestinal microbiota and ensure resistance to microorganisms. Paediatricians recommend breastfeeding until the child is one year old, but this is not always possible. There are some conditions, concerning both mother and her child, for which breastfeeding is contraindicated. Such mothers may decide to use milk replacers based on cow’s milk. However, even the best milk replacer will never be as perfect for an infant as breast milk due to composition differences. This article summarises the current knowledge about the composition of breast milk and the role of its individual components as well as compares the properties of human and cow’s milk.Mleko matki to najwłaściwszy pokarm dla nowo narodzonego dziecka. Na początku gruczoły mlekowe produkują siarę, która jest bogata w białka (w tym przeciwciała), a wraz z czasem laktacji kobiece mleko stopniowo dojrzewa i zmienia swój skład. Ma to zapewnić młodemu organizmowi optymalne warunki do prawidłowego rozwoju. Mleko w swoim składzie obok tłuszczów, białek oraz węglowodanów zawiera również witaminy i minerały. Lipidy biorą udział w rozwoju całego układu nerwowego, proteiny zaś w odpowiednim funkcjonowaniu układu pokarmowego i immunologicznego. Węglowodany są odpowiedzialne za rozwój flory fizjologicznej jelit oraz odporność przeciwko drobnoustrojom. Pediatrzy rekomendują karmienie piersią do 12. miesiąca życia dziecka, jednak nie zawsze jest to możliwe. Zdarzają się stany, zarówno ze strony matki, jak i dziecka, w których jest to przeciwwskazane. W takiej sytuacji kobiety decydują się na zastosowanie mieszanek mlekozastępczych, opartych na mleku krowim. Jednak ze względu na różnice w składzie obu produktów nawet najlepsze mleko sztuczne nigdy nie będzie równie doskonałe dla niemowlęcia co pokarm naturalny. Artykuł podsumowuje aktualną wiedzę na temat składu mleka kobiecego i funkcji poszczególnych jego składników, a także porównuje właściwości mleka kobiecego oraz krowiego

Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel

The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60–80% of definite FH patients and 20–30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease