Aims: Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing paediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods and results: Five established FH diagnostic criteria were assessed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N = 1360) and Portuguese (N = 340) paediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; P < 0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; P < 0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; P < 0.01) despite population differences. Conclusion: Current FH diagnostic criteria perform sub-optimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.

Introduction The global COVID-19 pandemic has presented extraordinary disruption to healthcare services and exposed them to numerous challenges. Newborn screening (NBS) programmes were also affected; however, scarce data exist on the impact of COVID-19 on NBS. Methods We conducted an international survey to assess the global impact of COVID-19 on NBS, with the main aim of gathering the experiences of the COVID-19 pandemic from a large and representative number of NBS centres worldwide. Results The results of our study showed that COVID-19 impacted the NBS programmes, at least partially, in 29 out of 38 responding countries. Majority of the screening centres experienced a broad spectrum of difficulties and most were affected more in the second wave of the pandemic. Delays and unreliability with the postal service as well as flight cancellations caused delays in samples arriving to screening centres and with the provision of laboratory equipment and reagents. The availability of laboratory staff was sometimes reduced due to infection, quarantine or reassignment within the healthcare facility. Sample collection at home, second-tier tests and follow-up were also affected. Social restrictions and interruptions in public transport added to these difficulties. Only a limited number of centres managed to retain a fully functioning NBS programme. Conclusion As the pandemic might continue or could recur in future years, it would be useful to develop guidelines to protect these valuable services.

Hypercholesterolemia is a major cause of atherosclerosis development and premature cardiovascular disease (CVD). It leads to inflammation, which further accelerates atherosclerosis progression. Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated serum LDL-c from birth, due to a disease-causing variant in one of the causative genes (LDLR, APOB, PCSK9). In polygenic hypercholesterolemia (PH), the disease-causing genetic variant is absent; it is likely the cumulative result of multiple single nucleotide polymorphisms in LDL metabolism-related genes and other factors, such as lifestyle and environment. In high risk groups, such as patients with FH, an effective primary prevention of CVD must begin in childhood. High-sensitivity C-reactive protein (hsCRP) and carotid intima media thickness (cIMT) are two potential minimally invasive correlates of inflammation and subclinical atherosclerosis progression. hsCRP and cIMT have been shown to be significantly increased in patients with FH and PH relative to healthy controls, with some studies yielding conflicting results. In this review, we aim to summarize current knowledge and recent findings regarding the applicability of hsCRP and cIMT as markers of low-grade inflammation and subclinical atherosclerosis, focusing especially on children and adolescents with hypercholesterolemia.

Aims: Lipoprotein(a) [Lp(a)] is a significant genetic risk factor for cardiovascular disease (CVD). Extremely high Lp(a) levels (153 mg/dL), affecting about 1 in 100 individuals, can elevate LDL cholesterol (LDL-C) due to structural similarities between Lp(a) and LDL-C particles. This study assessed the role and impact of Lp(a) on LDL-C in children with hypercholesterolaemia, a relationship that remains poorly understood. Methods and results: The study included 1418 children (median age: 6.34 years) with hypercholesterolaemia, identified by universal or cascade familial hypercholesterolaemia (FH) screening in Slovenia. Participants were categorized as 363 (25.6%) with definite FH (pathogenic variants in LDLR/APOB/PCSK9), 1014 (71.5%) with possible FH (no FH pathogenic variant), and 41 (2.9%) definite non-FH (siblings of definite FH cases without FH pathogenic variant). Elevated Lp(a) levels (>30 mg/dL) were found in 25.1% of definite FH and 34.9% of possible FH cases (P = 0.003). In definite FH, 32.7% of Lp(a) levels contributed to LDL-C levels, and 18.6% of Lp(a) levels contributed to apolipoprotein B (ApoB). The Lp(a) component of LDL-C varied widely (0–49.6%) and accounted for 10.3% of LDL-C variability. After adjusting for Lp(a), elevated LDL-C (>3.5 mmol/L) still persisted in 88.4% of definite FH and 30.4% of possible FH children. Conclusion: One in four children with FH and one in three children with polygenic hypercholesterolaemia have elevated Lp(a) levels, contributing notably to LDL-C levels and ApoB. Modifiable CVD risk factors (elevated LDL-C and obesity) are already present in those children, highlighting the need for early, targeted evaluation and management.

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients’ lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.