Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, with genetic and clinical heterogeneity emerging as significant challenges. Despite growing scholarly attention to MODY research, the overall knowledge structure, research priorities, and developmental trends in this field have not yet been systematically integrated. To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on MODY were retrieved from the Web of Science Core Collection (WoSCC) database from 2006 to 2025. Employing bibliometric methods and tools such as CiteSpace, VOSviewer, Scimago Graphica, and Microsoft Excel, we conducted visual analyses of publication trends, country and regional collaboration, institutional distribution, author contributions, co-cited journals, co-cited references, and keywords. From 2006 to 2025, a total of 1,610 publications related to MODY were identified, showing an overall increasing trend over time. The United States of America (USA), the United Kingdom (UK), and China were the major contributors to this field, with close collaborative relationships, particularly between the USA and the UK. The leading contributors by country, institution, and author were the USA (391 publications), the University of Exeter (105 publications), and Sian Ellard and Andrew T. Hattersley (50 publications each). High-frequency keywords included “gene”, “monogenic diabetes”, “children”, “prevalence”, “glucokinase”, and “mutation”. In the co-citation analysis, the study by Shields BM published in 2010 showed the highest citation frequency. These findings indicate that MODY research has primarily centered on genetic mechanisms, clinical diagnosis, and precision management, with recent attention gradually moving toward functional genomics and individualized therapeutic strategies. MODY research has evolved into a multidisciplinary field that bridges biological mechanisms, clinical characterization, and translational application. Future studies should broaden population coverage and translate molecular findings into more precise diagnosis and individualized management.
Rare liver diseases are associated with diagnostic delay, fragmented care, inconsistent management, and limited patient support. Patient pathways may help address these challenges by translating clinical guidance and patient priorities into practical, coordinated care processes. This manuscript presents a European template for developing patient-centred pathways for rare liver diseases within ERN RARE-LIVER. The template was developed through multidisciplinary collaboration involving hepatologists, specialist nurses, patient representatives, patient organisations, and EURORDIS, and was informed by clinical guidance, patient-journey principles, and iterative expert and patient review. The proposed framework follows four phases of the patient journey: pre-diagnosis, diagnosis, management, and long-term follow-up. It includes disease-specific sections, educational resources, frequently asked questions, and “10 key questions” to support shared decision-making. Pathways for non-cirrhotic portal vein thrombosis, polycystic liver disease, and portosinusoidal vascular disorder illustrate the practical application of the template. This European template provides a practical, adaptable framework aimed at supporting harmonised, multidisciplinary, and patient-centred care for rare liver diseases across European healthcare settings. Future work should evaluate implementation, usability, and impact on care coordination and patient experience.
Disease-modifying therapies for spinal muscular atrophy (SMA) require standardized follow-up to interpret treatment response. However, short-term changes may reflect measurement variability rather than true clinical change. We therefore assessed the test-retest reliability and relationships of routinely used outcome measures in adults with SMA using two standardized evaluations performed within a two-week interval. These assessments included motor function, upper-limb strength and dexterity, ambulatory performance, and respiratory function. Forty-four adults with SMA type 2 or 3 were included. No significant change was observed between test and retest visits. Most outcomes demonstrated excellent reproducibility, with intraclass correlation coefficients (ICC) >0.95. Measurement errors were low, with relative standard errors of measurement below 10
Hypoglycaemic brain injury is a persistent threat in the lives of children and young people (CYP) with hyperinsulinism (HI). Up to 50
This report aims to outline the complex and multifaceted framework within which the journey to European market access for a β-thalassemia gene therapy has unfolded, highlighting the clinical, ethical, economic, and regulatory challenges faced by all stakeholders involved. Focusing on betibeglogene autotemcel (Zynteglo), a gene therapy for β- thalassemia developed by the U.S. based biotech company Bluebird Bio, this paper analyzes official sources of information from the therapy developer, regulators, patients, health technology assessment bodies and payers with the aim of offering a measure of this complex operation that culminated in the therapy’s withdrawal from the European market in 2022.
Pathogenic variants in DEAF1 cause DEAF1-associated neurodevelopmental disorders (DAND) with autosomal-dominant (typically de novo) and autosomal-recessive (biallelic) presentations. We sought to characterize five unrelated children with de novo DEAF1 variants, define epilepsy phenotypes, and refine inheritance-specific genotype–phenotype architecture with developmental context. Trio-based whole-exome sequencing with Sanger confirmation was performed in five unrelated children. Missense variants were evaluated using structural modeling and in silico stability/physicochemical assessments. DEAF1 expression was examined using GTEx, the Human Protein Atlas, BrainSpan, Evo-devo mammalian organ transcriptomes, and single-cell brain organoid datasets. A systematic literature review (inception–March 2026) curated eligible cases for intersection-based UpSet analyses and system-level stacked summaries. Five unrelated children carried heterozygous de novo DEAF1 missense variants; four mapped to the SAND domain (p.Leu203Pro, p.Gly212Ser, p.Ile228Met, p.Leu272Ser) and one was N-terminal (p.Ala29Pro). p.Ala29Pro and p.Ile228Met were not recorded in ClinVar, HGMD Professional, or the reviewed literature. All five patients had intellectual disability/developmental delay with prominent expressive language impairment and motor delay/hypotonia. Epilepsy was observed in all patients, with onset ranging from 7 months to 2 years 8 months, and focal impaired consciousness seizures (FIC) predominated. EEG abnormalities were observed in 4 of the 5 patients, and all five were seizure-free on anti-seizure medications at the last follow-up. Structural modeling suggested variant-dependent perturbations, particularly among SAND-domain substitutions, but these findings remain computational predictions. Expression analyses supported brain-enriched, developmentally regulated DEAF1 expression and broad neuronal/progenitor expression in human brain organoids. A literature review identified 62 individuals from 15 studies; combined with our cohort, 67 individuals were analyzed (de novo n = 52; biallelic n = 15). De novo variants clustered within/around the SAND domain, whereas biallelic variants were more broadly distributed. UpSet and stacked-bar analyses revealed a shared neurodevelopmental core but distinct co-occurrence patterns, with autism/epilepsy shaping dominant intersections in de novo cases and microcephaly/MRI abnormalities contributing more prominently in biallelic disease. Our study refines the de novo clinical and allelic spectrum of DAND and delineates inheritance-specific genotype–phenotype architecture with developmental and cellular context.
Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder primarily associated with variants in the RYR1 gene. A significant proportion of identified RYR1 variants are classified as Variants of Uncertain Significance (VUS), posing a major challenge for clinical management and genetic counseling. We report a case of a 53-year-old male (proband) who developed fulminant MH during general anesthesia. Following clinical stabilization, whole-exome sequencing (WES) was performed. The initial analysis reported several variants of uncertain significance (VUS). Based on the compelling MH phenotype, the RYR1 gene was prioritized for further investigation. The candidate variant was validated by Sanger sequencing in the proband and his unaffected son and sister. WES revealed a heterozygous RYR1 variant, c.7108_7109delinsAAGCC (p.Gly2370delinsLysPro), initially classified as a VUS. Crucially, Sanger sequencing confirmed that this variant was absent in his unaffected son and sister, providing strong indirect evidence for a de novo origin. The proband’s clinical presentation was classic for MH: hyperthermia (39 °C), tachycardia, hypercapnia, muscle rigidity, hyperkalemia, and markedly elevated creatine kinase/myoglobin, which responded to dantrolene. Re-evaluation using ACMG/AMP guidelines identified the following key pathogenic evidence: PS4 (specific MH phenotype), supporting PS2 (probable de novo), PM2 (absent in population databases), PM4(in-frame indel), PP1(co-segregation in a micro-family), PP2(RYR1 is a known MH gene), PP3(computational evidence of deleteriousness), and PP4 (highly specific phenotype). This study is the first to report and validate the pathogenicity of the RYR1 c.7108_7109delinsAAGCC variant. By integrating a definitive clinical MH episode with familial segregation data, we successfully reclassified this VUS as Pathogenic. Our findings underscore the critical importance of phenotype-driven reassessment of VUS using the ACMG framework and provide definitive guidance for the lifelong anesthetic management of the proband and his family.
Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired phenylalanine (Phe) metabolism. The mainstay of treatment is a strict low-Phe diet, which can be burdensome. Sapropterin dihydrochloride (Kuvan®), a synthetic form of tetrahydrobiopterin (BH4), offers a pharmacological alternative, potentially improving metabolic control and dietary flexibility. However, treatment response varies, and long-term effects remain uncertain. This systematic review and meta-analysis aimed to evaluate the long-term efficacy of Sapropterin in PKU patients, focusing on blood Phe levels, dietary Phe tolerance, and patient-related outcomes such as BMI and IQ. A comprehensive literature search was conducted in PubMed/MEDLINE and Web of Science, following PRISMA guidelines. Studies were included if they reported long-term outcomes of Sapropterin therapy in PKU, assessing Phe levels, dietary tolerance, or patient-related parameters. Meta-analyses were performed using the Wilcoxon rank sum test and forest plots. Nineteen studies met the inclusion criteria, with 85 patients providing baseline Phe data and 54 with post-treatment values. Sapropterin significantly reduced blood Phe levels, especially in classic PKU patients with high baseline levels (p = 0.025). Effects on dietary Phe tolerance were variable, and meta-analysis results were inconsistent. Limited data on BMI and IQ precluded firm conclusions on growth and neurocognition. Genotype analysis (n = 70) highlighted frequent PAH variants (e.g., p.L48S, p.R261Q), but genotype–response associations remained unclear. Sapropterin effectively lowers blood Phe levels in classic PKU, but further studies with standardized measures are needed to clarify its impact on dietary tolerance, growth, cognition, and genotype-based treatment response.
The SF1 gene encodes the splicing factor 1, a part of the splicing machinery. Recently, loss-of-function (LoF) variants in the SF1 gene have been suggested as a molecular cause of a neurodevelopmental spliceosomopathy. We report a unique familial case of a novel truncating variant in a single Czech family presenting with mild neurodevelopmental disorders (NDD) and variable congenital abnormalities. The c.1764_1776del variant in the last exon of the SF1 gene (NM_004630.4) was identified through exome sequencing in three affected family members. Functional analyses at the transcriptional level confirmed that this alteration does not trigger nonsense-mediated decay (NMD), and aberrant transcripts with premature termination codons are preserved. This study expands the spectrum of pathogenic variants involved in the development of new SF1-related spliceosomopathy and its diverse phenotypic effects. Our data emphasise the clinical benefits of comprehensive exome sequencing for uncovering new gene-disease connections.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, fatal multisystem disorder characterized by significant genotypic and geographic heterogeneity. Despite recent therapeutic breakthroughs, overlapping clinical features frequently lead to misdiagnosis and delayed intervention. A comprehensive narrative review of the literature was conducted to synthesize recent advancements in the epidemiology, diagnostic workflows, and therapeutic landscape of ATTRv-PN, with an emphasis on clinical translation and multidisciplinary management. The epidemiological profile of ATTRv-PN highlights region-specific variant distributions (e.g., p.Val50Met, p.Ala117Ser). The diagnostic paradigm has shifted towards prioritizing early genetic testing and minimally invasive biopsies, complemented by emerging serum biomarkers like neurofilament light chain (NfL) and advanced neuroimaging. Therapeutically, the landscape has been transformed by disease-modifying therapies (DMTs). Gene-silencing agents (siRNAs and ASOs) and TTR stabilizers have demonstrated robust efficacy in halting neuropathy progression. Furthermore, novel modalities, including amyloid-depleting monoclonal antibodies and in vivo CRISPR/Cas9 gene-editing therapies, show unprecedented promise in ongoing clinical trials. ATTRv-PN has entered an era of precision medicine. Overcoming diagnostic delays through “red-flag” recognition and routine genetic screening is imperative. Early, stage-adapted initiation of DMTs within a multidisciplinary care framework is crucial for optimizing long-term patient outcomes.
Skeletal dysplasia (SD) is a clinically and genetically heterogeneous group of bone and cartilage disorders. Given the typically heterogeneous and nonspecific clinical manifestations associated with these conditions, molecular testing is essential to achieve a definitive diagnosis. To elucidate the clinical and molecular characteristics of genetic skeletal disorders in the Guangxi region, we conducted a retrospective single-center study involving 434 families suspected of having SD who underwent molecular analysis in our department over an eight-year period. We analyzed their clinical and molecular genetic data. Among our cohort, facial dysmorphism and short stature emerged as the most prevalent clinical manifestations, followed by growth delay and motor delay. Notably, molecular diagnoses were made at a relatively late age. Our findings revealed a total of 34 chromosomal abnormalities and 265 Mendelian genetic disorders. According to the Nosology of genetic skeletal disorders: 2023 revision, 75 genes were implicated in 199 positive molecular diagnoses, while the remaining 66 positive diagnoses were attributed to 56 causal genes. The most frequently identified causal gene was FGFR3, with the p.G380R substitution being the predominant pathogenic variant. The overall diagnostic yield through whole-exome sequencing was found to be 64.9
Thalassemia is classified globally as a rare disease; however, it represents a major public health burden in many low‑ and middle‑income countries due to its high prevalence and limited access to care. In Indonesia, one of the world’s most genetically diverse populations, thalassemia traits present epidemiological characteristics more consistent with a common disease than a rare one in certain populations. However, the national molecular spectrum of alpha‑ and beta‑thalassemia, essential for carrier screening and prevention programs, is still insufficiently characterized. Hematological screening (red cell indices and HbA₂ levels) remains the gold standard, but molecular diagnostics are required for definitive diagnosis and accurate carrier identification. This study analyzed archived data from 4,779 individuals across Western Island Southeast Asia and Eastern Island Southeast Asia collected between 1995 and 2016. Thalassemia screening was based on hematological criteria including MCV, RBC morphology, and HbA2 levels assessed via CBC and HPLC. For 180 whole-genome sequenced individuals, pathogenic variants in HBA1/HBA2 and HBB genes were identified by cross-referencing ClinVar. Pathogenic variants were detected in 13.2
Cardio-facio-cutaneous syndrome type 4 (CFC4) is a rare RASopathy caused by germline mutations in the MAP2K2 gene, which encodes the MEK2 protein - a key kinase in the Ras/MAPK signaling pathway. Although the Ras/MAPK cascade has been widely studied due to its essential role in development and its implication in cancer biology, CFC4 remains one of the least characterized syndromes within the RASopathy spectrum. Pathogenic MAP2K2 variants have received limited attention in the literature so far, with most data derived from isolated case reports. This review aims to synthesize current knowledge on MAP2K2-related CFC4 with a particular emphasis on the molecular and functional consequences of mutations in this protein. We explore findings from in silico, in vitro, and translational studies, and highlight how particular mutations alter MEK2 function and Ras/MAPK signaling. Where specific data on CFC4 are lacking, insights are drawn from broader RASopathy research to suggest mechanistic parallels and potential therapeutic implications. By gathering and integrating the current knowledge on MEK2 biology, this advances our understanding of MEK2-driven pathogenesis and supports the development of more effective therapeutic strategies for individuals affected by CFC4.
Neuronopathic mucopolysaccharidosis type II (MPS II; Hunter syndrome) is characterized by progressive multisystemic impacts, including cognitive impairment and behavioral problems. The Vineland Adaptive Behavior Scales, second edition (VABS-II) is recommended for assessing adaptive behavior in MPS II clinical studies; recently, an increase in VABS-II age-equivalent scores of 3 months (3AEq) has been defined as a threshold for improvement. The aim of the present study was to gain caregiver insights on what constitutes meaningful change on the VABS-II in response to treatment for children with neuronopathic MPS II. Ten semi-structured interviews were conducted with 11 caregivers of 11 children with neuronopathic MPS II aged 3–6 years old in the UK and USA. Caregivers were presented with hypothetical vignettes detailing changes in adaptive behavior and VABS-II scores in response to treatment over 1 year and were asked to select which one(s) represented a minimal meaningful change. The scores for the selected meaningful changes were then compared with those equivalent to an increase of 3AEq to assess the adequacy of this threshold. Caregivers discussed the rationale for their choices. For all nine VABS-II categories (feeding, drinking, undressing, dressing, brushing teeth and toileting [Personal Subdomain]; sharing skills [Interpersonal Relationships Subdomain]; Play and Leisure Subdomain; and Maladaptive Behavior Domain), the hypothetical vignette most commonly selected by caregivers as representing a minimal meaningful change was associated with the smallest change. The significant impact of small increases in independence and cognitive and physical abilities to perform daily activities were highlighted. For each functional activity within the Personal Subdomain, the majority of caregivers selected vignettes associated with changes in raw scores that were below the total Personal Subdomain raw score equivalent to a change of 3AEq. For sharing skills (Interpersonal Subdomain) and for the Play and Leisure Subdomain, the majority of caregivers chose vignettes associated with raw score changes that were below or equal, respectively, to raw scores associated with a change of 3AEq. These insights from caregivers support the use of VABS-II for assessing adaptive behavior in children with neuronopathic MPS II and the use of 3AEq as a threshold for meaningful change.
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Among 847 patients, the median age was 23 years, 27.5
Phenylketonuria (PKU) is a common inherited metabolic disorder in newborns. Early diagnosis and timely intervention are essential to prevent neurodevelopmental impairment. Traditional newborn screening primarily relies on measuring blood phenylalanine (Phe) levels, which can lead to both false-positive and false-negative results. Long-read sequencing (LRS) offers high coverage and long-fragment resolution, enabling comprehensive detection of PAH gene variants and potentially improving PKU screening and diagnosis. We developed a comprehensive PAH gene sequencing technology (CAPAH) based on the HiFi LRS platform, and applied it to the second-tier screening for PKU in newborns. First, CAPAH was validated for consistency with traditional NGS, MLPA, and Sanger sequencing in 20 samples with known genotypes. Subsequently, a retrospective analysis of 200 newborns with positive or borderline primary screening results was performed to assess the impact of CAPAH on variant detection, genotype-phenotype associations, and second-tier screening performance. CAPAH achieved complete consistency (100
Rare diseases affect millions globally but remain poorly understood due to low prevalence and fragmented healthcare responses. Patients face long diagnostic delays, known as the “diagnostic odyssey”, due to limited knowledge and awareness among healthcare professionals. This scoping review examines healthcare professionals’ knowledge and awareness of rare diseases. Findings highlight critical educational and systemic gaps across disciplines. Addressing these deficits is essential to improve early recognition, care coordination, and health outcomes for rare disease populations. This scoping review followed Arksey and O’Malley’s five-stage framework, enhanced by the Joanna Briggs Institute (JBI) methodology and PRISMA-ScR guidelines. The review mapped existing literature guided by the PCC framework. A comprehensive search strategy was developed and executed across four databases, CINAHL, Medline, PubMed, and Scopus, along with grey literature sources. After removing duplicates, 4539 records were screened, and 25 studies met the inclusion criteria. Data was charted and synthesised thematically using an inductive approach to identify key findings and gaps in professional education and awareness. Twenty-five studies from 2015 to 2025 were included, spanning diverse countries and healthcare professions. Most used cross-sectional surveys to assess knowledge, awareness, and confidence regarding rare diseases. Overall, healthcare professionals demonstrated limited knowledge, poor familiarity with rare disease definitions, and low use of specialist resources. Variability was observed across professional groups, with general practitioners and nurses demonstrating lower knowledge than specialists. Education and training were widely reported as insufficient, with gaps evident across both undergraduate and clinical settings. Despite low objective knowledge, many participants overestimated their competence. These knowledge gaps were associated with challenges in diagnosis and management, including delayed recognition of rare diseases. A strong demand for improved rare disease education and accessible guidelines was consistently expressed. Despite growing recognition of rare diseases as a public health priority, healthcare systems worldwide lack structured education, standardised guidelines, and accessible resources. The review calls for further research, urgent educational reform, improved digital resources, and targeted policy changes to integrate rare disease education into healthcare curricula and enhance clinical support. Addressing these gaps will improve care, facilitate earlier diagnoses, and ensure more equitable outcomes for rare disease patients.
Peroxisomal disorders comprise a heterogeneous group of inherited metabolic diseases including peroxisome biogenesis disorders (PBDs), single-enzyme defects, and peroxisomal dynamics disorders. Data from Middle Eastern populations remain limited despite high regional consanguinity rates. We aimed to characterize the clinical, genetic, and neuroimaging spectrum of peroxisomal disorders in a multicenter Iranian cohort. We performed a retrospective multicenter study of genetically confirmed pediatric peroxisomal disorders diagnosed between 2016 and 2023 across five referral centers. Clinical, neuroimaging, and molecular data were systematically reviewed. Patients were classified as PBDs or non-PBD peroxisomal disorders, while non-classical peroxisome-associated phenotypes were analyzed separately. A pragmatic retrospective severity index was applied to assess disease burden. Forty-two patients from 42 families with peroxisomal gene-associated disorders were identified, including 40 patients in the primary analysis cohort. PBDs accounted for 33 patients and non-PBD peroxisomal disorders for seven. PEX1 was the most frequently affected gene. Novel variants accounted for 67
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, resulting in glycosphingolipid accumulation and progressive involvement of multiple organ systems, particularly the kidneys, heart and cerebrovascular system. Clinical manifestations are highly heterogeneous, with disease onset ranging from early childhood to late adulthood depending on sex, genotype and phenotype. Although rare, FD can result in substantial morbidity and premature mortality when diagnosis is delayed or management is suboptimal. International registry data suggest that diagnostic delays of more than a decade are common, with many patients presenting with advanced organ involvement before treatment is initiated. Delayed diagnosis and late initiation of therapy may be associated with irreversible organ damage and substantial downstream healthcare use related to dialysis, cardiac complications and stroke. Earlier recognition may improve the opportunity for clinically beneficial intervention; however, whether earlier initiation of high-cost disease-specific therapy represents a cost-effective use of resources depends on phenotype, disease stage, expected treatment effect, treatment cost and the opportunity costs within the relevant healthcare system. Over the past decade, the international evidence base guiding FD management has evolved substantially. Contemporary consensus recommendations increasingly emphasise earlier initiation of disease-specific therapy, improved recognition of clinically significant disease in females, genotype-informed treatment strategies, and risk-stratified approaches to monitoring and longitudinal care. Advances in biomarkers, molecular diagnostics and cardiac imaging have further refined approaches to disease assessment and treatment decision-making. This commentary highlights key developments in the international management of FD since the publication of South African recommendations in 2015 and considers their implications for rare disease care in resource-constrained health systems. It proposes an adaptive, resource-stratified implementation framework that integrates evolving international recommendations with transparent treatment prioritisation, longitudinal monitoring, local real-world evidence generation and periodic reassessment. The framework recognises that treatment effects differ by phenotype, sex, organ involvement and disease stage, and that decisions concerning high-cost disease-specific therapies must consider expected benefit, uncertainty, equity, affordability and opportunity cost.
