Orphanet Journal of Rare Diseases最新文献

Background: Isobutyryl-coenzyme A dehydrogenase deficiency (IBDD) is a rare inborn error of valine metabolism caused by variants in the ACAD8 gene. Since its initial description in 1998, a wide range of clinical features has been reported, but the disease status and clinical significance of IBDD remain under debate. We systematically studied all published cases of IBDD to provide an overview of the reported phenotype and molecular spectrum.

Results: A comprehensive literature review identified 172 individuals with IBDD reported up to December 2024. Seven children were diagnosed following selective screening due to family history or clinical suspicion, while 165 were identified through expanded newborn screening programs. Elevated blood or plasma C4-acylcarnitine was observed universally, and isobutyrylglycinuria was a common but not invariable urinary marker. Of these 172 individuals, 146 were asymptomatic at follow-up, whereas 26 presented with diverse, non-specific manifestations, including motor delay, failure to thrive, muscular hypotonia, speech delay, developmental delay, and anemia-the latter being the most frequently reported abnormality. Biallelic pathogenic variants in ACAD8 were identified in most cases with available genetic information, with c.286G > A p.(Gly96Ser) emerging as the most prevalent variant, predominantly among individuals of Chinese origin. Notably, altered biochemical markers of liver function were reported in 19 individuals, including 18 with isolated elevations of serum transaminases and γ-glutamyl transferase. One 11-year-old boy exhibited hepatomegaly and ultrasound findings suggestive of hepatic steatosis, along with markedly elevated transaminase levels. Hepatic steatosis has also been observed in an IBDD mouse model, suggesting a potential link between IBDD and liver involvement.

Conclusions: Most individuals with IBDD remain asymptomatic following detection through newborn screening, yet a minority develop heterogeneous clinical features. Our overview highlights that some liver enzyme abnormalities and hepatic steatosis may occur in some individuals with IBDD. These findings suggest that further research is warranted to clarify possible hepatic implications of IBDD and to determine whether long-term monitoring of affected individuals should be considered, particularly in light of ongoing discussions about the appropriateness of IBDD as a target condition in newborn screening programs.

Background: Within the context of the COVID-19 pandemic and beyond, pandemic anxiety (PA) is of high social and psychopathological relevance. Compared to the general population and people living with common diseases, people living with rare diseases suffer more from the effects of a pandemic in various areas. To date, there are almost no systematic studies on PA in this subpopulation. Therefore, the current study examines the levels and factors associated with PA, as well as the relationship of PA with clinical measures of anxiety and depression disorders in people living with a wide range of different rare diseases.

Methods: Data are drawn from an online survey conducted between March 2022 and February 2023 at the Department of Medical Psychology, University Medical Center Hamburg-Eppendorf, on the care situation of people living with rare diseases during the COVID-19 pandemic. Analyses include descriptive statistics, Welch's t-tests, linear regressions, and a multivariate mediation model tested via structural equation modeling ([Formula: see text]).

Results: Compared to the general population, people living with rare diseases are more affected by PA during a pandemic. Female gender, age of 50 years and older, and living alone are risk factors for particularly high levels of PA. Furthermore, a previous COVID-19 infection is associated with lower PA; receiving vaccination correlates with higher PA. In addition to sociodemographic factors, health-related quality of life (HRQOL) and daily burden due to the rare disease are significantly associated with PA levels. Moreover, an increase in PA is associated with increased anxiety and depression scores in clinical screening questionnaires. Lastly, PA mediates the links of daily burden with anxiety and depression disorders.

Conclusions: Findings highlight specific factors that should be addressed to effectively improve the situation of people living with rare diseases in the likely event of another pandemic. In addition, it becomes apparent that PA has negative implications for mental health that can persist beyond the context of a pandemic. Hence, PA should not be trivialized as a temporary pandemic state. More research is needed to compensate for the limitations of the present study and to better understand the structure of PA in people living with rare diseases.

Background: Lysosomal storage disorders (LSDs) are a diverse group of over 70 rare, inherited metabolic conditions that present significant diagnostic and therapeutic challenges, especially in genetically diverse and resource-limited settings like India. To address the lack of a centralized clinical and genomic data registry for LSDs, we established the first government-supported national LSDs biobank in India. This study describes the infrastructure, sample collection, storage procedures, ethical framework, and expected impact of the biobank on research, diagnostics, and patient care.

Methods: The study includes biological samples and clinical-genetic data from 530 patients, (526 unrelated individuals and 2 sibling pairs), over a 17-year period (2008-2025). Biological samples including genomic DNA from blood, plasma, and urine precipitate were processed for enzyme and genetic investigations. A centralized webpage has been established to manage the biological sample data including clinical, enzyme and genetic data.

Results: The LSD biobank cohort encompasses 8 LSD subgroups across 27 disorders, with the most common being Gaucher disease (n = 70), Tay-Sachs disease (n = 62), Mucolipidosis (ML) II/III (n = 44), and Morquio-A (n = 40). Samples originated from 15 Indian states, with a predominance of pediatric cases. Detailed phenotypic, enzymatic, and genomic profiles were generated. Enzyme assays confirmed markedly reduced activity in most cases, with variable residual activity noted in few LSDs. Genetic analyses using Sanger sequencing, PCR-RFLP, targeted gene panel sequencing, and/ or whole exome sequencing detected causative variants. Notably, c.1469T > C in the IDUA gene (29.4% in Hurler disease), c.230 C > G in the GALNS gene (22.5% in Morquio-A disease), c.1448T > C in the GBA1 gene (56% in Gaucher disease), and c.1385 C > T and c.964G > T in the HEXA gene (11.3% and 8.1% respectively in Tay-Sachs disease) were the most common variants. Several novel, private mutations were also identified, broadening the mutational landscape of LSDs.

Conclusion: The present study represents a scalable model for rare disease research in low- and middle-income countries. This resource lays the foundation for genotype-phenotype correlation studies, natural history analyses, and future precision medicine strategies tailored to the Indian population.

Background: Inborn errors of immunity (IEI), though individually rare, collectively represent a significant disease burden. From 1980 to 2024, classified IEI disorders expanded from dozens to 559 entities, reflecting advances ranging from immunoglobulin replacement to gene therapy.

Methods: This bibliometric analysis-a comprehensive mapping of the global IEI landscape-analyzed 7,455 publications (1991-2025) from Web of Science Core Collection using Bibliometrix, VOSviewer, and CiteSpace.

Results: Key findings: (1) Annual publication growth: 10.27% (H-index = 173); (2) US dominance: 36.3% publications, 115,221 citations, and TLS = 105,825; (3) Research priorities: Immunodeficiency mechanisms, clinical diagnostics, and key diseases (SCID, CVID, APDS); (4) Therapeutic frontiers: HSCT, gene therapy, targeted signaling inhibitors. (5) Critical gaps: Newborn screening implementation, quality-of-life metrics.

Conclusion: This study provide a comprehensive, multidimensional visualization of the IEI research landscape over 35 years. Although the field maintains a high H-index and broad scope, the pace of research growth appears to have stabilized in the past five years. It is important to note that the observed flattening in total citation counts during this period may be influenced by citation windows and pandemic-related confounding, and should not be interpreted as definitive evidence of field maturity or stagnation. Nonetheless, this observed pattern highlights that that sustaining historical growth rates may require transformative technological advances-particularly in gene editing-to catalyze the next wave of progress in IEI research.

Background: Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by defects in propionyl-CoA carboxylase (PCC), a mitochondrial enzyme composed of six alpha (PCCA) and six beta (PCCB) subunits. Mutations in PCCA/PCCB genes disrupt PCC function, leading to toxic metabolite accumulation and clinical manifestations. Current research is limited by inadequate patient-derived cellular models and ethical constraints in sample acquisition.

Method: Using CRISPR/Cas9-mediated gene editing, we established an isogenic human induced pluripotent stem cell (iPSC) line carrying the PCCA c.2002G> A mutation. The mutant iPSCs were further subjected to directed cardiac differentiation. Characteristic metabolites in the iPSC-derived cardiomyocytes (iPSC-CMs) culture medium were analyzed via untargeted metabolomics, and contractile function was assessed by video-based motion analysis under propionate challenge.

Results: The mutant iPSCs showed sustained expression of pluripotency markers (OCT4, NANOG, SOX-2), maintained normal karyotype (46, XY), and retained trilineage differentiation capacity. Functional characterization demonstrated significantly reduced PCC enzyme activity, accurately modeling PA metabolic pathology. Furthermore, the mutant iPSCs successfully differentiated into cardiomyocytes and exhibited a PA-specific metabolic profile, including significantly elevated propionylcarnitine levels. Upon propionate treatment (2.5 mM), the contractile function of mutant iPSC-CMs was significantly impaired, whereas wild-type iPSC-CMs showed the opposite response with enhanced contraction.

Conclusions: This isogenic iPSC line provides an ethically unconstrained platform to investigate PA molecular mechanisms and genotype-phenotype relationships. The model enables systematic drug screening and therapeutic development while overcoming patient sample limitations.