Intractable & rare diseases research最新文献

With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267; p = 0.00799). Sensitivity analyses including various cis-SNPs, provided consistent estimates for S100A3 (inverse variance weighted (IVW) OR: 0.085, 95% CI: 0.032-0.225; p = 7.5 × 10^-7 and MR-Egger OR: 0.212, 95% CI: 0.013-3.376; p = 0.387). Colocalization analyses confirmed a shared genetic signal for S100A3 and PAH, with a posterior probability of 99.9%. Transcriptomic investigations further highlighted S100A3's protective role in CHD-PAH. Our study using SMR and GEO data identified S100A3 as a gene associated with a reduced risk of PAH in CHD patients. Elevated circulating levels of S100A3 were linked to a reduced PAH risk, and transcriptomic evidence further supported its protective function in CHD-PAH.

Right ventricular volume overload (RVVO) is a common hemodynamic abnormality in patients with congenital heart disease (CHD) and frequently leads to pathological cardiac remodeling. Our previous research demonstrated that RVVO disrupts the metabolic maturation of cardiomyocytes. Mitochondrial metabolic maturation, a crucial process in postnatal cardiomyocyte development, remains poorly understood under RVVO conditions. In this study, an mouse RVVO model was established on postnatal day 7 by creating a fistula between the abdominal aorta and inferior vena cava, confirmed by abdominal ultrasound and echocardiography. Transcriptomic analyses revealed significant downregulation of genes linked to mitochondrial metabolic maturation. Transmission electron microscopy showed impaired mitochondrial structure and maturation markers, while Seahorse assays demonstrated a marked reduction in oxidative phosphorylation rates in RVVO cardiomyocytes. These findings collectively indicated that RVVO restricted mitochondrial metabolic maturation in the postnatal RV. Targeting mitochondrial metabolic maturation could offer a promising therapeutic strategy to mitigate RVVO-induced pathological remodeling.

Intrahepatic bile duct stone disease has a high morbidity in China, with a high rate of additional surgery, a high rate of cancer development, and a high disease burden. Activation of the MAPK pathway leading to up-regulation of MUC5AC expression is an important factor in the formation of intrahepatic bile duct stones. Exosomes or extracellular vesicles (EVs) can be used as therapeutic vectors to encapsulate and carry drugs into diseased cells to achieve a therapeutic effect. The current study alleviated intrahepatic bile duct stone disease by preparing EVs carrying miR-141-3p. First, the researchers loaded mesenchymal stem cell (ESC)-derived EVs with miR-141-3p (miR-141-3p-EVs) and verified the phenotypes and characteristics of miR-141-3p-EVs. miR-141- 3p-EVs successfully reduced the inflammatory level of human biliary epithelial cells (HIBEC) and lowered, via the MAPK pathway, MUC5AC expression. In an experiment involving an animal model of intrahepatic bile duct stones, miR-141-3p-EVs effectively alleviated stone formation, and the intrinsic mechanism was associated with the decreased level of MAPK pathway expression. In conclusion, results suggested that the EV-based strategy of miR- 141-3p delivery to intrahepatic bile duct epithelial cells has value and provides a new approach for the treatment of intrahepatic biliary stone disease.

Primary hepatic angiosarcoma (PHA) is a rare hepatic mesenchymal tumor that accounts for 2% of all primary malignant liver tumors. It typically presents with nonspecific symptoms, is highly aggressive, and there are limited treatment options. Imaging characteristics of PHA overlap with that of hepatic hemangioma, a common benign hepatic lesion, creating a potential diagnostic pitfall. We present a case of PHA that mimicked hepatic hemangioma on imaging. We review the differentiating characteristics between these two hepatic tumors. PHAs demonstrate irregular/infiltrating margins, higher lesion multiplicity, higher risk of tumor rupture, and rapid growth, which are not typically seen with hepatic hemangiomas.

Lipid storage myopathies (LSM) are a group of inherited metabolic muscle disorders characterized by abnormal lipid metabolism and the deposition of lipids within muscle fibers. Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is the most common type of LSM in China, caused by mutations in the gene expressing electron transfer flavoprotein dehydrogenase (ETFDH). Here, we report a 14-year-old girl presenting with exercise intolerance, followed by muscle weakness and pain. Initially, the patient showed rhabdomyolysis (RML) and was misdiagnosed with polymyositis (PM). However, muscle biopsy and genetic analysis led to a diagnosis of MADD. After the initiation of vitamin B2 administration, her symptoms were rapidly ameliorated. Genetic testing revealed compound heterozygous mutations in the ETFDH gene, specifically c.250G>A and c.929A>G, the second of which has not previously been reported. In conclusion, we report a novel mutation of ETFDH in a patient with riboflavin-responsive MADD, which expands our knowledge of MADD-related gene variants in the Chinese population.

This study aimed to understand research trends, determine frontier topics, and explore the developments in and the differences between research conducted in China and the rest of the world. We analyzed the research status of rare diseases in China and globally over the past decade using bibliometric methods. We focused on rare disease literature indexed in the Web of Science (WoS) and China National Knowledge Infrastructure (CNKI) databases from January 2013 to December 2023. We selected studies based on inclusion and exclusion criteria. CiteSpace 6.1.R6 software were used to prepare knowledge graphs and perform comparative analyses of authors, institutions, content, and hot topics between both databases. A total of 10,754 articles from the WoS and 969 from the CNKI met the inclusion criteria. In the past 10 years, the diagnosis and treatment of rare diseases have been a common research focus in both China and the world. China has emphasized more on "orphan drugs". "Genes" and "management" were focused globally. The United States had the greatest number of publications. China ranks high in terms of publication volume and institutional ranking. Research interest in rare diseases has gradually increased worldwide, with European and American countries maintaining a leading position. China has made significant contributions. China's research is lagging compared to global trends, lacking collaboration with other countries. The diagnosis and treatment of rare diseases remain central themes, whereas genetic research, artificial intelligence, and sociological studies on rare disease populations are emerging as hot topics.

This article aims to identify research hotspots and trends in research on SLC26A4 gene-related hearing loss through bibliometric and visual analyses, providing a reference and direction for future research. Publications on SLC26A4 gene research in hearing loss from 1994 to 2023 were retrieved from the Web of Science Core Collection database. Bibliometric analysis was conducted using the Bibliometrix 4.0.0 R package, CiteSpace 6.2.R6 software, and VOSviewer 1.6.20. The analysis encompassed journals, authors, keywords, institutions, countries, and references. Based on the analysis results, network maps were generated to evaluate collaborations among authors, countries, institutions, keyword co-occurrences, and co-citation references. This study identified 1,308 publications from 62 countries. Annual publication numbers have increased with fluctuations, showing rapid growth since 2011. The USA emerged as the leading contributor in this field based on scientific production, citations, and cooperation networks. International Journal of Pediatric Otorhinolaryngology had the highest number of publications, while Laryngoscope was the most cited journal. Harvard University was the most productive institution. Key researchers included Dai Pu, Griffith Andrew J., and Usami Shin-Ichi. There have been active collaborations between countries, authors, and institutions. The primary research topics focused on genotype-phenotype correlations, genetic screening, diagnostic advancements, and exploration of pathogenic mechanisms. Research on SLC26A4 gene-related hearing loss has notably increased since 2011, with ongoing clinical investigations and basic research efforts. Future studies may further explore disease mechanisms and potential therapeutic interventions related to the SLC26A4 gene.

This study utilizes CiteSpace (version 6.2.R3) to visually analyze literature related to rare diseases, summarizing the current research status and hotspots in the field. The goal was to provide broader perspectives and references for researchers in rare diseases. A comprehensive search for relevant literature in the rare diseases domain was conducted through the China Knowledge Network (CNKI) and Web of Science (WOS), spanning the years 1985 to 2024. Then, CiteSpace software was utilized to create a visual map of the annual publication volume, authors, institutions, keywords, and other content. After screening, 2,293 Chinese and 2,262 English articles were included in the study. Over the last several decades, the diagnosis and treatment of rare diseases have been a common research focus in both China and foreign countries, but there is a significant research depth and breadth gap. In China, there is a shortage of core authors and high-quality literature, and the level of collaboration among research teams is significantly lower compared to the robust international cooperation between authors and institutions. High-frequency and central keywords in the field include "orphan drugs", "children", and "genetic mutations", reflecting research hotspots in this domain. Research on rare diseases has been increasing annually, with key directions focusing on orphan drug development, novel therapeutic agents, genetic therapies, and healthcare security. In the research field of rare diseases, emphasis should be placed on early detection, early prevention, and early treatment. The application of genetic diagnostic techniques in clinical practice will have a broader prospect. This will be one of the direction for future research in this area.

This study aims to evaluate the relationship between mandibular developmental abnormalities and swallowing function in children with Pierre Robin Sequence (PRS). Swallowing function was assessed by a Modified Kubota Drinking Test (MKDT). Pre- and postoperative CT scans of PRS patients who underwent Mandibular Distraction Osteogenesis (MDO) were analyzed through three-dimensional (3D) digital reconstruction technology. Mandibular and airway evaluation parameters were measured, including the distance between bilateral mandibular angular, the length of bilateral mandibular ramus, mandibular notch angle (α), mandibular angle (β), mandibular body angle (γ), and the lateral and longitudinal dimensions of the posterior lingual airway. Results showed that the length of the bilateral mandibular rami and posterior lingual airway dimensions were significantly reduced postoperatively compared to controls (p < 0.01). After MDO, the length of mandibular rami and lateral retroglossal airway dimensions increased, α and β angles increased, while γ angle decreased (p < 0.05). Notably, the distance between bilateral mandibular angles, mandibular rami length, and lateral retroglossal airway dimensions had the strongest impact on swallowing score. In conclusion, mandibular width, length, and airway dimensions were closely linked to swallowing function in PRS patients. MDO effectively improved mandibular hypoplasia, improved swallowing dysfunction, and significantly enhanced quality of life for the patients.

Varicella zoster virus (VZV) causes chickenpox as the primary infection and then becomes latent in the cranial and spinal ganglia. VZV can reactivate with aging, immunosuppression, stress, and other factors. In our series of 15 patients with herpes zoster (HZ) central nervous system complications (8 males and 7 females, ages 41-86 years), we identified several types of complications: acute encephalitis, vasculitis, meningitis, and cranial nerve palsies, with acute limbic encephalitis (ALE) (n = 5) being particularly noteworthy. The elderly patient treated initially showed skin rash around the eye, altered consciousness, and medial temporal lesions on MRI; four similar patients were then observed. Aside from a few case reports, there are no comprehensive reports of HZ ALE. The HZ rashes of our five HZ ALE patients were mostly in the trigeminal nerve area, with two cases of disseminated rashes. Five patients had positive cerebrospinal fluid VZV polymerase chain reaction results, and MRI revealed medial temporal lobe lesions. Compared to HZ peripheral nerve complications, more variable invasive routes were presumed, via the brain-stem, vasculopathy root, meningeal spread, and viremia. The incidence of HZ is increasing worldwide, and clinicians should be aware of HZ ALE that shows fever, HZ skin rash, and altered consciousness.