Intractable & rare diseases research最新文献

Frailty is an independent risk factor linked to a higher likelihood of various diseases. With limited healthcare resources worldwide - especially in developing countries - the factors that contribute to frailty need to be understood across different populations and a universal model needs to be developed. This could help reduce the burden on healthcare systems and lessen the negative health effects of frailty. This review aims to summarize current evidence on the key factors influencing frailty and its impact on disease outcomes in different countries. The goal is to facilitate the development of strategies that can help prevent or even reverse frailty. Studies were included if they examined physical frailty using validated assessment tools in older adults and explored how various factors affect its development and progression. A comprehensive search of the PubMed database was conducted from March 1 to March 31, 2024 using the keywords "vulnerability" and "influencing factors." Studies published between January 1, 2001, and March 31, 2025 were considered. A total of 1,614 articles were initially identified, with 50 studies ultimately meeting the predefined inclusion and exclusion criteria. The findings indicate that frailty is influenced by a wide range of interrelated risk and protective factors, which in turn have various effects on different disease outcomes. These interconnected factors highlight both the complexity and the potential for targeted intervention. The review provides a comprehensive understanding of the factors associated with frailty in older adults across diverse settings and underscores the urgent need to develop a robust, evidence-based frailty model to facilitate the early identification, prevention, and possibly reversal of frailty.

Ulnar-mammary syndrome (UMS) is caused by TBX3 mutation and is a disorder characterized by altered limb, breast, tooth, hair, apocrine gland, and genital development. The clinical and genetic data of a 5.5^th boy with UMS were carefully analyzed. Clinical biochemical data, pituitary MRI, and whole exome gene detection were analyzed. The impact of the mutation and stability of TBX3 on the mRNA structure was analyzed by the M-fold program. Three-dimensional protein structures were calculated and analyzed. The patient presented with a hypoplastic left fifth finger, an absence of interphalangeal creases, a large space between the fourth and fifth fingers, no bending ability of the fifth finger, absent nipples, high palates, a flat nasal bridge, a micropenis, micro-testes, short stature and reduced axillary sweating. Pituitary magnetic resonance imaging (MRI) revealed pituitary gland hypoplasia with a thin pituitary stalk and loss of a strong signal in the posterior pituitary. A novel variant (c.1142_1146) in the TBX3 gene was detected in the proband and further verified by DNA sequencing. M-fold results revealed that the variant altered the mRNA structure and stability of the TBX3 gene. Clinical, genetic, and biochemical studies confirmed that the congenital normal idiopathic hypogonadotropic hypogonadism was associated with pituitary hypoplasia. After half a year of treatment with human chorionic gonadotropin (HCG), the micropenis was significantly improved. After 3.5 years of treatment with recombinant human growth hormone, the body height was largely improved. One novel variant of the TBX3 gene was confirmed in an UMS patient, which enriched the spectrum of TBX3 genotypes.

Mitochondria are present in cells throughout the body and play a crucial role in energy production. They contain their own DNA, and mutations in this DNA can lead to a reduction in pancreatic beta cells and decreased insulin secretion, contributing to the development of diabetes. Insulin therapy has been considered a rational treatment, as the primary issue is impaired insulin secretion, but it primarily serves as a coping mechanism. Recently, however, imeglimin ‒ a drug believed to influence various mitochondria-mediated processes ‒ has been introduced and is expected to offer therapeutic benefits for mitochondrial diabetes. Here, we report a case of successful glycemic control following the addition of imeglimin in a patient with mitochondrial diabetes mellitus. After starting imeglimin, the patient's blood glucose levels stabilized, and he continues treatment. While the molecular target of imeglimin remains unknown, it is possible that the drug may offer significant benefits for patients with mitochondrial diabetes mellitus.

In recessive monogenic diseases, individuals with a single pathogenic variant are typically asymptomatic and symptomatic disease is only observed in patients with two pathogenic variants. Assuming that disease only occurs where protein concentrations or activity are below 50% of normal (since in recessive diseases, most carriers are asymptomatic) some hypomorphic variants could be deleterious in association with a LoF variant, but nevertheless yield > 50% protein activity/concentration when homozygous. These types of variants would be very weakly eliminated by natural selection, if at all, and thus their frequency in the population could increase by genetic drift. Thus the population frequency criterion often used to qualify variants as benign would be misleading. One such variant may be c.5603A>T (p.Asn1868Ile), in ABCA4 (which causes Stargardt disease-1). This variant is pathogenic in trans with a null or missense variant but not when homozygous. We refer to these variants using the blend word "pathonign", since they are simultaneously pathogenic and benign in the population.

Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.

Primary rectal malignant melanoma with schistosomiasis is extremely rare. To date, only a few cases have been reported in the literature. Due to its high mortality rate, most patients with rectal malignant melanoma die within five years of diagnosis. However, the etiology and optimal treatment strategies remain controversial. A 79-year-old female patient presented with intermittent hematochezia for 2 months. Digital rectal examination, computed tomography (CT) scan, and colonoscopy revealed a fleshy mass measuring 3 cm in diameter in the rectum. A biopsy confirmed a preoperative diagnosis of malignant melanoma of the rectum, and a radical rectal resection was performed. Histopathological examination of the surgical specimen confirmed malignant melanoma, and numerous Schistosoma japonicum organisms were identified within the tumor. The patient subsequently received Dabrafenib and Trametinib therapy and remained disease-free for 5 years postoperatively, with no evidence of recurrence. This case highlights the potential treatment strategies for this rare carcinoma and underscores the need for further investigation into the relationship between schistosomiasis and melanoma.

Small bowel Crohn's disease (SBCD) presents unique surgical challenges due to segmental lesions and the need to balance radical resection with bowel function preservation. Current guidelines lack standardized surgical classifications, leading to variable outcomes. This study proposes a four-tier surgical strategy (R0-R3) tailored to lesion severity and functional preservation. R0 involves complete resection for localized mild lesions (creeping fat, no fibrosis) with ≥ 3 meters of residual bowel, using wide resection margins and anti-TNF-α therapy postoperatively. R1 preserves mild (non obstructive fibrotic) lesions and resects moderate to severe segments, with imaging surveillance support. R2 combines resection of severe lesions (fibrotic strictures/obstruction) with strictureplasty or partial preservation of moderate lesions to avoid short bowel syndrome. R3 employs temporary stoma creation for extensive complex lesions or high-risk patients, deferring definitive surgery until stabilization. This framework emphasizes individualized decision-making, prioritizing anatomical clearance, bowel conservation, and postoperative biologics to reduce recurrence. Compared to traditional approaches, the R0-R3 system enhances flexibility in managing heterogeneous SBCD, particularly in extensive disease. Future validation through multicenter trials and biomarker-driven predictive models is recommended to optimize long-term outcomes and quality of life. This strategy aligns with personalized surgical trends, addressing gaps in current guidelines by integrating lesion severity, functional prognosis, and staged interventions.

Rare and intractable diseases affect an estimated 3.5% to 5.9% of the global population but remain largely underserved in terms of diagnosis and treatment, with effective therapies available for only about 5% of conditions. This paper presents an overview of recent advances in artificial intelligence (AI) applications targeting these challenges. In diagnostic support, AI has been utilized to analyze genomic data and facial images, enhancing the accuracy and efficiency of identifying rare genetic syndromes. In therapeutic development, AI-driven analysis of biomedical knowledge graphs has enabled the prediction of potential treatment candidates for diseases lacking existing therapies. Additionally, generative models have accelerated drug discovery by identifying novel targets and designing candidate compounds, some of which have progressed to clinical evaluation. AI has also facilitated clinical trial support by automating patient eligibility screening using electronic health records, improving recruitment efficiency for trials that often struggle with small, geographically dispersed patient populations. Despite these advancements, challenges remain in ensuring data quality, interpretability of AI outputs, and the standardization of infrastructure across institutions. Moving forward, international data-sharing platforms integrating diverse modalities - clinical, genomic and image - are expected to play a pivotal role in enabling reliable, scalable, and ethically responsible AI applications. These developments hold the potential to transform the landscape of rare disease diagnosis, treatment, and research.

Sickle cell disease (SCD) is an orphan and extremely rare condition in Colombia and worldwide. However, a significant number of cases were identified in San Basilio de Palenque, Bolívar, enabling a pharmacotherapeutic follow-up study. This population represents a genetic bottleneck with limited admixture, making it crucial for further genetic and clinical research. Despite being largely unexplored due to lack of awareness and state neglect, SCD persists in this community. This study aimed to characterize and follow up pharmacotherapeutically on patients with SCD and traits. An observational, cross-sectional analytical study was conducted in 20 patients, assessing sociodemographic factors, pharmacotherapeutic follow-up, and pharmaceutical interventions. Results showed that 75% of patients were female, and 40% were homozygous. The most commonly used medications included folic acid, analgesics (paracetamol, tramadol, naproxen, codeine, ibuprofen, morphine), L-glutamine, and enalapril. Pain from vaso-occlusive crises and hemolytic episodes was the main reason for analgesic use. Notably, 62% of homozygous patients were not receiving baseline treatment with hydroxycarbamide, increasing their risk of complications. Addressing this gap through pharmaceutical interventions was one of the study's key contributions. In conclusion, this research highlights the need for a multidisciplinary approach to optimize treatment and improve the quality of life of affected patients. Given its genetic significance, San Basilio de Palenque represents a unique setting for further studies on SCD.

A tenosynovial giant cell tumor (TGCT) is a rare benign neoplasm arising from the tendon sheaths, bursae, or synovial lining of joints and is characterized by locally aggressive growth and the potential for recurrent disease. Surgery is still the main form of treatment for a TGCT, but these neoplasms, and most notably the diffuse type, exhibit a high proclivity for recurrence, thus highlighting the unmet clinical need for novel therapeutic modalities. At the same time, a subgroup of patients deemed ineligible for surgery are confronted with limited therapeutic alternatives, further underscoring the urgent need for innovative treatment paradigms. On February 14, 2025, the US Food and Drug Administration approved a new colony-stimulating factor 1 receptor (CSF1R) inhibitor, vimseltinib, for the treatment of symptomatic TGCTs in adult patients for whom surgical resection would likely result in severe functional limitations or serious complications. As the second-in-class CSF1R inhibitor approved for TGCTs, vimseltinib exhibits enhanced selectivity for CSF1R over pexidartinib, the first-in-class agent, suggesting potential translational benefits in safety profiles. The clinical utility of vimseltinib is anticipated to be further elucidated by real-world evidence and expanded clinical evaluations.