Nat Commun. 2023 Jul 11;14(1):4109. doi: 10.1038/s41467-023-39645-5.

ABSTRACT

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

PMID:37433783 | DOI:10.1038/s41467-023-39645-5

Am J Manag Care. 2023 Jun;29(7 Suppl):S120-S126. doi: 10.37765/ajmc.2023.89388.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatally progressive degenerative disease, with many patients succumbing to the condition within 3 to 5 years after diagnosis. It is a rare, orphan disease with an estimated US prevalence of 25,000 patients. Patients with ALS and their caregivers are faced with a substantial financial burden as a result of the condition, as ALS has an estimated national financial burden of $1.03 billion. A significant driver of the patient financial burden includes the continued need for caregiver support as the weakening of muscles progresses to dysphagia and dyspnea, making it difficult to complete activities of daily living as the disease progresses. Caregivers also experience financial burdens, as well as feelings of anxiety, depression, and decreased quality of life. In addition to needed caregiver support, patients with ALS and their families also incur substantial nonmedical costs including travel expenses, home modifications such as ramps, and indirect costs such as productivity loss. Due to the wide range of clinical symptoms that patients may exhibit when first presenting with ALS symptoms, diagnosis is often delayed, which negatively affects patient outcomes and impacts missed opportunity for clinical trial recruitment aimed at developing new disease-modifying therapies. Additionally, delay in diagnosis and referral to ALS treatment centers results in increased overall health care costs. Telemedicine may be a tool used to promote timely care from an ALS treatment center in addition to clinical trial participation for those patients who cannot overcome mobility barriers for care. Currently, 4 therapies are approved for the treatment of ALS. Riluzole has demonstrated modest improvement in survival. Other recently approved therapies include oral edaravone, a combination therapy of sodium phenylbutyrate and taurursodiol (PB/TURSO), and tofersen, which is administered intrathecally and approved under an accelerated approval. Long-term studies have shown PB/TURSO to have a dual benefit on survival and function. The Institute for Clinical and Economic Review (ICER) 2022 Evidence Report for ALS does not value the high price points of edaravone and PB/TURSO as cost-effective based on the current evidence, despite valuing the need for new treatment options for this patient population.

PMID:37433093 | DOI:10.37765/ajmc.2023.89388

Cancer Res. 2023 Jul 11:CAN-23-0013. doi: 10.1158/0008-5472.CAN-23-0013. Online ahead of print.

ABSTRACT

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy of paclitaxel given by IP administration using three orthotopic patient-derived xenograft (PDX) models of AA established in immunodeficient NSG mice. Weekly IP paclitaxel treatment dramatically reduced AA tumor growth in all three PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration, IP delivery of paclitaxel was more effective with reduced systemic side effects in mice. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.

PMID:37433032 | DOI:10.1158/0008-5472.CAN-23-0013

Pediatrics. 2023 Aug 1;152(2):e2022061027. doi: 10.1542/peds.2022-061027.

ABSTRACT

Imaging modalities such as computed tomography (CT) are critical for monitoring musculoskeletal abnormalities in children with rare diseases. However, CT exposes patients to radiation, which limits its utility in the clinical setting, particularly during longitudinal evaluation. Synthetic CT is a novel, noncontrast, and rapid MRI method that can provide CT-like images without any radiation exposure and is easily performed in conjunction with traditional MRI, which detects soft-tissue and bone marrow abnormalities. To date, an evaluation of synthetic CT in pediatric patients with rare musculoskeletal diseases has been lacking. In this case series, the capability of synthetic CT to identify musculoskeletal lesions accurately in 2 rare disease patients is revealed. In Case 1, synthetic CT, in agreement with routine CT, identified an intraosseous lesion in the right femoral neck in a 16-year-old female with fibrous dysplasia, whereas standard-of-care MRIs additionally revealed mild surrounding edema-like bone marrow signal. For Case 2, synthetic CT applied to a 12-year-old female with fibrodysplasia ossificans progressiva revealed heterotopic ossification present along the cervical spine that had caused the fusion of multiple vertebrae. Our evaluation of synthetic CT offers important insights into the feasibility and utility of this methodology in children with rare diseases affecting the musculoskeletal system.

PMID:37416976 | PMC:PMC10389770 | DOI:10.1542/peds.2022-061027

Healthc Pap. 2023 Apr;21(2):11-12. doi: 10.12927/hcpap.2023.27111.

ABSTRACT

The comments provided by Rawson and Adams (2023) miss the mark of our articles (Sirrs et al. 2023a, 2023b). We agree that the patient perspective is critical and that patients with "rare diseases have a right to healthcare and have huge unmet needs …" (p. 7). However, we challenge Rawson and Adams' (2023) thesis that keeping drug prices higher in Canada than in most other countries would solve the problem of access to therapies for rare diseases that have no available treatment.

PMID:37417344 | DOI:10.12927/hcpap.2023.27111

Healthc Pap. 2023 Apr;21(2):4-10. doi: 10.12927/hcpap.2023.27112.

ABSTRACT

Sirrs et al. (2023a) discuss what they consider "explosive growth" (p. 11) in the research and development (R&D) and commercialization of expensive drugs for rare diseases (DRDs). They contend that the "status quo is no longer an option" (Sirrs et al. 2023b: 75), so it is critical to drastically reduce the prices of DRDs and/or ration access.

PMID:37417343 | DOI:10.12927/hcpap.2023.27112

Epigenetics. 2023 Dec;18(1):2230670. doi: 10.1080/15592294.2023.2230670.

ABSTRACT

Epimutations are rare alterations of the normal DNA methylation pattern at specific loci, which can lead to rare diseases. Methylation microarrays enable genome-wide epimutation detection, but technical limitations prevent their use in clinical settings: methods applied to rare diseases' data cannot be easily incorporated to standard analyses pipelines, while epimutation methods implemented in R packages (ramr) have not been validated for rare diseases. We have developed epimutacions, a Bioconductor package (https://bioconductor.org/packages/release/bioc/html/epimutacions.html). epimutacions implements two previously reported methods and four new statistical approaches to detect epimutations, along with functions to annotate and visualize epimutations. Additionally, we have developed an user-friendly Shiny app to facilitate epimutations detection (https://github.com/isglobal-brge/epimutacionsShiny) to non-bioinformatician users. We first compared the performance of epimutacions and ramr packages using three public datasets with experimentally validated epimutations. Methods in epimutacions had a high performance at low sample sizes and outperformed methods in ramr. Second, we used two general population children cohorts (INMA and HELIX) to determine the technical and biological factors that affect epimutations detection, providing guidelines on how designing the experiments or preprocessing the data. In these cohorts, most epimutations did not correlate with detectable regional gene expression changes. Finally, we exemplified how epimutacions can be used in a clinical context. We run epimutacions in a cohort of children with autism disorder and identified novel recurrent epimutations in candidate genes for autism. Overall, we present epimutacions a new Bioconductor package for incorporating epimutations detection to rare disease diagnosis and provide guidelines for the design and data analyses.

PMID:37409354 | DOI:10.1080/15592294.2023.2230670

Nat Med. 2023 Jul;29(7):1615-1616. doi: 10.1038/s41591-023-02417-1.

NO ABSTRACT

PMID:37400642 | DOI:10.1038/s41591-023-02417-1

Orphanet J Rare Dis. 2023 Jul 3;18(1):176. doi: 10.1186/s13023-023-02725-2.

ABSTRACT

In France, all patients followed by Rare Disease (RD) expert centers have to be registered in the National Rare Disease Registry (BNDMR). This database collects a minimum data set including diagnosis coded using the Orphanet nomenclature. Overall, 753,660 patients were recorded from 2007 to March 2022 including 493,740 with at least one rare disease diagnosis. Among these rare disease diagnoses, 1,300 diagnoses gathered between 10 and 70 patients and 792 gathered more than 70 patients, corresponding to more than one patient per million inhabitants. A total of 47 rare disease diagnoses with point prevalence or incidence reported in the literature below 1/1,000,000 have more than 70 patients in the BNDMR, suggesting larger BNDMR cohorts than expected from reported literature. As a conclusion, our national RD registry is a great resource to facilitate patients' recruitment in clinical research and a better understanding of RD natural history and epidemiology.

PMID:37400917 | PMC:PMC10318625 | DOI:10.1186/s13023-023-02725-2

Front Public Health. 2023 Jun 16;11:1198368. doi: 10.3389/fpubh.2023.1198368. eCollection 2023.

ABSTRACT

BACKGROUND: Failing to provide social support to cover healthcare costs for rare diseases would lead to great financial distress for the patients and their families. People from countries without a well-developed health safety-net are particularly vulnerable. Existing literature on rare diseases in China focuses on the unmet needs for care of the patients and the difficulties of caregivers and physicians. Very few studies examine the state of social safety-net, the unresolved issues and whether the current localized arrangements are sufficient. This study aimed to gain in-depth knowledge of the current policy system and make sense of the local varieties, which would be essential for developing strategies for future policy changes.

METHODS: This systematic policy review focuses on the provincial level policies on subsidizing the healthcare costs for people with rare diseases in China. The cut-off point for the policies was March 19, 2022. The researchers coded the healthcare cost reimbursement policies and identified the different provincial level models based on the usage of reimbursement components in each provinces reimbursement arrangements.

RESULTS: 257 documents were collected. Five provincial level models (Process I, II, III, IV and V) have been identified with the five components across the country: Basic Medical Insurance for Outpatient Special Diseases (OSD), Catastrophic Medical Insurance for Rare Diseases (CMIRD), Medical Assistance for Rare Diseases (MARD), Special Fund for Rare Diseases (SFRD) and Mutual Medical Fund (MMF). The local health safety-net in each region is a combination of one or more of the five processes. Regions vary greatly in their rare diseases coverage and reimbursement policies.

CONCLUSION: In China, the provincial health authorities have developed some level of social protection for rare disease patients. However, there are still gaps regarding coverage and regional inequality; and there is room for a more integrated healthcare safety-net for people suffering from rare diseases at the national level.

PMID:37397721 | PMC:PMC10311551 | DOI:10.3389/fpubh.2023.1198368

Zhonghua Nei Ke Za Zhi. 2023 Jul 1;62(7):869-875.

ABSTRACT

罕见病影响全球3亿多人口，提高疾病筛查与诊断能力对改善患者预后、减少医疗资源消耗至关重要。随着信息技术飞速进步，临床决策支持系统（clinical decision support system，CDSS）为疾病筛查与诊断提供了技术支撑，特别是在病历电子化时代，CDSS在数据集成、行为干预等方面有了更大进展，但同时亦面临诸多挑战。本文通过对罕见病 CDSS的进展进行综述，剖析存在的挑战与发展方向，为国内罕见病筛诊领域CDSS的建设提供参考。.

PMID:37394860

Bioinformatics. 2023 Jul 1;39(7):btad418. doi: 10.1093/bioinformatics/btad418.

ABSTRACT

MOTIVATION: Knowledge graphs (KGs) are a powerful approach for integrating heterogeneous data and making inferences in biology and many other domains, but a coherent solution for constructing, exchanging, and facilitating the downstream use of KGs is lacking.

RESULTS: Here we present KG-Hub, a platform that enables standardized construction, exchange, and reuse of KGs. Features include a simple, modular extract-transform-load pattern for producing graphs compliant with Biolink Model (a high-level data model for standardizing biological data), easy integration of any OBO (Open Biological and Biomedical Ontologies) ontology, cached downloads of upstream data sources, versioned and automatically updated builds with stable URLs, web-browsable storage of KG artifacts on cloud infrastructure, and easy reuse of transformed subgraphs across projects. Current KG-Hub projects span use cases including COVID-19 research, drug repurposing, microbial-environmental interactions, and rare disease research. KG-Hub is equipped with tooling to easily analyze and manipulate KGs. KG-Hub is also tightly integrated with graph machine learning (ML) tools which allow automated graph ML, including node embeddings and training of models for link prediction and node classification.

AVAILABILITY AND IMPLEMENTATION: https://kghub.org.

PMID:37389415 | PMC:PMC10336030 | DOI:10.1093/bioinformatics/btad418

BMC Genom Data. 2023 Jun 30;24(1):36. doi: 10.1186/s12863-023-01137-2.

ABSTRACT

OBJECTIVES: Inborn error of immunity (IEI) comprises a broad group of inherited immunological disorders that usually display an overlap in many clinical manifestations challenging their diagnosis. The identification of disease-causing variants from whole-exome sequencing (WES) data comprises the gold-standard approach to ascertain IEI diagnosis. The efforts to increase the availability of clinically relevant genomic data for these disorders constitute an important improvement in the study of rare genetic disorders. This work aims to make available WES data of Brazilian patients' suspicion of IEI without a genetic diagnosis. We foresee a broad use of this dataset by the scientific community in order to provide a more accurate diagnosis of IEI disorders.

DATA DESCRIPTION: Twenty singleton unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil were enrolled in our study. Half of the patients were male with mean ages of 9 ± 3, while females were 12 ± 10 years old. The WES was performed in the Illumina NextSeq platform with at least 90% of sequenced bases with a minimum of 30 reads depth. Each sample had an average of 20,274 variants, comprising 116 classified as rare pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics and the Association (ACMG) guidelines. The genotype-phenotype association was impaired by the lack of detailed clinical and laboratory information, besides the unavailability of molecular and functional studies which, comprise the limitations of this study. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Therefore, by making these data available, we aim to increase the number of WES data from Brazilian samples despite contributing to the study of monogenic IEI-disorders.

PMID:37391719 | PMC:PMC10314602 | DOI:10.1186/s12863-023-01137-2

Front Immunol. 2023 Jun 14;14:1195988. doi: 10.3389/fimmu.2023.1195988. eCollection 2023.

ABSTRACT

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.

PMID:37388737 | PMC:PMC10303123 | DOI:10.3389/fimmu.2023.1195988

Ann Agric Environ Med. 2023 Jun 26;30(2):394-397. doi: 10.26444/aaem/166324. Epub 2023 Jun 20.

ABSTRACT

In December 2019, an atypical form of severe pneumonia emerged in Wuhan in China's Hubei province, which in February 2020 was named COVID-19. The disease may have features of interstitial pneumonia and severe respiratory failure requiring intensive oxygen therapy. Spontaneous pneumomediastinum is a rare pathological condition with air in the mediastinum outside the trachea, oesophagus and bronchi. It is potentially life-threatening complication of both invasive and non-invasive mechanical ventilation. There have been reports that it may complicate the course of interstitial lung disease in the course of COVID-19. The report describes two cases of young patients who spontaneously developed this complication. Immediate diagnose is important in order to applicate adequate procedures.

PMID:37387393 | DOI:10.26444/aaem/166324

Stud Health Technol Inform. 2023 Jun 29;305:444-447. doi: 10.3233/SHTI230527.

ABSTRACT

The objective is to identify clinical screening criteria for a rare disease,- Behcet's disease and to analyse the digitally structured and unstructured components of the Identified Clinical criteria, build a clinical archetype using OpenEHR editor to be used by learning health support systems for clinical screening of the disease. Methods/Search Strategy: Literature search was conducted, 230 papers were screened, and finally 5 papers were retained, analysed and summarised. Digital Analysis of the clinical criteria was done and a sandardised clinical knowledge model of the same was built using OpenEHR editor, underpinned by OpenEHR international standards. Results The structured and unstructured components of the criteria analysed to be able to incorporate them in a learning health system to screen patients for Behcet's disease. SNOMED CT and Read codes were assigned to the structured componenets. Possible misdiagnosis were identified, along with their corresponding clinical terminology codes that can be incorporated in the Electronic Health Record systems. Conclusion: The identified clinical screening was digitally analysed which can be embedded into a clinical decision support system that can be plugged onto the primary care systems to give an alert to the clinicians if a patient needs to be screened for a rare disease, for e.g., Behcet's.

PMID:37387061 | DOI:10.3233/SHTI230527

Stud Health Technol Inform. 2023 Jun 29;305:139-140. doi: 10.3233/SHTI230443.

ABSTRACT

Current challenges of rare diseases need to involve patients, physicians, and the research community to generate new insights on comprehensive patient cohorts. Interestingly, the integration of patient context has been insufficiently considered, but might tremendously improve the accuracy of predictive models for individual patients. Here, we conceptualized an extension of the European Platform for Rare Disease Registration data model with contextual factors. This extended model can serve as an enhanced baseline and is well-suited for analyses using artificial intelligence models for improved predictions. The study is an initial result that will develop context-sensitive common data models for genetic rare diseases.

PMID:37386977 | DOI:10.3233/SHTI230443

Indian J Pediatr. 2023 Jun 30. doi: 10.1007/s12098-023-04665-y. Online ahead of print.

ABSTRACT

Bronchiectasis is a pathologic state of conducting airways manifested radiographically by evidence of bronchial dilation and clinically by chronic productive cough. Considered an "orphan disease" for long, it remains a major contributor to morbidity and mortality in both developed and underdeveloped countries. With the advances in the medical field accompanied by widespread access to vaccines and antibiotics, improved health services and better access to nutrition, the incidences of bronchiectasis have markedly decreased, particularly in developed countries. This review summarizes the current knowledge pertaining to the clinical definition, etiology, clinical approach and management related to pediatric bronchiectasis.

PMID:37389774 | DOI:10.1007/s12098-023-04665-y

J Am Coll Cardiol. 2023 Jul 4;82(1):30-40. doi: 10.1016/j.jacc.2023.04.046.

ABSTRACT

BACKGROUND: Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease. Interleukin (IL)-1α and IL-1β are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence. We created a phase II/III study with a new IL-1 inhibitor-goflikicept in IRP.

OBJECTIVES: This study sought to evaluate the efficacy and safety of goflikicept treatment in patients with IRP.

METHODS: We conducted a 2-center open-label study of goflikicept in patients with IRP with and without recurrence at time of enrollment. The study consisted of 4 periods: screening, run-in (open-label treatment period), randomized withdrawal, and follow-up. Patients with clinical response to goflikicept in the run-in period were randomized (1:1) to a placebo-controlled withdrawal period, where the time to first pericarditis recurrence (primary endpoint) was evaluated.

RESULTS: We enrolled 22 patients, and 20 of these patients were randomized. Reduction of C-reactive protein level accompanied by reduction of chest pain and pericardial effusion compared to baseline was demonstrated during the run-in period. Recurrence of pericarditis occurred in 9 of 10 patients in the placebo group, and there were no recurrence events in goflikicept group within 24 weeks after randomization (P < 0.001). A total of 122 adverse events were reported in 21 patients (95.5%), with no deaths and no new safety signals identified for goflikicept.

CONCLUSIONS: Treatment with goflikicept prevented recurrences and maintained IRP remission with a favorable risk-benefit ratio. Goflikicept reduced the risk of recurrence compared with placebo. (Study to Evaluate the Efficacy and Safety of RPH-104 Treatment in Patients With Idiopathic Recurrent Pericarditis; NCT04692766).

PMID:37380301 | DOI:10.1016/j.jacc.2023.04.046

Genes (Basel). 2023 Jun 10;14(6):1241. doi: 10.3390/genes14061241.

ABSTRACT

Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.

PMID:37372421 | DOI:10.3390/genes14061241