Lancet Haematol. 2023 Aug;10(8):e687-e694. doi: 10.1016/S2352-3026(23)00182-5. Epub 2023 Jul 11.

ABSTRACT

Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.

PMID:37451300 | DOI:10.1016/S2352-3026(23)00182-5

Am J Hum Genet. 2023 Jul 6:S0002-9297(23)00213-6. doi: 10.1016/j.ajhg.2023.06.012. Online ahead of print.

ABSTRACT

Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.

PMID:37451268 | DOI:10.1016/j.ajhg.2023.06.012

Head Neck. 2023 Jul 14. doi: 10.1002/hed.27457. Online ahead of print.

ABSTRACT

Sinonasal cancer is a heterogeneous orphan disease of diverse histologies, each with distinct clinical, oncologic, and toxicity profiles. Because of the comparative rarity of these cancers, sinonasal cancers are treated as a grouped diagnosis despite their clinical and biological heterogeneity. Multimodality treatment with a combination of surgery, chemotherapy, and/or radiotherapy is the standard-of-care for advanced-stage patients but there are few surveillance or follow-up practice guidelines or formalized survivorship care pathways. A scoping literature review was conducted via PubMed, EMBASE, and Google Scholar. A total of 112 studies were included, which were grouped along the following topics: surveillance, second primary tumors, quality of life, and symptom burden. Sinonasal cancer tends to exhibit a higher rate of local failure and occur in a delayed fashion compared to mucosal malignancies of the head and neck. Moreover, the site of failure and time-varying risk of recurrence is histology-specific. Following multimodality treatment of the skull base, patients may experience endocrine, visual, auditory, sinonasal, olfactory, and neurocognitive deficits, as well as psychosocial impairments that impact multiple physical and neuropsychological domains, resulting in diminished quality of life. Sinonasal cancer patients would benefit from tailored, histology-specific survivorship programs to address the recurrence, second primary, and functional impairments resulting from disease and treatment toxicity.

PMID:37449544 | DOI:10.1002/hed.27457

J Dermatolog Treat. 2023 Dec;34(1):2235443. doi: 10.1080/09546634.2023.2235443.

ABSTRACT

Dissecting cellulitis of the scalp (DCS) is a rare recurrent inflammatory disease of unknown etiology. Ideal treatment of DCS remains unclear. We treated DCS with 2940-nm erbium Yttrium-aluminum-garnet (YAG) laser in 12 patients and assessed the efficacy by Physicians Global Assessment (PGA), number of inflammatory nodules, abscesses, and area of alopecia. After a mean treating session of 2.2 months, 10 patients reached PGA 0 (initial PGA 1) or 1 (initial PGA ≥2). At the end of treatment, there was 84%, 100%, and 74% regression in nodules, abscesses, and alopecia area, respectively. No severe adverse effect was observed. 2940-nm erbium: YAG laser may be an effective and safe way to treat DCS resistant to other therapies.

PMID:37439301 | DOI:10.1080/09546634.2023.2235443

BMJ Case Rep. 2023 Jul 12;16(7):e252672. doi: 10.1136/bcr-2022-252672.

ABSTRACT

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a multisystemic rare genetic disorder characterised by abnormalities of the immune system. We report the ocular features of APECED in two siblings of an Indian family, out of four who are still living. The ocular features of this disorder primarily included madarosis, refractive error, heterochromia, corneal opacity and peripheral retinal pigment epithelium degeneration. There is marked phenotypical heterogeneity in this disorder. We found differences even between monozygotic twins. While one of the twins did not have any ocular issues, the other one did. The child with corneal involvement was the most symptomatic; however, it did not lead to visual impairment. On genetic workup, homozygous p.M1V mutation was found in exon 1 of AIRE gene that has not been studied in Indian subjects with APECED. To the best of our knowledge, there is no report in literature describing ocular features of APECED in an Indian family with distinctive genetic involvement.

PMID:37437958 | DOI:10.1136/bcr-2022-252672

Eur Respir Rev. 2023 Jul 12;32(169):220200. doi: 10.1183/16000617.0200-2022. Print 2023 Sep 30.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by pulmonary, otological and sino-nasal manifestations. Well-defined clinical outcome measures are needed in such rare diseases research to improve follow-up and treatments. Pulmonary outcome measures have recently been described. The aim of this study was to identify ear and upper airway outcome measures that could be used for longitudinal follow-up of individuals with PCD.

METHODS: A scoping review was performed by systematically searching MEDLINE, Embase and Cochrane Database of Systematic Reviews online databases for studies published from January 1996 to March 2022 that included at least 10 adult or paediatric PCD patients and reported ear and upper airway outcomes.

RESULTS: 33 studies (1794 patients) were included. 10 ear and upper airway outcomes were reported. 17 studies reported audiometry, 16 reported otoscopic findings, and 13 reported rhinoscopic findings and sinus imaging. Health-related quality of life questionnaires were performed in seven studies. There was a high variability in definitions and measurement of outcomes between studies.

CONCLUSIONS: This scoping review highlights the lack of data regarding ear and upper airway outcomes in PCD. It also reports a high heterogeneity in outcome definitions or measures. We provide well-founded specific suggestions to standardise ear and upper airway outcome definitions and reporting for future PCD research studies.

PMID:37437912 | PMC:PMC10336562 | DOI:10.1183/16000617.0200-2022

Cien Saude Colet. 2023 Jul;28(7):1881-1889. doi: 10.1590/1413-81232023287.18122022. Epub 2023 Mar 15.

ABSTRACT

Rare or orphan diseases have played an important role in the pharmaceutical industry. On the other hand, the impact of new technologies derived from genomic research has been growing in this industry, with new drugs being launched on the market at unsustainable prices for health systems and patients. This double tendency poses important and growing challenges to public policies on Health Technology Assessment, whose hegemonic rationale is based on cost-benefit analysis between therapies. The very high prices of these drugs require revisiting this rationale and the recent negotiations between the Brazilian Ministry of Health and Novartis regarding a possible risk-sharing agreement for the incorporation of the drug Zolgensma is an opportunity for this revisitation.

PMID:37436303 | DOI:10.1590/1413-81232023287.18122022

Nature. 2023 Jul 12. doi: 10.1038/s41586-023-06277-0. Online ahead of print.

ABSTRACT

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

PMID:37438524 | DOI:10.1038/s41586-023-06277-0

Eur J Dermatol. 2023 Apr 1;33(2):157-159. doi: 10.1684/ejd.2023.4455.

ABSTRACT

BACKGROUND: Chromosome 15q24 microdeletion is a rare genetic disorder, and the skin manifestations are poorly documented.

OBJECTIVES: In this cross-sectional observational study using social media (Facebook), we investigated the prevalence of atopic dermatitis in 15q24 microdeletion syndrome.

MATERIALS & METHODS: Parents and caregivers of a child with the syndrome were asked to participate using a validated self-reporting questionnaire.

RESULTS: In total, 60 participants completed the questionnaire. The prevalence of atopic dermatitis was 35% among patients with chromosome 15q24 deletion. Few patients received treatment according to international guidelines.

CONCLUSION: We describe the largest cohort of patients with 15q24 microdeletion syndrome, revealing a high prevalence of atopic dermatitis. Patients with 15q24 microdeletion syndrome should undergo dermatological evaluation for screening and management of atopic dermatitis. Approaching individuals via social media is a successful strategy, resulting in good information which may be used to counsel families.

PMID:37431118 | DOI:10.1684/ejd.2023.4455

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