Am J Hum Genet. 2022 Nov 3;109(11):1947-1959. doi: 10.1016/j.ajhg.2022.10.002.

ABSTRACT

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.

PMID:36332610 | DOI:10.1016/j.ajhg.2022.10.002

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2022 Nov;65(11):1117-1118. doi: 10.1007/s00103-022-03604-0. Epub 2022 Nov 4.

NO ABSTRACT

PMID:36331592 | PMC:PMC9636115 | DOI:10.1007/s00103-022-03604-0

Syst Rev. 2022 Nov 3;11(1):235. doi: 10.1186/s13643-022-02105-0.

ABSTRACT

BACKGROUND: Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present.

MAIN TEXT: A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto.

CONCLUSION: Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

PMID:36329524 | PMC:PMC9635082 | DOI:10.1186/s13643-022-02105-0

Neurol Genet. 2022 Oct 25;8(6):e200027. doi: 10.1212/NXG.0000000000200027. eCollection 2022 Dec.

ABSTRACT

BACKGROUND AND OBJECTIVES: Centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene, DNM2, is a rare neuromuscular disease about which little is known. The objective of this study was to describe the range of clinical presentations and subsequent natural history of DNM2-related CNM.

METHODS: Pediatric and adult patients with suspicion for a CNM diagnosis and confirmed heterozygous pathogenic variants in DNM2 were ascertained between December 8, 2000, and May 1, 2019. Data were collected through a retrospective review of genetic testing results, clinical records, and pathology slides combined with patient-reported clinical findings via questionnaires.

RESULTS: Forty-two patients with DNM2-related CNM, whose ages ranged from 0.95 to 75.76 years at most recent contact, were enrolled from 34 families in North or South America and Europe. There were 8 different DNM2 pathogenic variants within the cohort. Of the 32 biopsied patients, all had histologic features of CNM. The disease onset was in infancy or childhood in 81% of the cohort, and more than half of the patients had high arched palates, indicative of weakness in utero. Ambulation was affected in nearly all (92%) the patients, and while the rapidity of progression was variable, most (67%) reported a "deteriorating course." Ptosis, ophthalmoparesis, facial weakness, dysphagia, and respiratory insufficiency were commonly reported. One-third of the patients experienced restricted jaw mobility. Certain pathogenic variants appear to correlate with a more severe phenotype.

DISCUSSION: DNM2-related CNM has a predominantly early-onset, often congenital, myopathy resulting in progressive difficulty with ambulation and occasionally bulbar and respiratory dysfunction. This detailed characterization of the phenotype provides important information to support clinical trial readiness for future disease-modifying therapies.

PMID:36324371 | PMC:PMC9621335 | DOI:10.1212/NXG.0000000000200027

Aliment Pharmacol Ther. 2022 Nov 2. doi: 10.1111/apt.17251. Online ahead of print.

ABSTRACT

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive liver disease with poor prognosis and no effective therapies to prevent progression. An aetiopathological link between PSC and gastrointestinal microbial dysbiosis has been suggested.

AIM: To evaluate all potential medical therapies which may exert their effect in PSC by modulation of the gut-liver axis.

METHODS: We conducted a comprehensive scoping review of PubMed and Cochrane Library, including all articles evaluating an intervention aimed at manipulating the gastrointestinal microbiome in PSC.

RESULTS: A wide range of therapies proposed altering the gastrointestinal microbiome for the treatment of PSC. In particular, these considered antibiotics including vancomycin, metronidazole, rifaximin, minocycline and azithromycin. However, few therapies have been investigated in randomised, placebo-controlled trials. Vancomycin has been the most widely studied antibiotic, with improvement in alkaline phosphatase reported in two randomised controlled trials, but with no data on disease progression. Unlike antibiotics, strategies such as faecal microbiota transplantation and dietary therapy can improve microbial diversity. However, since these have only been tested in small numbers of patients, robust efficacy data are currently lacking.

CONCLUSIONS: The gut-liver axis is increasingly considered a potential target for the treatment of PSC. However, no therapies have been demonstrated to improve transplant-free survival. Innovative and well-designed clinical trials of microbiome-targeted therapies with long-term follow-up are required for this orphan disease.

PMID:36324251 | DOI:10.1111/apt.17251

Zhonghua Zhong Liu Za Zhi. 2022 Oct 23;44(10):1003-1010. doi: 10.3760/cma.j.cn112152-20220803-00531.

NO ABSTRACT

PMID:36319447 | DOI:10.3760/cma.j.cn112152-20220803-00531

Zhonghua Er Ke Za Zhi. 2022 Nov 2;60(11):1097-1099. doi: 10.3760/cma.j.cn112140-20220919-00815.

NO ABSTRACT

PMID:36319139 | DOI:10.3760/cma.j.cn112140-20220919-00815

JAMA. 2022 Nov 1;328(17):1680. doi: 10.1001/jama.2022.19801.

NO ABSTRACT

PMID:36318147 | DOI:10.1001/jama.2022.19801

MMW Fortschr Med. 2022 Nov;164(19):25-26. doi: 10.1007/s15006-022-2044-z.

NO ABSTRACT

PMID:36310264 | DOI:10.1007/s15006-022-2044-z

Brain. 2022 Oct 31:awac391. doi: 10.1093/brain/awac391. Online ahead of print.

ABSTRACT

In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood (median: 24 months, IQR = 24), a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps, and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale (SPRS) scores, SPATAX Disability Scores and the 4-Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney-U test, p < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, p = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.

PMID:36315648 | DOI:10.1093/brain/awac391

Health Expect. 2022 Dec;25(6):3175-3191. doi: 10.1111/hex.13625. Epub 2022 Oct 28.

ABSTRACT

INTRODUCTION: Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs.

METHODS: We used a mixed-methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open-ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively.

RESULTS: Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co-developed, centralized, high-level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision-making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development.

CONCLUSION: This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy.

PATIENT OR PUBLIC CONTRIBUTION: In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions.

PMID:36307981 | PMC:PMC9700154 | DOI:10.1111/hex.13625

Orphanet J Rare Dis. 2022 Oct 28;17(1):396. doi: 10.1186/s13023-022-02552-x.

ABSTRACT

BACKGROUND: More people with rare diseases likely receive disease education and emotional and practical support from peer-led support groups than any other way. Most rare-disease support groups are delivered outside of the health care system by untrained leaders. Potential benefits may not be achieved and harms, such as dissemination of inaccurate information, may occur. Our primary objective was to evaluate the effects of a rare-disease support group leader education program, which was developed collaboratively by researchers, peer support group leaders, and patient organization leaders, compared to waitlist control, on peer leader self-efficacy among scleroderma support group leaders.

METHODS: The trial was a pragmatic, two-arm partially nested randomised controlled trial with 1:1 allocation into intervention or waitlist control. Eligible participants were existing or candidate peer support group leaders affiliated with a scleroderma patient organization. Leader training was delivered in groups of 5-6 participants weekly for 13 weeks in 60-90 min sessions via the GoToMeeting® videoconferencing platform. The program included 12 general leader training modules and one module specific to scleroderma. Primary outcome was leader self-efficacy, measured by the Support Group Leader Self-efficacy Scale (SGLSS) immediately post-intervention. Secondary outcomes were leader self-efficacy 3 months post-intervention; emotional distress, leader burnout, and volunteer satisfaction post-intervention and 3 months post-intervention; and program satisfaction among intervention participants post-intervention.

RESULTS: One hundred forty-eight participants were randomised to intervention (N = 74) or waitlist (N = 74). Primary outcome data were provided by 146 (99%) participants. Mean number of sessions attended was 11.4 (standard deviation = 2.6). Mean program satisfaction score (CSQ-8) was 30.3 (standard deviation = 3.0; possible range 8-32). Compared to waitlist control, leader self-efficacy was higher post-intervention [SGLSS; 16.7 points, 95% CI 11.0-22.3; standardized mean difference (SMD) 0.84] and 3 months later (15.6 points, 95% CI 10.2-21.0; SMD 0.73); leader volunteer satisfaction was significantly higher at both assessments, emotional distress was lower post-intervention but not 3 months later, and leader burnout was not significantly different at either assessment.

CONCLUSIONS: Peer support group leader education improved leader self-efficacy substantially. The program could be easily adapted for support group leaders in other rare diseases.

TRIAL REGISTRATION: NCT03965780 ; registered on May 29, 2019.

PMID:36307891 | PMC:PMC9616616 | DOI:10.1186/s13023-022-02552-x

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2022 Nov;65(11):1151-1158. doi: 10.1007/s00103-022-03606-y. Epub 2022 Oct 28.

ABSTRACT

People with rare diseases (RDs) have particular potential to benefit from digitisation in the healthcare system. The National Action Alliance for People with Rare Diseases (NAMSE) has campaigned for SE to be specifically taken into account in the digitisation of the healthcare system in Germany. The topic was addressed within the Medical Informatics Initiative (MII) of the Federal Ministry of Education and Research (BMBF). Here, starting with university hospitals, a digital infrastructure is currently being established for the data protection-compliant multiple use of standardised care and research data. Since 2020, part of the initiative has been the CORD-MI project (Collaboration on Rare Diseases) in which university hospitals and other partners throughout Germany have joined forces to improve patient care and research in the field of rare diseases.This article highlights how the MII takes into account the concerns of SE and what opportunities the "new routine data" obtained offer. A SE module was included in the "MII core data set" - an information model based on the data standard fast healthcare interoperability resources (FHIR). Data collected in the context of care and research routines can thus be exchanged between the participating institutions in the future and support, for example, diagnosis, therapy selection and research projects in the field of SE. The CORD-MI project has set itself the goal of obtaining insights into the care situation of people with SE with the help of exemplary questions and then drawing conclusions for further necessary steps in the area of digitalisation.

PMID:36305897 | PMC:PMC9636299 | DOI:10.1007/s00103-022-03606-y

Orphanet J Rare Dis. 2022 Oct 27;17(1):389. doi: 10.1186/s13023-022-02529-w.

ABSTRACT

Scientific advances in the understanding of the genetics and mechanisms of many rare diseases with previously unknown etiologies are inspiring optimism in the patient, clinical, and research communities and there is hope that disease-specific treatments are on the way. However, the rare disease community has reached a critical point in which its increasingly fragmented structure and operating models are threatening its ability to harness the full potential of advancing genomic and computational technologies. Changes are therefore needed to overcome these issues plaguing many rare diseases while also supporting economically viable therapy development. In "Data silos are undermining drug development and failing rare disease patients (Orphanet Journal of Rare Disease, Apr 2021)," we outlined many of the broad issues underpinning the increasingly fragmented and siloed nature of the rare disease space, as well as how the issues encountered by this community are representative of biomedical research more generally. Here, we propose several initiatives for key stakeholders - including regulators, private and public foundations, and research institutions - to reorient the rare disease ecosystem and its incentives in a way that we believe would cultivate and accelerate innovation. Specifically, we propose supporting non-proprietary patient registries, greater data standardization, global regulatory harmonization, and new business models that encourage data sharing and research collaboration as the default mode. Leadership needs to be integrated across sectors to drive meaningful change between patients, industry, sponsors, and academic medical centers. To transform the research and development landscape and unlock its vast healthcare, economic, and scientific potential for rare disease patients, a new model is ultimately the goal for all.

PMID:36303170 | DOI:10.1186/s13023-022-02529-w

Ir Med J. 2022 Aug 18;115(7):635.

ABSTRACT

Introduction In the Republic of Ireland, there are no tuberous sclerosis complex (TSC) specialist clinics. Methods A clinical audit was carried out to assess the care received by patients attending two specialist adult epilepsy specialist centres, measuring their care against the UK guidelines. Results Although many baseline investigations are carried out, only one-third of patients had diagnostic genetic testing results available. Neuropsychiatry is largely neglected, and the completion of neuropsychiatric assessments checklists is inadequate. Discussions concerning SUDEP are not happening and access to treatment is limited. Reporting of radiological findings in TSC is inconsistent and the number of adults with TSC accessing specialist epilepsy services appear to be low. Discussion TSC care in the Republic of Ireland is fragmented, difficult to navigate and wasteful of resources due to the complex nature of the disease and no formal clinical setting to manage it. The service gaps echo the demand for an improved care system including consistent radiological reporting of TSC pathology. The absence of a specialist TSC clinic compounds the complexity of navigating care for individuals with TSC, families and healthcare professionals. Extending this audit nationally will give a more complete picture and highlight the resources required to bring care of these patients in line with recommended guidelines.

PMID:36300768

Ned Tijdschr Geneeskd. 2022 Oct 24;166:D6706.

ABSTRACT

BACKGROUND: The vulvar form of lymphangioma circumscriptumis a rare condition. It is part of the acquired lymphangiectasia and arises secondary, for example, after surgery, radiotherapy for malignancies in the pelvic region, inflammation in which vulvar lymphedema occurs or Morbus Crohn.

CASE DESCRIPTION: A 44-year-old woman presented to the gynaecology outpatient department with a vulvar abnormality that was accompanied by pain and pruritus. Her medical history consisted of premalignant cervical abnormalities and a vulvar lichen simplex chronicus. A biopsy was taken and the diagnosis lymphangioma circumscriptum was made. Due to the growth and the complaints, the decision was made to remove the lesion in the operating room.

CONCLUSION: Lymphangioma circumscriptum is a rare condition that is often misdiagnosed. This case may describe the development of lymphangioma circumscriptum from a lichen simplex chronicus, which has not been described before. It also demonstrates that surgical treatment appears to be a good treatment with few complications in the postoperative course.

PMID:36300473

Int J Environ Res Public Health. 2022 Oct 15;19(20):13319. doi: 10.3390/ijerph192013319.

ABSTRACT

OBJECTIVE: The affordability of rare disease drugs has become a social issue that cannot be ignored. This study aims to evaluate the current price and affordability of rare disease drugs in China, with evidence from Shandong province.

METHODS: Data on prices and affordability of 50 drugs for 22 rare diseases were collected from secondary and tertiary public hospitals in Shandong Province, using an adaptation of the World Health Organization/Health Action International (WHO/HAI) methodology. Prices were measured as Median Price Ratios (MPRs). Affordability was measured as days of daily per capita disposable income required for the cost of one month's treatment.

RESULTS: Out of the 50 rare disease drugs, 11 drugs had MSH reference prices and 34 had PBS reference prices. Median prices of 11 drugs were higher than MSH reference prices (median 1.33), and median prices of 34 drugs were higher that Australian PBS prices (median 1.97). Thirty-six (72.00%) and forty-four (88.00%) drugs were unaffordable for urban and rural residents, respectively. Thirty-four (68.00%) and thirty-eight (76.00%) drugs were unaffordable for urban and rural residents even after reimbursement by the health insurance schemes of China, respectively.

CONCLUSIONS: The affordability of some rare disease drugs remained poor with their relatively high prices in Shandong Province. Sustainable mechanisms are needed to reduce the price of rare disease drugs and to improve the affordability of rare disease patients.

PMID:36293897 | DOI:10.3390/ijerph192013319

Genes (Basel). 2022 Oct 17;13(10):1880. doi: 10.3390/genes13101880.

ABSTRACT

Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.

PMID:36292765 | DOI:10.3390/genes13101880

Genes (Basel). 2022 Sep 23;13(10):1707. doi: 10.3390/genes13101707.

ABSTRACT

Launched in 2014, the RARE Compassion Program is the first international educational program to pair medical students with rare disease patients in order to enhance exposure to and comfort with rare diseases. As part of ongoing quality improvement, this study retrospectively reviewed four years of participant registration data to conduct a program evaluation of the RARE Compassion Program between 2014-2018. During the study period, there were 334 student participants, representing 67.3% of Association of American Medical Colleges (AAMC) member medical schools, and 5389 rare disease volunteers. Despite not requiring in-person interaction, 90.64% of student-volunteer interactions were in-person, while only 5.89% and 3.46% were by video messaging or email correspondence, respectively (p = 0.0002). In a limited post participation survey, 91.7% of students, who matched to 19 out of 27 residency specialities, indicated they would recommend the program to their peers. These findings suggest that the RARE Compassion Program, designed to increase medical student engagement with rare disease patients, has broad appeal. It serves as a novel case study of how extracurricular initiatives supported by non-profit organizations can augment the medical training experience and improve understanding of important and often neglected perspectives.

PMID:36292592 | DOI:10.3390/genes13101707

Genes (Basel). 2022 Sep 21;13(10):1690. doi: 10.3390/genes13101690.

ABSTRACT

Studying rare diseases, particularly those with neurological dysfunction, is a challenge to researchers and healthcare professionals due to their complexity and small population with geographical dispersion. Universal and standardized biomarkers generated by tools such as functional neuroimaging have been forged to collect baseline data as well as treatment effects. However, the cost and heavily infrastructural requirement of those technologies have substantially limited their availability. Thus, developing non-invasive, portable, and inexpensive modalities has become a major focus for both researchers and clinicians. When considering neurological disorders and diseases with executive dysfunction, EEG is the most convenient tool to obtain biomarkers which can correlate the objective severity and clinical observation of these conditions. However, studies have also shown that EEG biomarkers and clinical observations alone are not sensitive enough since not all the patients present classical phenotypical features or EEG evidence of dysfunction. This article reviews disorders, including two rare disorders with neurological dysfunction and the usefulness of functional near-infrared spectroscopy (fNIRS) as a non-invasive optical modality to obtain hemodynamic biomarkers of diseases and for screening and monitoring the disease.

PMID:36292574 | DOI:10.3390/genes13101690