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

Ter Arkh. 2022 Oct 12;94(8):992-998. doi: 10.26442/00403660.2022.08.201833.

ABSTRACT

The first documented case of mitochondrial neurogastrointestinal encephalomyopathy was described in 1962 by R. Luft. The variety and am-biguity of the clinical manifestations of the disease complicate its early diagnosis and treatment. The first clinical manifestations of the disease are associated with the pathology of the gastrointestinal tract. Low alertness and insufficient awareness of doctors delays the timely diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. The aim of the work is to increase the alertness and awareness of narrow specialties about the possibility of differential diagnosis of an extremely rare detected disease on the base of our clinical observation.

PMID:36286980 | DOI:10.26442/00403660.2022.08.201833

Rev Neurol. 2022 Nov 1;75(9):261-267. doi: 10.33588/rn.7509.2022298.

ABSTRACT

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare disease whose diagnosis and treatment are complex. In Spain, there are two orphan medicines that are currently financed by the state, nusinersen and onasemnogene abeparvovec and, a third in process, risdiplam. The objective was to detect possible causes of inequity in the diagnosis and treatment of SMA in Spain.

MATERIALS AND METHOD: Descriptive study realized in two phases: a first phase of bibliographic revision and a second phase of semi-structured interviews with clinical experts in SMA in Andalusia, Castilla-La Mancha, Catalonia and Murcia.

RESULTS: The number of centers, services or units of reference, the availability of regional autonomous plans for rare diseases and pilot programs of neonatal screenings can regulate access to treatments. The number of new patients diagnosed per year is estimated between one and six in the four autonomous communities (ACs) of Spain studied. Differences were not found in logistical resources. Two of the four ACs studied have regional autonomous plans for rare diseases, however, their utility has only had relevance in one of two of the ACs.

CONCLUSIONS: Important differences in access to nusinersen were not identified in the studied ACs The diagnosis of SMA requires clinical specialized experts and specialized centers for early intervention of disease-modifying therapies.

PMID:36285446 | DOI:10.33588/rn.7509.2022298

Vnitr Lek. 2022 Fall;68(E-5):4-19. doi: 10.36290/vnl.2022.070.

ABSTRACT

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder. Autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum, prostate and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD and in 2019 four Clinical phenotypes of IgG4-related disease were described. Diagnosis is based on morphological examination with typical findings of lymphoplasmocellular inflammation, storiform fibrosis and obliterative phlebitis in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. New diagnostic criteria for IgG4-RD have been published recently in 2019 and 2021. This review summarizes current knowledge on pathophysiology, clinical manifestations, diagnosis and differential diagnosis of IgG4-RD from the point of view 2022 and in next article brings overview of the IgG4-RD therapy.

PMID:36283812 | DOI:10.36290/vnl.2022.070

Medicine (Baltimore). 2022 Oct 21;101(42):e31060. doi: 10.1097/MD.0000000000031060.

ABSTRACT

BACKGROUND: Fabry disease (FD) is a rare, inherited disease lysosomal storage disorder caused by the lack of an alpha-galactosidase enzyme. This genetic disease can affect both men and women. The understanding of FD is very important as this condition can be effectively treated. For women who may exhibit normal residual enzyme activity, the diagnosis is more challenging.

CASE PRESENTATION: Herein, we reported on a case of IgA nephropathy and renal disease that mimicked FD in a female patient. The presence of zebra bodies in the cytoplasm of glomerular podocytes is widely accepted as a hallmark pathological manifestation of FD. In the present case, renal biopsy analysis revealed the presence of zebra bodies; however, genetic testing indicated that the patient did not have FD. The mechanisms and causes of zebra body formation remained unclear in the present case. However, the patient responded well to treatment with an angiotensin receptor blocker.

CONCLUSIONS: The reported findings can be useful for the differential diagnosis of FD and renal diseases in the future. Our results also highlight the clinical significance of zebra bodies in renal disease.

PMID:36281086 | DOI:10.1097/MD.0000000000031060

J Clin Invest. 2022 Oct 25:e163235. doi: 10.1172/JCI163235. Online ahead of print.

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

PMID:36282598 | DOI:10.1172/JCI163235

Soc Sci Med. 2022 Dec;314:115465. doi: 10.1016/j.socscimed.2022.115465. Epub 2022 Oct 19.

ABSTRACT

This study explores parental expectations and value-making processes in respect to pediatric clinical genomic sequencing for socially disadvantaged families. Drawing on interviews and ethnographic observations with parents of children with undiagnosed physical and/or intellectual differences seeking to find whether these differences have a genetic etiology, we explore expectations and parental assessments of the value of genomic sequencing within the context of an ongoing research study. We demonstrate how the value of sequencing to parents goes well beyond finding diagnostic results or receiving prescriptive guidance as to the best care and treatment of their child; instead, value is co-created by parents, clinicians, and genetic counsellors throughout the enrollment and return of results process. Parents in our study found that clinicians and genetic counsellors repeatedly reenforce that parents need to lower their expectations and be prepared to wait for genetic science to provide more definitive answers. At the same time, parents experience that clinical teams validate parents for having made a good choice in their undertaking of genomic sequencing and, no matter the result, that they are not to blame for their child's symptoms. The experience of many parents (although not all) is that genomic science reduces or removes their sense of guilt for their child's condition, providing a platform that affirms them as "good parents." Moreover, rather than being voiceless and isolated, socially disadvantaged parents who enter into diagnostic sequencing find themselves in a familial-biosocial framework wherein they are co-partners in a socially and biologically authoritative vision of the future.

PMID:36279794 | DOI:10.1016/j.socscimed.2022.115465