Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives.

The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the mendelian forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. Within this group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate "neurodevelopmental proteasomopathies". Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.

Concurrent Encounter of Superior Mesenteric Artery Syndrome and Nutcracker Syndrome in a Young Female Patient: A Case Report and Literature Review.

Superior mesenteric artery (SMA) syndrome causes duodenal obstruction between the SMA and aorta, which culminates into bowel obstruction. Meanwhile, nutcracker syndrome (NCS) involves left renal vein compression between the aorta and SMA, categorized by the compression site. We present a 15-year-old female with no prior medical or surgical history who displayed early signs of the rarely coexisting SMA and nutcracker phenomena, which were managed symptomatically along with nutritional support to reach her optimal body mass index.

Healthcare Stakeholder Perspectives on a Value Assessment Approach for Duchenne Muscular Dystrophy Therapies.

Purpose: Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The objective of this study was to identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies. Patients and Methods: Three stakeholder groups (6 patient advocates, 4 clinicians, 3 health economists; N = 13) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research's Value Flower, which includes elements to consider within value assessments of healthcare technologies. Results: All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that using the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; meaningful attributes for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers. Conclusion: These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and health economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne.

Pleomorphic adenoma and carcinoma ex-pleomorphic adenoma tumorigenesis: A proteomic analysis.

OBJECTIVES: To conduct a comprehensive proteomic analysis of normal salivary gland tissue, pleomorphic adenoma (PA), and carcinoma ex-pleomorphic adenoma (CXPA), and validate the proteomic findings using immunohistochemistry. METHODS: Six normal salivary gland tissues, seven PA and seven CXPA samples underwent laser microdissection followed by liquid chromatography coupled to mass spectrometry. Protein identification and quantification were performed using MaxQuant software. Statistical analysis and functional enrichment were conducted using the Perseus platform and STRING tool, respectively. Immunohistochemistry was used for validation. RESULTS: Comparative proteomic analysis revealed 2680 proteins across the three tissue types, with 799 significantly altered between groups. Translocation protein SEC63 homolog, Annexin A6 and Biglycan were up-regulated in CXPA compared to PA. Decorin was markedly up-regulated in both PA and CXPA compared to normal salivary gland (log2 fold changes of 7.58 and 7.38, respectively). Validation confirmed elevated levels of Biglycan and Decorin in the extracellular matrix of CXPA compared to PA. CONCLUSIONS: Proteomic analysis identified differential protein expression patterns associated with malignant transformation of PA into CXPA. Findings indicate a crucial role for extracellular matrix proteins, specifically Biglycan and Decorin, in the tumorigenic progression of PA and CXPA.

Navigating the Unique Challenges of Caregiving for Children with Rare Diseases: Are the Care Experiences of All Caregivers the Same? A Focus on Life-Limiting Rare Diseases.

Background: Caregiving experiences in rare diseases (RDs) vary based on factors such as specific clinical entity, disease severity, the child's age, and available support and resources, leading to challenges that significantly impact caregivers' lives. This study investigates whether caregivers of children with different RDs encounter varied aspects of care. Methods: This study was conducted as a self-administered, anonymous, computer-assisted online survey, focusing on the challenges of caregiving for children with RDs. Questions covered aspects such as information availability on RDs, diagnostic processes, modern treatment accessibility, family physicians and specialists, the impact of caregiving on personal life, family dynamics, and financial challenges. To achieve our study objectives, we categorized caregivers of children with RDs into two groups to compare various aspects of caregiving: caregivers of children with phenylketonuria (PKU) (n = 175) and those caring for children with life-limiting rare diseases (LLRD) (n = 226). Results: Caregivers of children with LLRD reported greater emotional challenges, personal sacrifices, and financial burdens compared to caregivers of children with PKU. Significant differences included heightened emotional distress, more frequent conflicts, and lower assessments of healthcare support among LLRD caregivers. Although family support ratings were similar between the groups, perceptions of financial concerns and interactions with the healthcare system varied significantly. Conclusions: This study, representing the inaugural systematic comparison of specific caregiver cohorts overseeing children with RDs across a substantial sample size, provides valuable insights. The findings lay a crucial foundation for precisely tailoring assistance and support initiatives to meet the unique needs of caregivers facing various RDs in diverse contexts.

"In God We Trust": An Exploratory Study of the Associations Between Religiosity and the Caregiving Experiences of Parents of Children with Rare Diseases in Poland.

Most children with a rare disease are cared for by their family members but parenting such a child is extremely demanding due to the complexity and severity of symptoms, with serious physical, emotional, social, and financial consequences for caregivers. Although religion may serve as a positive coping strategy, little is known about its role in helping caregivers manage the stress related to the burden of caregiving in Poland. Therefore, we surveyed 925 Polish family caregivers of children with rare diseases to understand the association between caregivers' religiosity and their caring experiences. The findings suggest that parents' religiosity is associated with a more positive caregiving experience, perceived quality of life, and experienced caregiving burden. While religious caregivers reported experiencing less distressing emotions and stressed the encouraging impact of their child's disease on their life more often, non-religious caregivers experienced role captivity and role overload more frequently. Since religion may serve as a source of strength and a protecting factor against mental health problems and the burden of caregiving, healthcare professionals should be aware of the importance of religious and spiritual care, and caregivers' religiosity should be considered an integral part of a holistic approach.

Collaborative effort: managing Bardet-Biedl syndrome in pediatric patients. Case series and a literature review.

Bardet-Biedl Syndrome (BBS) is an autosomal recessive non-motile ciliopathy, caused by mutations in more than twenty genes. Their expression leads to the production of BBSome-building proteins or chaperon-like proteins supporting its structure. The prevalence of the disease is estimated at 1: 140,000 - 160,000 of life births. Its main clinical features are retinal dystrophy, polydactyly, obesity, cognitive impairment, hypogonadism, genitourinary malformations, and kidney disease. BBS is characterized by heterogeneous clinical manifestation and the variable onset of signs and symptoms. We present a case series of eight pediatric patients with BBS (6 boys and 2 girls) observed in one clinical center including two pairs of siblings. The patients' age varies between 2 to 13 years (average age of diagnosis: 22 months). At presentation kidney disorders were observed in seven patients, polydactyly in six patients' obesity, and psychomotor development delay in two patients. In two patients with kidney disorders, the genetic tests were ordered at the age of 1 and 6 months due to the presence of symptoms suggesting BBS and having an older sibling with the diagnosis of the syndrome. The mutations in the following genes were confirmed: BBS10, MKKS, BBS7/BBS10, BBS7, BBS9. All described patients developed symptoms related to the urinary system and kidney-function impairment. Other most common symptoms are polydactyly and obesity. In one patient the obesity class 3 was diagnosed with multiple metabolic disorders. In six patients the developmental delay was diagnosed. The retinopathy was observed only in one, the oldest patient. Despite having the same mutations (siblings) or having mutations in the same gene, the phenotypes of the patients are different. We aimed to addresses gaps in understanding BBS by comparing our data and existing literature through a narrative review. This research includes longitudinal data and explores genotype-phenotype correlations of children with BBS. BBS exhibits diverse clinical features and genetic mutations, making diagnosis challenging despite defined criteria. Same mutations can result in different phenotypes. Children with constellations of polydactyly and/or kidney disorders and/or early-onset obesity should be managed towards BBS. Early diagnosis is crucial for effective monitoring and intervention to manage the multisystemic dysfunctions associated with BBS.

Spectrum of pathogenic variants and high prevalence of pathogenic BBS7 variants in Russian patients with Bardet-Biedl syndrome.

Introduction: Bardet-Biedl syndrome is a rare condition characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney anomalies. This syndrome has an autosomal recessive type of inheritance. For the first time, molecular genetic testing has been provided for a large cohort of Russian patients with Bardet-Biedl syndrome. Materials and methods: Genetic testing was provided to 61 unrelated patients using an MPS panel that includes coding regions and intronic areas of all genes (n = 21) currently associated with Bardet-Biedl syndrome. Results: The diagnosis was confirmed for 41% of the patients (n = 25). Disease-causing variants were observed in BBS1, BBS4, BBS7, TTC8, BBS9, BBS10, BBS12, and MKKS genes. In most cases, pathogenic and likely pathogenic variants were localized in BBS1, BBS10, and BBS7 genes; recurrent variants were also observed in these genes. Discussion: The frequency of pathogenic and likely pathogenic variants in the BBS1 and BBS10 genes among Russian patients matches the research data in other countries. The frequency of pathogenic variants in the BBS7 gene is about 1.5%-2% of patients with Bardet-Biedl syndrome, while in the cohort of Russian patients, the fraction is 24%. In addition, the recurrent pathogenic variant c.1967_1968delinsC was detected in the BBS7 gene. The higher frequency of this variant in the Russian population, as well as the lack of association of this pathogenic variant with Bardet-Biedl syndrome in other populations, suggests that the variant c.1967_1968delinsC in the BBS7 gene is major and has a founder effect in the Russian population. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene for patients with Bardet-Biedl syndrome in the Russian population.

Preclinical alternative drug discovery programs for monogenic rare diseases. The case of hereditary spastic paraplegias.

Patients diagnosed with rare diseases and their and families search desperately to organize drug discovery campaigns. Alternative models that differ from default paradigms offer real opportunities. There are, however, no clear guidelines for the development of such models, which reduces success rates and raises costs. We address the main challenges in making the discovery of new preclinical treatments more accessible, using rare hereditary paraplegia as a paradigmatic case. First, we discuss the necessary expertise, and the patients' clinical and genetic data. Then, we revisit gene therapy, de novo drug development, and drug repurposing, discussing their applicability. Moreover, we explore a pool of recommended in silico tools for pathogenic variant and protein structure prediction, virtual screening, and experimental validation methods, discussing their strengths and weaknesses. Finally, we focus on successful case applications.

Evaluation of BERT-Based Models on Patient Data from French Social Media.

With the objective of extracting new knowledge about rare diseases from social media messages, we evaluated three models on a Named Entity Recognition (NER) task, consisting of extracting phenotypes and treatments from social media messages. We trained the three models on a dataset with social media messages about Developmental and Epileptic Encephalopathies and more common diseases. This preliminary study revealed that CamemBERT and CamemBERT-bio exhibit similar performance on social media testimonials, slightly outperforming DrBERT. It also highlighted that their performance was lower on this type of data than on structured health datasets. Limitations, including a narrow focus on NER performance and dataset-specific evaluation, call for further research to fully assess model capabilities on larger and more diverse datasets.

Team-based learning (TBL) curriculum combined with video vignettes improves performance of undergraduate medical students on OSCE compared with TBL alone.

BACKGROUND: Clinical practitioners think of frequent causes of diseases first rather than expending resources searching for rare conditions. However, it is important to continue investigating when all common illnesses have been discarded. Undergraduate medical students must acquire skills to listen and ask relevant questions when seeking a potential diagnosis. METHODOLOGY: Our objective was to determine whether team-based learning (TBL) focused on clinical reasoning in the context of rare diseases combined with video vignettes (intervention) improved the clinical and generic skills of students compared with TBL alone (comparator). We followed a single-center quasi-experimental posttest-only design involving fifth-year medical students. RESULTS: The intervention group (n = 178) had a significantly higher mean overall score on the objective structured clinical examination (OSCE) (12.04 ± 2.54 vs. 11.27 ± 3.16; P = 0.021) and a higher mean percentage score in clinical skills (47.63% vs. 44.63%; P = 0.025) and generic skills (42.99% vs. 40.33%; P = 0.027) than the comparator group (n = 118). Success on the OSCE examination was significantly associated with the intervention (P = 0.002). CONCLUSIONS: The TBL with video vignettes curriculum was associated with better performance of medical students on the OSCE. The concept presented here may be beneficial to other teaching institutions.

Time to diagnosis for a rare disease: managing medical uncertainty. A qualitative study.

BACKGROUND: People with a rare disease commonly experience long delays from the onset of symptoms to diagnosis. Rare diseases are challenging to diagnose because they are clinically heterogeneous, and many present with non-specific symptoms common to many diseases. We aimed to explore the experiences of people with myositis, primary immunodeficiency (PID), and sarcoidosis from symptom onset to diagnosis to identify factors that might impact receipt of a timely diagnosis. METHODS: This was a qualitative study using semi-structured interviews. Our approach was informed by Interpretive Phenomenological Analysis (IPA). We applied the lens of uncertainty management theory to tease out how patients experience, assess, manage and cope with puzzling and complex health-related issues while seeking a diagnosis in the cases of rare diseases. RESULTS: We conducted interviews with 26 people with a rare disease. Ten participants had been diagnosed with a form of myositis, 8 with a primary immunodeficiency, and 8 with sarcoidosis. Time to diagnosis ranged from 6 months to 12 years (myositis), immediate to over 20 years (PID), and 6 months to 15 years (sarcoidosis). We identified four themes that described the experiences of participants with a rare disease as they sought a diagnosis for their condition: (1) normalising and/or misattributing symptoms; (2) particularising by clinicians; (3) asserting patients' self-knowledge; and (4) working together through the diagnosable moment. CONCLUSIONS: Managing medical uncertainty in the time before diagnosis of a rare disease can be complicated by patients discounting their own symptoms and/or clinicians discounting the scale and impact of those symptoms. Persistence on the part of both clinician and patient is necessary to reach a diagnosis of a rare disease. Strategies such as recognising pattern failure and accommodating self-labelling are key to diagnosis.

Burden of rare genetic disorders in India: twenty-two years' experience of a tertiary centre.

BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Interventions to support young adults and families with the healthcare transition between paediatric and adult nephrology health services: A systematic scoping review.

BACKGROUND: Healthcare transition can be challenging for young people and families living with chronic kidney conditions, including those with rare renal disorders who often have multi-systemic conditions, those who have undergone kidney transplantation, and those who face intense treatments like dialysis. Comprehensive, holistic healthcare transition interventions are required, encompassing physical, psychosocial, sexual, educational and vocational support. AIM: This manuscript presents a systematic scoping review synthesising the healthcare transition interventions to support youth and families within nephrology services. METHODS: This review followed Arksey and O'Malley's five-stage framework, updated by Levac, Colquhoun and O'Brien and the Joanna Briggs Institute. Six databases were systematically searched: CINAHL Plus with Full Text, Embase, PsycINFO, Web of Science, PubMed, and the Applied Social Sciences Index and Abstracts (ASSIA), locating 12,662 records. Following a systematic screening process, 28 articles met the inclusion criteria. Results were analysed systematically and presented using the PAGER framework developed by Bradbury-Jones et al. (2022). RESULTS: Various interventions were sourced. Three broad patterns emerged: 1. Contextual Factors, e.g. cultural differences between paediatric and adult services; 2. Major Intervention Components, e.g. parental/familial/peer-to-peer support, and 3. Personal factors, e.g., self-management ability. CONCLUSION: Few interventions are available to support youth with rare renal disorders, specifically. Future research must be directed at this cohort. Healthcare transition timing remains hotly contested, with additional guidance required to support decision-making. Finally, limited interventions have been evaluated for practice. IMPLICATIONS: This review has provided various considerations/recommendations that should be taken into account when designing, implementing or evaluating future healthcare transition supports.

Improving Clinical Documentation of Rare Neuromuscular Diseases: Development of a Standardised Information Model.

Rare neuromuscular diseases (NMDs) encompass various disorders of the nervous system and skeletal muscles, and present intricate challenges in diagnosis, treatment, and research due to their low prevalence and often diverse multisystemic manifestations. Leveraging collected patient data for secondary use and analysis holds promise for advancing medical understanding in this field. However, a certain level of data quality is a prerequisite for the methods that can be used to analyze data. The heterogeneous nature of NMDs poses a significant obstacle to the creation of standardized documentation, as there are still many challenges to accurate diagnosis and many discrepancies in the diagnostic process between different countries. This paper proposes the development of an information model tailored to NMDs, aiming to augment visibility, address deficiencies in documentation, and facilitate comprehensive analysis and research endeavors. By providing a structured framework, this model seeks to propel advancements in understanding and managing NMD, ultimately benefiting patients and healthcare providers worldwide.

Modeling Rare Disease Datasets with ART-DECOR.

This paper presents ongoing work on the modeling of different datasets using the ART-DECOR modeling tool, with a focus on adherence to the FAIR principles (Findable, Accessible, Interoperable, and Reusable). The successful modeling of the French minimal dataset for rare diseases (Set de donnees minimal des maladies rares (SDM-MR.fr)) should provide inspiration for the development of the German minimal dataset for rare diseases (Minimalbasisdatensatz fur Seltene Erkrankungen (MBDS-SE.de)).

Privacy-Preserving Linkage of Distributed Pseudonymised Datasets in a Virtual European Rare Disease Platform.

Secondary use of data for research purposes is especially important in rare diseases (RD), since, per definition, data are sparse. The European Joint Programme on Rare Diseases (EJP RD) aims at developing an RD infrastructure which supports the secondary use of data. Significant amounts of RD data are a) distributed and b) available only in pseudonymised format. Privacy-Preserving Record Linkage (PPRL) concerns the linking of such distributed datasets without disclosing the participant's identities. We present a concept for linking a PPRL Service to the EJP RD Virtual Platform (VP). Level 1 (resource discovery) connection is provided by running an FDP within the PPRL Service. On Level 2 (data discoverability), the PPRL Service can represent both, an individual and a catalog endpoint. Our solution can count patients in PPRL-supporting resources, count duplicates only once, and count only patients registered to multiple resources. Currently, we are preparing the deployment within the EJP RD VP.

Acute kidney injury, an underrecognized feature of VEXAS syndrome.

OBJECTIVES: VEXAS syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. METHODS: Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first acute kidney injury (AKI) event. For patients with a kidney biopsy, histopathologic findings were reviewed. RESULTS: Eighty-one patients were included, all white men, with a mean age of 66.3±8.6 years. Median (IQR) follow up was 3.5 (2.1-5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80-11.3%), 16.7% (7.5-25.0%) and 27.9% (14.9-38.9%), respectively. Age and baseline C-reactive protein were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1), and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. CONCLUSION: AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

Comprehensive Multidisciplinary Management of Hyper-IgE Syndrome in an 11-Year-Old Female: A Pediatric Case Report.

Hyper-IgE syndrome (HIES) or Job syndrome is a rare immunodeficiency characterized by elevated levels of IgE and recurrent infections, eczema, and connective tissue abnormalities. Patients with HIES are prone to recurrent pyogenic and opportunistic infections due to impaired immune responses. Here, we present the case of an 11-year-old female diagnosed with HIES, who was admitted to the hospital with bacterial pneumonia and leg pain associated with a history of osteopenia. The patient's clinical course included fever, cough, throat pain, and leg pain. Management involved a rigorous course of antibiotics, antifungals, and cultures of pertinent pathogens, along with imaging of the lower extremity. This case underscores the importance of appropriate management strategies for patients with HIES and their comorbidities to mitigate the risk of infections and improve patient outcomes.