Orphanet Journal of Rare Diseases

BackgroundOsteogenesis Imperfecta is a rare connective tissue disorder resulting in a diverse range of musculoskeletal deformities. Patient education is an important aspect of medical care, and the internet is a popular place in which patients seek information about their medical conditions. This is a cross-sectional study aimed to evaluate the quality of online patient educational websites about Osteogenesis Imperfecta. MethodsThe authors searched for patient education websites using Google and Bing. Twenty patient education websites about Osteogenesis Imperfecta were collected from each. Websites meeting inclusion criteria were evaluated using the DISCERN tool, JAMA Benchmark Criteria evaluation, and a Flesch-Kincaid Readability test. T-tests were used to compare search engine results. Websites were also collected from ChatGPT3.5, however, due to hallucinations and exclusion criteria, the sample size was too small to compare to the search engines. ResultsNo significant differences were found between search engines, and the quality of the websites was not high. Average overall ratings for DISCERN were mediocre, and for the JAMA criteria they were low. The average readability scores required 8-9 grade level reading comprehension, although there was variability within each search engine. ConclusionNeither search engine provided significantly better sources than the other, the overall quality of the websites was not high, and the low readability scores could make these difficult for patients with lower health literacy to understand

BackgroundSudden cardiac death (SCD) is a devastating event and a leading cause of mortality, globally. In the young (2-45 years), SCD is often attributable to a heritable cardiac condition. Death investigators are often responsible for investigating the cause of death and communicating their results and risk of heritable cardiac conditions with family members of SCD victims. Family often struggles to comprehend the information that is communicated to them. PurposeTo understand the delivery, reach and impact of communication strategies informing family members of SCD victims about their relatives cause of death and their own risk for heritable cardiac conditions. MethodsWe conducted an explanatory sequential mixed methods study. We collected quantitative data via a web-based survey and qualitative data via telephone interviews to investigate how death investigators in Ontario and Nova Scotia, Canada, communicate with family members of SCD victims. We used descriptive statistics to analyze the survey data and thematic analysis to analyze the qualitative data. We triangulated data at multiple levels. ResultsBetween October 2022 and July 2023, we surveyed 78 death investigators and interviewed a subset (n=20). Death investigators reported that SCDs due to suspected heritable cardiac conditions were more difficult (40%, n=31) or slightly more difficult (35%, n = 27) to investigate, often requiring a higher frequency of communication with families. Death investigators reported contacting family members via phone (n=75, 96.1%) and used various strategies to achieve their communication goals. Strategies were influenced by family characteristics; involvement of other professionals; characteristics of the investigation, access to resources, and system-level barriers. ConclusionSCD investigations in the young due to suspected heritable cardiac conditions were more challenging and required a higher frequency of communication. Death investigators used various strategies to achieve their communication goals. Further research should examine how systematic changes can improve communication with family members. What is Known?O_LISudden cardiac death (SCD) is a devastating and unexpected event that can be caused by heritable cardiac conditions, putting the decedents family at risk of SCD. C_LIO_LICommunication with death investigators and other health care professionals influences families experiences learning about the cause of death and about their risk for heritable cardiac condition. C_LI What this Study AddsO_LIAccording to death investigators, SCD cases due to suspected heritable cardiac conditions are more difficult to investigate, require a higher frequency of communication with family members than other types of cases, and benefit from using different communication modalities. C_LIO_LIDespite their best intentions, death investigators are contending with many factors beyond their control that influence how communication with family members is carried out. C_LIO_LIProvincial death investigation systems alone do not currently provide families of SCD victims with sufficient communication, as families often seek external resources. C_LI

IRF2BPL-related disorder is a neurodevelopmental disorder caused by heterozygous variants in the IRF2BPL (Interferon Regulatory Factor 2 Binding Protein-Like) gene. The few reports available in the literature suggest that common symptoms include developmental delay, intellectual disability and developmental regression. There are no reports of genotype-phenotype correlations. We developed a retrospective and prospective patient-reported survey to assess diagnostic information, presenting symptoms and longitudinal follow-up of neurological symptoms for up to two years. Clinical information was available for all 32 participants and was highly variable in regards to age at symptom onset, severity of neurologic manifestations, and progressivity. For 27 of the 32 participants, diagnostic genetic test results were available. Genetic mutation analysis revealed 22 individuals with truncating variants and five participants with unique missense variants in IRF2BPL. The study data support the hypothesis that IRF2BPL missense variants are associated with a less severe disease presentation and progression than participants with truncating variants. The purpose of this study is to further define IRF2BPL-related disorder and provide more clinical and molecular insight into this ultra-rare disease. Highlights- Patient-reported clinical history at diagnosis and up to two years of follow up - The clinical spectrum is increasingly heterogeneous - We report 32 patients, 27 with noted IRF2BPL variants, 14 being novel to literature. - Data supports the notion that IRF2BPL missense variants may be associated with less severe disease than truncations (nonsense/frameshifts).

BackgroundOnly twice have variants in the ITPR1 gene been described among patients with ataxia and miosis. Functional characterization of these variants is lacking. ObjectiveTo characterize a family affected by congenital ataxia and miosis associated with a novel ITPR1 variant and to provide a functional assessment for it and two previously reported variants. MethodsClinical characterization, genetic investigations, and segregation were performed. A novel variant c.7697T>C in ITPR1 was identified, HEK cells were transfected with vectors carrying our variant and two other previously published variants associated with ataxia and miosis. ResultsAtaxia was non-progressive in the reported family, the c.7697T>c ITPR1 variant segregated with disease. Functional validation showed that all the three ITPR1 variants were associated with reduced intracellular calcium release. ConclusionsHere, we present for the first time evidence of pathogenicity for 3 heterozygous ITPR1 variants in association with ataxia and miosis. Despite being localized in different ITPR1 protein domains, these variants converged on common functional defects.

Background and objectivesMacrocephaly is among the most common findings in neurofibromatosis type 1 (NF1) and may be associated with other clinical manifestations of the genetic syndrome. NF1-specific growth charts that account for expected macrocephaly may increase sensitivity to detect atypical growth. We aimed to produce NF1-specific growth charts of head circumference for the age range of 0 to 3 years and to assess their potential clinical impact. MethodsUsing electronic health records from the Childrens Hospital of Philadelphia, we collected head circumference measurements from children with NF1 and a community control cohort seen at scheduled well-child visits. We compared head circumference normed using Center for Disease Control (CDC) growth charts between these groups over time. We constructed NF1-specific growth charts using two independent methods. Finally, we used mixed-effects models to relate the resulting centile scores with developmental delay assessed with the Survey of Well-being of Young Children. ResultsOur dataset contained 2180 observations from 305 individuals (167 male) with NF1, and 104,750 observations from 16,742 individuals (8809 male) in the community control cohort, all aged 0 to 3 years old. Head circumference was significantly elevated in NF1 throughout the age range (Padjusted <0.05), but the effect sizes varied nonlinearly with age, starting moderate at 1 month (d = 0.56), then small at four months (d = 0.28), moderate again at 15 months (d = 0.58), and finally large at 28 months (d = 0.8). NF1-specific growth curves demonstrated slower rate-of-growth for head circumference in the first two months of life yet more sustained growth over time. Although none of the children with NF1 met the standard for microcephaly according to CDC charts, smaller head circumference benchmarked against NF1-specific charts was correlated with developmental delay (standardized beta = 0.24; P = 0.013). DiscussionWe present the first NF1-specific growth charts for head circumference covering ages 0 to 3 years. Macrocephaly in NF1 becomes more exaggerated over time as rate-of-growth is sustained compared to controls. Smaller head size relative to NF1 growth expectations is not captured by CDC charts yet nevertheless relates to developmental delay, suggesting that NF1-specific charts may increase sensitivity to clinically concerning patterns of growth in children with NF1.

IntroductionAlstrom syndrome (ALMS, #203800) is an ultra-rare monogenic recessive disease. This the syndrome is associated with mutations in the ALMS1 gene, which codes for a centrosome structural protein responsible for centrosome cohesion. The type of mutation associated with ALMS is mostly cLOF (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with little success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study. MethodsIn this study we have collected all cases published to date for ALMS. We have created a database with those patients who had a genetic diagnosis and an individualised clinical history. Finally, we have attempted to establish a genotype-phenotype correlation using the truncation site of the patients longest allele as a grouping criterion. ResultsWe collected a total of 357 patients of which 227 had complete clinical information, complete genetic diagnosis and meta information regarding sex and age. We have seen that there are 5 variants in high frequency with p.(Arg2722Ter) being the most common variant with 28 alleles. There are no gender differences in disease progression. Finally, truncating mutations in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS. ConclusionThe location of the mutation in the ALMS1 gene does not have a major impact on the phenotype developed by the patient. Only mutations in exon 10 of the ALMS1 gene were associated with a higher prevalence of liver disease.

Fabry disease is a rare lysosomal storage condition in which sphingolipid levels build up to harmful levels in various bodily organs, eventually leading to life-threatening complications such as stroke and kidney failure. Fabry disease is caused by rare pathogenic alleles in the GLA gene on chromosome X and may present as an early or late-onset disease depending on the identity of the causal allele and the severity of its effect on the gene product. Epidemiological studies have widely varied in their estimation of Fabry disease prevalence: estimates based on reported clinical cases range from 1 in 40,000 to 1 in 170,000 individuals, whilst recent estimates based on newborn screening are much higher, ranging from 1 in 1,250 to 1 in 21,973 individuals. The primary aim of this study was to estimate the prevalence of Fabry disease in the US in 2024 by analysing selected GLA variants mostly associated with late-onset Fabry disease, projecting their allele frequencies to the US population and applying penetrance data from the literature to calculate how many causal allele carriers would be expected to be symptomatic for the disease at some point within their lifetime. 8 causal genetic variants were selected for analysis in this study based on their inclusion in a previous Fabry disease study using data from the UK Biobank. Allele frequencies for all 8 variants in global ancestry groups were extracted from gnomAD v4.1. The size and demographic makeup of the US population in 2024 was obtained from the US Census Bureau and mapped to gnomAD v4.1 ancestry groups, using previously reported estimates of the ancestral composition of Census groups encompassing multiple ancestry groups. Carrier counts by sex and ethnic group were calculated by projecting the summed allele frequencies to the US population using the Hardy-Weinberg equation and taking into consideration the X-linked mode of inheritance, assuming each individual can only carry 1 pathogenic variant. It was found that pathogenic alleles are present in the gnomAD v4.1 sample for all variants in the non-Finnish European gnomAD ancestry group, for 2 variants in South Asian ancestry group, and for 1 variant in the African / African American and East Asian ancestry groups. For the remaining 5 ancestry groups, there are no pathogenic alleles recorded in the gnomAD v4.1 dataset across all 8 variants included for analysis in the study. Results show the highest pathogenic allele carrier frequencies in the European (non-Finnish) ancestry group, followed by the South Asian, East Asian and African / African American ancestry groups. Using reported penetrance figures of 100% for males and 70% for females, it is estimated that the carrier and symptomatic populations of Fabry disease in the US in 2024, based on analysis of the 8 included variants, are 12,024 male carriers (or 1 in 14,022 males) who will all develop symptoms, and 24,845 female carriers (or 1 in 6,978 females), of whom 17,392 will develop symptoms. Of these carriers who will develop symptoms, around 98.6% (corresponding to 11,858 men and 17,153 women) will carry a variant primarily associated with late-onset or both forms of Fabry disease. The prevalence figures presented in this study are significantly higher than those based on reported clinical cases and are in line with those presented more recently based on newborn screening studies and with the prevalence reported in the UK Biobank analysis. The US National Institute of Health reports Fabry disease prevalence at around 1 in 50,000 males (which would correspond to 1 in 25,000 females). Analysing just 8 of the potentially hundreds of causal variants within the GLA gene, this study suggests that Fabry disease may be over 3 times as prevalent as is currently believed. This work highlights the vast potential of large genetic databases to analyse rare diseases, which will continue to progress as these datasets add more data, which will improve their power and diversity. What Is Already Known On This TopicO_LIFabry Disease is a rare X-linked lysosomal storage disorder with historical prevalence estimates ranging from 1 in 40,000 to 1 in 170,000 males, based on case ascertainment. C_LIO_LIMore recent newborn screening studies that test alpha-galactosidase A activity or perform genetic testing within the GLA gene, in addition to a UK Biobank study examining the prevalence of selected causal Fabry disease variants, have consistently suggested that Fabry disease may be far more prevalent than the estimates based on case ascertainment. C_LI What This Study AddsO_LITo our knowledge, this is the first study providing population-level estimates of the number of causal Fabry disease carriers and of the symptomatic population in the US using publicly available data from gnomAD v4.1. Our estimates are consistent with those produced by newborn screening studies and the UK Biobank analysis, and suggest that late-onset Fabry disease may affect >1 in 10,000 people in the US in 2024 at some point during their lifetime. C_LIO_LIThis study also demonstrates the potential of large genetic databases, such as gnomAD, for the study of rare genetic diseases, which are often misdiagnosed and may consequently be believed to be rarer than they are in reality. C_LI How This Study May Affect ResearchO_LIThis study highlights two areas for improvement which would be significantly beneficial to the study of rare genetic diseases. {circ}While this study demonstrates the utility of genetic databases to study certain rare genetic diseases, it is likely that the study of rarer conditions, in particular those manifesting during childhood and/or with a dominant mode of inheritance, would be more difficult using genetic databases, as individuals with such conditions are less likely to be included in population-level genetic biobanks (such as UK Biobank) due to a healthy volunteer bias. It is important that future genetic datasets are more representative in their recruitment to ensure that rare genetic diseases are not systematically excluded or underrepresented among participants. Studies such as All Of Us in the US, and Our Future Health and the Generation Study in the UK, will be extremely helpful in addressing this point. {circ}Estimates of the symptomatic Fabry disease population in the US in 2024 were calculated using the most up-to-date penetrance estimates in males and females. However these estimates were calculated using individuals already present in a Fabry registry and therefore may overestimate the penetrance, and especially among females, since asymptomatic carriers may be less likely to join a disease registry. Accurate calculation of the symptomatic population with a given genetic disease relies upon accurate penetrance estimates, which are not always available. These estimates are best calculated from large population-level resources with linked genetic and electronic health record data. C_LI

BackgroundAs SCD in the young can be caused by heritable cardiac conditions, up to 50% of family members may be at risk. Coroners are often responsible for communicating this risk, in addition to investigating the cause of death. PurposeTo explore how family members of SCD victims experience the type, timing, and suitability of communication with coroners about the cause of death and their own risk for SCD. MethodsWe conducted an explanatory sequential mixed methods study. Eligible family members of SCD victims who died in 2021 from a potentially heritable cardiac condition and were investigated by the Office of the Chief Coroner of Ontario (Canada) were invited tocomplete a web survey and/or telephone interview. We used descriptive statistics to analyze the survey data and thematic analysis to analyze the interview data. Integration occurred at multiple levels. ResultsWe sent survey invitations to 126 family members of 115 SCD victims; 50 family members completed the web-based survey between September 2022 and February 2024. We interviewed a subset of 17 family members. Most participants received initial communication by phone (n=30, 60%) or in-person (n=13, 26%). While many participants (n=39; 78%) received a timeline of when to expect death investigation results, 16 (32%) did not receive results within the expected timeframe. Family members characterized effective communication as clear, with coroners being perceived as kind, accessible, and approachable. When communication needs went unmet, families relied on external support networks to fill information gaps. Suggestions for improved communication included repeating information and using differing modes of communication to enhance understanding. ConclusionsThese findings emphasize the need for coroners to adopt empathetic approaches and to deliver information in a timely and clear manner. Addressing current gaps in communication may ensure the needs of grieving family members of SCD victims are met. What is Known- The unexpected and sometimes unclear cause of sudden cardiac death (SCD), particularly in young persons, leaves families grieving, often with unanswered questions. - In many jurisdictions, coroners investigate SCDs and have the most information regarding the circumstances and possible causes. - Communication with coroners influences families experiences with respect to learning about the cause of death and their own personal risk for a heritable cardiac condition. What this Study Adds- Family members of SCD victims seek clarity, accessibility, approachability, and kindness in their interactions with coroners. - When family members communication needs went unmet, many independently sought resources and support networks outside the coroner system. - Family members recommend improving coroner communication by providing clear timelines for death investigation results, repeating key information using several different modes of communication, and directing the family to counseling resources.

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) disease progression is associated with muscle inflammation, although its role in FSHD muscle pathology is unknown. MethodsWe have developed a novel humanized mouse strain, NSG-SGM3-W41, that supports the co- engraftment of human hematopoietic stem cells (HSCs) and muscle myoblasts as an experimental model to investigate the role of innate immunity in FSHD muscle pathology. ResultsThe NSG-SGM3-W41 mouse supports the selective expansion of human innate immune cell lineages following engraftment of human HSCs and the co-engraftment and differentiation of patient-derived FSHD or control muscle myoblasts. Immunohistological and NanoString RNA expression assays establish that muscle xenografts from three FSHD subjects were immunogenic compared to those from unaffected first-degree relatives. FSHD muscle xenografts preferentially accumulated human macrophages and B cells and expressed early complement genes of the classical and alternative pathways including complement factor C3 protein, which is a mediator of early complement function through opsonization to mark damaged cells for macrophage engulfment. FSHD muscle xenografts also underwent immune donor dependent muscle turnover as assayed by human spectrin {beta}1 immunostaining of muscle fibers and by NanoString RNA expression assays of muscle differentiation genes. ConclusionsThe NSG-SGM3-W41 mouse provides an experimental model to investigate the role of innate immunity and complement in FSHD muscle pathology and to develop FSHD therapeutics targeting DUX4 and the innate immunity inflammatory responses.

BackgroundEquitable representation of all populations is crucial for generalizing rare disease (RD) clinical research outcomes, especially given the low prevalence and geographically sparse distribution of patients with RDs. In our companion manuscript (Current State and Demographic Trends of Medically Underserved Populations in Rare Disease Research, Manjunatha et al.) we quantified reporting of demographics, socioeconomic factors (SF), and participation trends of medically underserved populations (MUPs) in RD research and clinical trials. MethodsThe study builds on the findings of Manjunatha et al., where we analyzed the reporting of demographics and SF in RD clinical research, here we perform a representation and policy gap analysis of this extracted data. The representation analysis evaluated 13 variables, including age, sex or gender, race, ethnicity, and SF, using four key analyses: reporting statistics, representation, participant distribution, and benchmarking against the US census data. The qualitative policy analysis included existing national and international policies and guidelines. ResultsOnly age, sex or gender, race, and ethnicity had sufficient data for the representation analysis. While diversity was moderate for these variables, equity, inclusion, and accessibility were low, particularly for racial and ethnic minorities, nonbinary genders, and older adults. Data were insufficient for MUPs such as lesbian, gay, bisexual, transgender, queer or questioning individuals, rural residents, veterans, military spouses, people affected by poverty, and religious minorities. Based on the representation analysis and building upon existing foundational policies and guidelines, we propose three recommendations and a six-pillar framework to mandate and standardize data reporting practices and improve the representation of MUPs in RD clinical research with broader relevance to all clinical research in general. The six pillars are patient advocacy, policy legislation, governmental oversight, standardized data collection and reporting, technological enablement, and global epidemiological research. ConclusionsAddressing the historical underrepresentation of MUPs requires upgrading the foundation of clinical research instead of a piecemeal, siloed approach. This study underscores the systemic gaps in the representation of MUPs in RD research and proposes a six-pillar actionable framework to address these disparities. The systematic implementation of these six pillars can enhance the integrity and outcomes of future RD clinical research.

IntroductionSocial media has become a platform for healthcare providers and parents to communicate about common and rare pediatric disorders. Neurocutaneous syndromes including Tuberous Sclerosis Complex, Neurofibromatosis, and Sturge-Weber syndrome require lifelong monitoring and complex treatments. Clinician directed information is supplemented by online support groups, non-profit fundraising organizations, and educational programs through various Facebook features. ObjectiveThe objective of this study is to explore the socialization patterns of individuals affected by neurocutaneous syndromes as they interact and engage within various Facebook forums. MethodsPublic accounts on Facebook were analyzed throughout August 2022. The search terms used were "Sturge-Weber Syndrome", "Sturge Weber", "SWS", "Tuberous Sclerosis", "Tuberous Sclerosis Complex (TSC)", and "Neurofibromatosis", "Neurofibromatosis 1 (NF1)", and "Neurofibromatosis 2 (NF2)". Facebook accounts were analyzed on the basis of page ownership and video content. ResultsSearching Sturge-Weber syndrome (SWS) yielded 99 Facebook pages and 37 Facebook videos. Tuberous sclerosis resulted in 100 Facebook pages and 139 Facebook videos. Neurofibromatosis yielded 102 Facebook pages and 129 Facebook Videos. Patient released stories comprised 51% of the Facebook videos (157/305), educational videos comprised 37% (112/305), and 12% (36/305) related to the syndromes awareness day. Facebook Pages were managed by nonprofit organizations 37% (111/301), community support groups 36% (108/301), and patients creating a "private blog" 23% (70/301), and physicians 4% (12/301). Figure 1 shows a breakdown of the Facebook page ownership and video content of neurocutaneous syndromes. ConclusionThis study describes the online discussion of neurocutaneous syndromes through social media. The benefits of anonymized discussion for patients and families are many. Physicians manage only 4% of the Facebook pages and this may represent an opportunity to further disseminate medical advice in the future.

BackgroundThe diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases. MethodsWe performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis. FindingsOur search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations. ConclusionsML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases.

BackgroundWeakness of facial, ocular, and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. MethodsWe analysed exome and genome sequencing data from three unrelated individuals with congenital myopathy characterised by striking facial, ocular, and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-seq data of one proband and performed gene expression outlier analysis in 129 samples. ResultsThe three probands had remarkably similar clinical presentation with prominent facial, ocular, and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but most prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatiguability. While muscle biopsy on light microscopy did not show any obvious morphological abnormalities, ultrastructural analysis showed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified three unique homozygous loss of function variants in JPH1, encoding junctophilin-1 in the three families; a stop-gain (c.354C>A; p.Tyr118*) and two frameshift (c.373del p.Asp125Thrfs*30 and c.1738del; p.Leu580Trpfs*16) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. ConclusionsJunctophilin-1 is critical to the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement. Key messageThis study identified novel homozygous loss-of-function variants in the JPH1 gene, linking them to a unique form of congenital myopathy characterised by severe facial and ocular symptoms. Our research sheds light on the critical impact on junctophilin-1 function in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype. What is already known on this topicPrevious studies have shown that pathogenic variants in genes encoding triad proteins lead to various myopathic phenotypes, with clinical presentations often involving muscle weakness and myopathic facies. The triad structure is essential for excitation-contraction (EC) coupling and calcium homeostasis and is a key element in muscle physiology. What this study adds and how this study might affect research, practice or policyThis study establishes that homozygous loss-of-function mutations in JPH1 cause a congenital myopathy predominantly affecting facial and ocular muscles. This study also provides clinical insights that may aid the clinicians in diagnosing similar genetically unresolved cases.

Background and ObjectivesDystonia is a common, debilitating, and often treatment refractory motor symptom of cerebral palsy (CP), affecting 70-80% of this population based on research assessments. However, routine clinical evaluation for dystonia in CP has failed to match these expected numbers. Addressing this diagnostic gap is a medical imperative because the presence of dystonia rules in or out certain treatments for motor symptoms in CP. Therefore, our objective was to optimize rates of clinical dystonia screening to improve rates of clinical dystonia diagnosis. MethodsUsing the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we developed and implemented interventions to increase the documentation percentage of five features of dystonia in young people with CP, aged 3-21 years old. This QI initiative was implemented by seven physiatry and pediatric movement disorders physicians at four tertiary-care pediatric hospitals between 10/10/21 and 7/1/23. We collected visit data cross-sectionally across all participating sites every 2 weeks and tracked our progress using control charts. ResultsWe assessed 847 unique visits, mostly for established patients (719/847, 85%) who were 9.2 years old on average (95% CI 8.8-9.5). By 4/10/22, the mean percentage of dystonia screening elements documented across all sites rose from 39% to 90% and the mean percentage of visits explicitly documenting the presence or absence of dystonia rose from 65% to 94%. By 10/23/22, the percentage of visits diagnosing dystonia rose from 57% to 74%. These increases were all sustained through the end of the study period in 7/1/23. DiscussionUsing a rigorous QI-driven process across four member sites of a North American learning health network (CPRN), we demonstrated that we could increase screening for dystonia and that this was associated with increased clinical dystonia diagnosis, matching expected research-based rates. We propose that similar screening should take place across all sites caring for people with CP.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

BackgroundAlthough individually uncommon, rare diseases (RD) collectively affect an estimated 329-624 million people worldwide There are over 6,500 known RD, 85% of which affect fewer than 1 person per million. As a result, the critical amount of data necessary to improve knowledge, care, and treatment can only be achieved through cumulative data collection across different countries in a standardized manner. However, RD are under-represented in medical terminologies and classification systems, hindering data sharing, interoperability, and public health monitoring. ObjectiveThe aim of this paper is to present the Orphanet Nomenclature and Classification of RD. We detail its content as well as its production and update methodology, and an overview of its mappings to other semantic resources. In addition, this work provides a clear and up-to-date count of RD based on the consensus operational definition of RD, and it details the distribution of RD by medical domain. MethodsThe Orphanet Nomenclature of RD is a multilingual standardized system composed of clinical entities, each defined by a unique and time-stable ORPHAcode, a preferred term, synonyms, a classification level, and a textual definition. This nomenclature is structured into three classification levels organized within a multi-hierarchical and multi-parental classification system by medical domain. Its production, updates, and mappings to major biomedical resources rely on standardized and published procedures, continuous literature review, manual curation and expert validation, reflecting advancements in RD knowledge and clinical practice. Presented data metrics were computed using the Orphanet July 2025 release to quantitatively characterize the content, structure, classification, and semantic alignments of the Orphanet Nomenclature and Classification system. ResultsAs of July 2025, the Orphanet Nomenclature of RD includes a total of 9,784 active clinical entities, including 6,527 disorders (corresponding to the RD definition), 1,084 subtypes of disorders, and 2,173 groups of disorders. Disorders are multiclassified into 29 classification hierarchies, each corresponding to a distinct medical domain, accurately representing the complex multisystemic nature of RD. Extensive qualified mappings ensure semantic interoperability: 97.4% of disorders are mapped to at least one ICD-10 code (6.4% with an exact proximity relationship), 71.8% are mapped to at least one ICD-11 MMS code (14.7% with an exact relationship) and 94.8% are mapped to SNOMED CT (all with an exact relationship). Genetic disorders represent 72.2% of all RD, and 63.4% are mapped to at least one phenotypic OMIM number. ConclusionsThe Orphanet Nomenclature and Classification of RD is the only RD-specific interoperable medical terminology meeting the needs of healthcare, research, and public health systems. By addressing the underrepresentation of RD in medical terminologies, it enables accurate RD identification, coding, and monitoring, supporting cross-border data interoperability, and contributing to improved knowledge, policy-making, and ultimately better care for people living with a RD.

The primary progressive aphasias (PPA) present complex and diverse challenges of diagnosis, management and prognosis. A clinically-informed, syndromic staging system for PPA would take a substantial step toward meeting these challenges. This study addressed this need using detailed, multi-domain mixed-methods symptom surveys of people with lived experience in a large international PPA cohort. We administered structured online surveys to caregivers of patients with a canonical PPA syndromic variant (nonfluent/agrammatic (nvPPA), semantic (svPPA) or logopenic (lvPPA)). In an exploratory survey, a putative list and ordering of verbal communication and nonverbal functioning (nonverbal thinking, conduct and wellbeing, physical) symptoms was administered to 118 caregiver members of the UK national PPA Support Group. Based on feedback, we expanded the symptom list and created six provisional clinical stages for each PPA subtype. In a consolidation survey, these stages were presented to 110 caregiver members of UK and Australian PPA Support Groups, and refined based on quantitative and qualitative feedback. Symptoms were retained if rated as present by a majority (at least 50%) of respondents representing that PPA syndrome, and assigned to a consolidated stage based on majority consensus; the confidence of assignment was estimated for each symptom as the proportion of respondents in agreement with the final staging for that symptom. Qualitative responses were analysed using framework analysis. For each PPA syndrome, six stages ranging from 1 ( Very mild) to 6 ( Profound) were identified; earliest stages were distinguished by syndromic hallmark symptoms of communication dysfunction, with increasing trans-syndromic convergence and dependency for basic activities of daily living at later stages. Spelling errors, hearing changes and nonverbal behavioural features were reported at early stages in all syndromes. As the illness evolved, swallowing and mobility problems were reported earlier in nfvPPA than other syndromes, while difficulty recognising familiar people and household items characterised svPPA and visuospatial symptoms were more prominent in lvPPA. Overall confidence of symptom staging was higher for svPPA than other syndromes. Across syndromes, functional milestones were identified as key deficits that predict the sequence of major daily life impacts and associated management needs. Qualitatively, we identified five major themes encompassing 15 subthemes capturing respondents experiences of PPA and suggestions for staging implementation. This work introduces a prototypical, symptom-led staging scheme for canonical PPA syndromes: the PPA Progression Planning Aid (PPA2). Our findings have implications for diagnostic and care pathway guidelines, trial design and personalised prognosis and treatment for people living with these diseases.

IntroductionRelatives of a victim of sudden cardiac death in the young (SCDY) may be at risk for hereditary cardiomyopathies and arrhythmias. Family leaders are often responsible for communicating risk to surviving family at a difficult time. PurposeExplore barriers and facilitators to communication about cascade screening in families who have lost a family member to SCDY MethodsSemi-structured interviews (n = 14) were conducted with family members of a SCDY decedent. Participants were recruited from the Sudden Arrhythmia Death Syndrome advocacy group. Interviews were conducted until data saturation was reached. Interviews were audio recorded, transcribed, and analyzed using conventional content analysis. ResultsFive categories were identified from the interviews: 1. Participants understood fundamental risks but the clinical variability in arrhythmia and cardiomyopathy was difficult to interpret and convey; 2. Family leaders felt some family disregarded risk information; 3. Grief interfered with communication; 4. Communication aids were insufficient stand-alone interventions; 5. Families advocated for a "genetic family navigator". ConclusionThe five categories provide practical strategies to improve clinical care and communication for families after a SCDY and emphasize the need for genetic family navigators to facilitate cascade screening. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/24302009v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@25844aorg.highwire.dtl.DTLVardef@11029d6org.highwire.dtl.DTLVardef@2ad67dorg.highwire.dtl.DTLVardef@67bb17_HPS_FORMAT_FIGEXP M_FIG C_FIG

Misophonia is a disorder of decreased tolerance to specific sounds or their associated stimuli that has been characterized using different language and methodologies. The absence of a common understanding or foundational definition of misophonia hinders progress in research to understand the disorder and develop effective treatments for individuals suffering from misophonia. From June 2020 through January 2021, a project was conducted to determine whether a committee of experts with diverse expertise related to misophonia could develop a consensus definition of misophonia. An expert committee used a modified Delphi method to evaluate candidate definitional statements that were identified through a systematic review of the published literature. Over four rounds of iterative voting, revision, and exclusion, the committee made decisions to include, exclude, or revise these statements in the definition based on the currently available scientific and clinical evidence. A definitional statement was included in the final definition only after reaching consensus at 80% or more of the committee agreeing with its premise and phrasing. The results of this rigorous consensus-building process were compiled into a final definition of misophonia that is presented here. This definition will serve as an important step to bring cohesion to the growing field of researchers and clinicians who seek to better understand and support individuals experiencing misophonia.

BackgroundAutism is a normal part of cognitive diversity, resulting in communication and sensory processing differences, which can become disabling in a neurotypical world. Autistic people have an increased likelihood of physical and mental co-occurring conditions and die earlier than neurotypical peers. Inaccessible healthcare may contribute to this. Autism Health Passports (AHPs) are paper-based or digital tools which can be used to describe healthcare accessibility needs; they are recommended in UK clinical guidance. However, questions remained as to the theoretical underpinnings and effectiveness of AHPs. MethodsWe undertook a systematic literature search identifying studies focused on AHPs for adults (aged over 16 years) from five databases. Included literature was subjected to realist evaluation. Data were extracted using a standardised form, developed by the research team, which considered research design, study quality for realist review and the Context, Mechanisms and Outcomes (CMOs) associated with each AHP tool. Findings162 unique records were identified, and 13 items were included in the review. Only one item was considered high quality. Contextual factors focused on the inaccessibility of healthcare to Autistic patients and staff lack of confidence and training in supporting Autistic needs. Interventions were heterogeneous, with most sources reporting few details as to how they had been developed. The most frequently included contents were communication preferences. Mechanisms were often not stated or were inferred by the reviewers and lacked specificity. Outcomes were included in four studies and were primarily focused on AHP uptake, rather than Outcomes which measured impact. ConclusionThere is insufficient evidence to conclude that AHPs reduce the health inequalities experienced by Autistic people. Using an AHP tool alone, without the inclusion of the local Autistic community developing the tool, and a wider intervention, such as training for staff or the use of local champions, may mean that AHPs do not trigger any Mechanisms, and thus cannot affect Outcomes.