Orphanet Journal of Rare Diseases

Background CLN2 disease, Neuronal Ceroid Lipofuscinosis (NCL) type 2, is a rare, genetic neurodegenerative condition predominantly affecting children. CLN2 disease is characterized by seizures, language and motor decline, vision loss, and premature death. Currently, the only regulatory-approved therapy is the enzyme replacement therapy (ERT) Cerliponase alfa, administered fortnightly via intracerebroventricular infusion as a lifelong treatment. While ERT has been shown to slow motor and language decline, it is not curative and does not fully address disease progression, including retinal degeneration. To better understand the lived experience of affected families, and perspectives on current and emerging treatments, we conducted a community survey of parents and caregivers of individuals with CLN2 disease. Methods A 25-question anonymous, voluntary survey was distributed through the BDSRA Foundation and international partner patient advocacy organisations via email and social media. Eligible participants included current and bereaved parents or primary caregivers of individuals with CLN2 disease, regardless of treatment history. The survey explored treatment experiences, unmet needs, and knowledge of and attitudes toward emerging therapeutic approaches, particularly gene-based therapies. Results Ninety-eight respondents from 19 countries completed the survey. Fifty-seven respondents reported current or prior use of ERT, with 94.7% (n=54/57) actively receiving treatment at the time of survey. ERT was perceived to provide greatest benefit for motor function and seizure control; however, respondents reported substantial treatment burden (mean burden score 4.8/7, n=66). Despite treatment availability, 94.9% of respondents (n=75/79) indicated a need for alternative therapeutic options and 94.8% (73/77) expressed interest in learning more about gene therapy. Overall, 72.4% (n=55/76) reported they were likely or very likely to consider participation in an investigational gene therapy trial. Key factors influencing decision-making included potential safety risks (57.9%, n=44/76), preclinical safety and efficacy evidence (54.0%, n=41/76), and whether ERT discontinuation would be required to participate (54.0%, n=44/76). Conclusion While ERT has altered the treatment landscape for CLN2 disease, this survey highlights the ongoing disease burden and treatment challenges experienced by families. Findings demonstrate strong community interest in next-generation therapies that may reduce treatment burden and provide more comprehensive disease modification, including effects on both central nervous system (CNS) and ocular manifestations.

BackgroundKATNIP (Katanin-interacting protein), also known as KIAA0556, is one of the human genes with pathogenic variants linked to Joubert syndrome, an archetypal neurodevelopmental ciliopathy. KATNIP is a scaffolding protein with a critical role in ciliogenesis. In this study, we characterized the ciliopathy phenotypes due to KATNIP gene deletion. ResultsWe produced a Katnip null mouse model using CRISPR-Cas12a (Cpf1). The null heterozygotes appeared normal while the homozygotes died around postnatal day 9, showing severe hydrocephalus and deficiency in neuroprogenitor cell proliferation. Katnip-deficient cells in the brain have a higher rate of cilia formation and longer cilia than wild type cells. ConclusionKATNIP loss of function gives rise to hydrocephalus found in Joubert syndrome. The results indicate that KATNIP restricts ciliogenesis and cilia extension and supports proliferation of neuroprogenitor cells in the brain.

Background: Adult autism services research is hampered by a lack of accessible self-reported outcome measures. The AASPIRE Outcomes Project used a community-based participatory research (CBPR) approach to create and test the AASPIRE Measurement Toolkit, a set of accessible survey instruments for use in real-world settings. The core toolkit contains 12 characteristics modules and 19 outcome measures, each with self-reported and caregiver-reported versions. Methods: In a prior phase of the project, we collaboratively adapted, revised, or co-created all instruments. We used our CBPR-nested Delphi process, our collaborative adaptation/creation process, and cognitive interviews to ensure accessibility and content validity. We then conducted a longitudinal survey to validate the 19 outcome measures in a pragmatic sample of 870 autistic adults from two healthcare systems, two disability service systems, and the larger autistic community in the United States. Participants completed surveys at 3 time points over 12-18 months. A 15% random subset completed an additional retest survey 2 weeks after the second time point. We assessed 1) accessibility using completion rates and perceived ease of use; 2) internal consistency using Cronbach's alphas and omegas; 3) convergent validity using Pearson's correlations; 4) two-week test-retest reliability using interclass correlation coefficients; and 5) six-month responsiveness to change by comparing self-perceived change with change in scores. Results: Over 90% of participants reported the survey items were easy to understand; over 90% of participants who started the survey completed all applicable sections at each time point; and participants answered 99% of items on each instrument. The outcome measures and their pre-determined subscales demonstrated strong accessibility, content validity, internal consistency reliability, test-retest reliability, convergent and discriminant validity, and responsiveness to change. Conclusion: The AASPIRE Measurement Toolkit is accessible and includes 19 outcome measures with strong initial psychometric properties. We will report in-depth assessments of construct and structural validity separately for each measure. All instruments are available for free and can help clinicians, service providers, advocacy organizations, and researchers assess the effectiveness of interventions and follow changes in outcomes over time.

IntroductionNeuromuscular disorders (NMDs) encompass a broad group of conditions that primarily affect the peripheral nervous system. They are often caused by genetic alterations that impair skeletal muscle function and result in debilitating symptoms. Obtaining an accurate molecular diagnosis remains a challenge, potentially because variants in genes that have yet to be identified as causal. We therefore used advanced computational methods to study the genetic architecture of NMDs and to identify key features that distinguish NMD genes from other genes in the broader genome. MethodsCurated genes implicated in NMDs (n = 639; GeneTable of NMDs) were obtained and merged with a comprehensive set of genomic features for human autosomal protein-coding genes. Machine-learning-based feature selection and ranking were performed using Boruta, along with complementary analytical approaches. These analyses were used to identify the most important genic features (n = 134, subcategories: gene complexity, genetic variation, expression patterns, and other general gene traits) for discriminating NMD genes from other genes in the genome ResultsNMD genes exhibit enriched expression in disease-relevant tissues, including skeletal muscle and heart. Additionally, compared with other protein-coding genes, these genes exhibit increased transcriptomic complexity (e.g., longer transcripts and more unique isoforms), contain more short tandem repeats, and show greater variation in conservation across model organisms. ConclusionsThis study identified several key genomic features that may distinguish NMD genes from the rest of the genome. This may enhance the identification of novel causal genes and could ultimately facilitate earlier diagnosis and medical management for affected individuals.

Background and ObjectivesHereditary transthyretin amyloidosis (hATTR) manifests as cardiomyopathy and/or polyneuropathy. Patients may be thought to have neuropathy for a variety of reasons, but the clinical evidence supporting that impression varies. We used ICD-10 coding to broadly capture patients thought to have neuropathy in a V142I-predominant cohort and examined what clinical documentation actually supported the diagnosis and whether documentation level influences treatment selection. MethodsRetrospective chart review of 54 patients identified by co-occurring ICD-10 codes for hereditary transthyretin amyloidosis and polyneuropathy at a major academic medical center, with pathogenic TTR variant confirmation. Neuropathy codes were then classified by the level of clinical evidence supporting the diagnosis. Treatment with TTR stabilizers and gene silencers was assessed. ResultsOf 54 patients (88.9% African American, 85.2% V142I), 51 (94.4%) had confirmed cardiac involvement with 40/42 eligible (95.2%) receiving stabilizers. Sixteen patients (29.6%) received gene silencers, with 13 receiving both concurrently. Clinical evidence supporting the neuropathy code was identified in 30 patients (55.6%): ancillary testing confirmation in 17 (31.5%), provider documentation without ancillary testing in 13 (24.1%), and symptoms only in 10 (18.5%). The remaining 14 (25.9%) had no clear clinical basis for the code. Gene silencer use was highest among those with ancillary testing (47.1%) versus symptoms only (10.0%). DiscussionAmong hATTR patients coded for neuropathy, only 31.5% had ancillary testing confirmation. Gene silencer use tracked with documentation quality rather than the presence of a code alone. These findings highlight the gap between administrative coding and clinical documentation and support standardized neurological assessment in hATTR.

BackgroundFabry disease (O_SCPLOWFDC_SCPLOW) is a rare and severe disease affecting multiple organ systems. However, its non-specific and heterogeneous presentation poses a critical challenge for early diagnosis, often delaying necessary treatment. In re-cent years, imaging-based biomarkers have been increasingly proposed to improve the understanding of O_SCPLOWFDC_SCPLOW and aid its diagnosis. This study presents a comprehensive comparative analysis of several previously proposed imaging-based cardiac biomarkers to assess their potential for diagnostic use. MethodsWe have developed a fully automated image analysis pipeline for quantifying cardiac metrics based on short-axis cine O_SCPLOWCMRC_SCPLOW data available on the UK Biobank. ResultsBased on the UK Biobank cohort, our analyses confirm the diagnostic relevance of the maximum myocardial wall thickness, a metric that mimics the current clinical practice for diagnosing left ventricular hypertrophy. Initial evidence also suggests that the PM/LV ratio, which measures the papillary muscle hypertrophy as the ratio between the areas of the papillary muscles and the left ventricular cavity, has potential prognostic relevance. ConclusionThis study contributes towards a better understanding of the cardiac presentation of FD, which may support future research in improving the diagnostic process. Additionally, our analysis pipeline can serve as a valuable basis for additional data analysis of imaging-based biomarkers for O_SCPLOWFDC_SCPLOW and other diseases.

Jordans Syndrome (JS) is a rare, neurodevelopmental disorder caused by de novo missense mutations in protein phosphatase 2 regulatory subunit Bdelta (PPP2R5D). JS is characterized by severe neurological impairments starting in early life. PPP2R5D encodes for B56{delta}, one of the regulatory subunits of protein phosphatase 2A (PP2A). PP2A is a heterotrimeric protein serine/threonine phosphatase that is highly expressed in the brain and the liver. Past studies have focused on PP2As role in liver and little is known about the holoenzymes behavior in neuronal cells. Although B56{delta} is known to play an important role in the substrate specificity of PP2A, the identification of validated downstream substrates in JS remains unclear. To better understand how the mutations affect neuronal cells, we developed cerebral cortical-like organoids from an engineered allele series of the most common JS mutations to characterize the physiological changes throughout different stages of neurodevelopment. Organoids were assessed for transcriptomic, protein, and electrophysiological changes utilizing bulk RNA sequencing, immunocytochemistry, Western Blot, and high-density MicroElectrode Array. The results identify differentially expressed genes and translated proteins, potential neuronal substrates, and significant electrophysiological signatures that suggest mutations in B56{delta} lead to variant-specific dysfunction of PP2A. Overexpression of PPP2R5D through AAV transduction of organoids rescued several phenotypes in the variants, suggesting different pathogenetic etiology underneath. Our findings successfully characterized cerebral cortical-like organoids in JS cell lines and demonstrated its potential as a model for studying neurodevelopmental disorder and for screening therapeutic approaches.

Background: The Colour Blind Quality of Life Scale (CBQoL) is a questionnaire developed to assess the quality of life of individuals with congenital colour vision deficiency (CVD). This study aimed to translate the English version of the CBQoL into Vietnamese and evaluate the validity and reliability of the Vietnamese version (CBQoL-VN). Methods: A forward-backward translation method was performed to produce the Vietnamese text. Content validity was assessed by six experts in vision care. Reliability testing involved 30 participants with congenital CVD, while discriminant validity was evaluated by comparing this group against 30 participants with normal colour vision. Results: Following expert consensus, two items were removed and one transportation-related item was added. The content validation index (CVI) values of 1.0 for relevance, clarity, and understandability indicated excellent content validity. Internal consistency was high, with a Cronbach's alpha of 0.95 for the full scale. Discriminant validity analysis showed that participants with congenital CVD scored significantly lower across all CBQoL-VN domains compared to those with normal colour vision. Conclusions: The modified CBQoL-VN is a valid and reliable instrument for assessing the quality of life of individuals with congenital CVD in the Vietnamese population.

Background Heterotaxy (HTX) describes abnormal left-right arrangement of the organs, often associated with complex congenital heart disease (CHD). HTX is enriched in the respiratory condition primary ciliary dyskinesia (PCD) due to defective nodal cilia. A subset of patients presents with HTX and mild respiratory phenotypes but normal respiratory cilia function. The mechanisms underlying situs defects in these non-PCD patients remain unclear. Methods Retrospective diagnostic data were analysed from 73 HTX patients who had been referred to the Royal Brompton Hospital PCD Diagnostic Service (1997 to 2023). Data included clinical history, high-speed video microscopy, transmission electron microscopy of ciliary ultrastructure, PCD genotype and clinical imaging for cardiac and abdominal situs. Results 30 patients were diagnosed with PCD, and 43 patients did not have PCD. CHD was observed in both PCD and non-PCD groups. Atrioventricular discordance was more frequent in non-PCD HTX (20.9% vs 0%; p=0.0102). Midline Liver position was also enriched in the non-PCD HTX group compared to PCD patients with HTX (54.3% vs 25.9% p=0.0377). TEM revealed 24.4% of the non-PCD patients had extra ciliary microtubules and 24.4% demonstrated microtubular disorganization. Review of diagnostic results from 2,823 referred patients showed a higher incidence of ultrastructural ciliary anomalies, such as extra microtubules or microtubular disorganisation, in individuals with CHD who did not have PCD (p=0.04 when compared to patients without CHD, regardless of HTX). Quantitative ciliary function assessment demonstrated preserved or higher ciliary beat amplitude in non-PCD HTX compared to PCD patients. Conclusions In conclusion, HTX can be linked to respiratory ciliary dysfunction, even in patients without classical PCD. Subtle ciliary defects in non-PCD HTX patients associate with higher rates of CHD and abnormal organ situs. Genetic and phenotypic diversity in HTX highlights the need for expanded genetic testing and future multicentre studies to assess outcome.

Self-determination has been assessed as an internal psychological construct. External factors may also affect self-determination, but opportunities to make choices and decisions remain understudied. We developed and evaluated the AASPIRE-Choices and Decisions Scale (AASPIRE-CDS), a new measure of autistic adults opportunities to make choices and decisions, using a community-based participatory approach. We created and refined the AASPIRE-CDS through an iterative process. Data, from the AASPIRE Outcomes Project, included 839 autistic adults participating through direct report, supported direct report, and caregiver report (CR). Exploratory and confirmatory analyses supported a unidimensional structure. Measurement invariance analyses supported configural, metric, and partial scalar invariance across report type without CR, and across living status, with and without CR. The AASPIRE-CDS showed high internal consistency, test-retest reliability, and responsiveness to change over time. Convergent validity analyses showed that higher AASPIRE-CDS scores were associated with greater self-determination and communication fluency, more independent living, and fewer support needs. The AASPIRE-CDS showed weaker (albeit significant) associations with quality of life, overall health, and employment satisfaction than the self-determination measure showed with these variables. This pattern suggests that opportunities for choice-making are related to, but distinct from, commonly used measures of self-determination. Findings support the AASPIRE-CDS as a valid and reliable measure of choice-making opportunities in autistic adults across support needs but suggest caution interpreting CR. They underscore the importance of supporting autistic adults choice-making and evaluating opportunities for choice alongside internal self-determination. Future research should use larger CR samples to examine the validity of caregiver-reported choice-making opportunities.

Background: Diagnosing the over 700 known rare bone diseases (RBDs) is inherently challenging and often requires extensive time and multiple clinical visits. Effective treatment, particularly for RBDs with approved therapies, depends on early and precise identification of the specific RBD type. Image recognition artificial intelligence (AI) has the potential to significantly enhance diagnostic processes and improve patient outcomes. Many of these disorders cause characteristic skeletal changes, especially in the hands, and are associated with growth abnormalities. Consequently, affected children routinely undergo hand radiographs for bone age assessment, making these images a widely available yet underutilized diagnostic resource. Materials and Methods: We retrospectively compiled 5,623 multi-institutional hand radiographs from 2,471 patients with 45 different RBDs and 1,382 unaffected controls. We trained two deep learning models: a binary classifier to differentiate between RBD and non-RBD hand radiographs, and a multi-class classifier covering ten RBDs (or RBD groups), using 5-fold cross-validation. Preprocessing included masking, normalization, and data augmentation. Additionally, we applied occlusion sensitivity mapping to visualize class-specific features and evaluated the learned representations through cosine-based retrieval and UMAP projections of the feature space. Results: The affected versus unaffected classifier achieved a balanced accuracy of 85.5% on the test dataset. The ten-class classifier reached a balanced (top-1) accuracy of 76.6%, with top-3 accuracy exceeding 90%. Disorders with highly distinctive phenotypes, such as achondroplasia, achieved accuracies above 95%, whereas phenotypically overlapping disorders, such as ACAN- and SHOX-related short stature, were more frequently confused. Feature space analysis showed that validation samples clustered closely with their respective training distributions, supporting the consistency and generalizability of the learned embeddings. Conclusion: This manuscript presents a proof of principle for the development of Bone2Gene, a next-generation phenotyping (NGP) tool for the detection and differential diagnosis of RBDs, currently based on hand radiographs. Ongoing efforts focus on expanding the dataset to include additional RBDs or RBD groups in the current multi-class classifier for differential diagnosis and to further evaluate its generalizability. The Bone2Gene study is open to collaboration.

IntroductionSpinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD) are progressive genetic neuromuscular disorders imposing substantial caregiving demands on families. In Pakistan, where disease-modifying therapies remain largely inaccessible, care is predominantly supportive, frequently resulting in psychological distress and diminished caregiver confidence. An individuals belief in their capacity to execute required behaviours, self-efficacy, is a recognised determinant of caregiving quality, yet evidence on caregiver self-efficacy in SMA and DMD within low-resource settings remains sparse. This study aims to evaluate the effect of a multicomponent, digitally delivered intervention on self-efficacy among primary caregivers of children with SMA and DMD in Pakistan. Methods and AnalysisThis single-group, pre-post study will recruit 30 primary caregivers of children with SMA or DMD enrolled in the Treat-NMD Registry of Pakistan. An eight-week intervention will be delivered via online support groups, comprising educational video clips, expert-led live sessions, pictorial guides, and progressively tapering audio reminders. The primary outcome, self-efficacy, will be measured using a culturally adapted, content-validated Urdu version of the DMD Caregiver Self-Efficacy Scale (DMD-CSES), assessed at baseline (T0) and eight weeks post-intervention (T1). Pre-post scores will be compared using a paired t-test or Wilcoxon signed-rank test depending on data distribution, with analyses conducted in STATA Version 17. Ethics and DisseminationEthical approval has been granted by the Ethics Review Committee of Aga Khan University (2025-11875-37040). Verbal informed consent will be obtained from all participants, with confidentiality maintained throughout. Findings will be disseminated via peer-reviewed publication, conference presentations, and shared with the Treat-NMD registry network. Trial registration numberNCT07356063, Date of registration: 11/January/2026

BackgroundAdministering and interpreting intelligence tests for adults with visual impairment (VI) presents practical and methodological challenges, because standard test batteries rely heavily on visual tasks and lack specific norm-groups tailored to this population. This study examined practical adaptations and interpretation strategies currently used in intelligence testing based on international literature and input from Dutch low vision service (LVS) providers. MethodsA mixed-method design was applied. An exploratory literature review was conducted using PubMed, PsycINFO, Google Scholar and Web of Science to identify studies published in the past ten years addressing adaptations and/or interpretation of intelligence tests. Additionally, semi-structured interviews were held with nine healthcare professionals (HCPs) from Dutch LVS organizations to explore current practices and perceived needs. ResultsEight publications met inclusion criteria. All reported use of intelligence tests; six described task adaptations, which varied considerably. One addressed interpretation of results for adults with VI. None reported norm-groups adapted for people with VI. Interviews highlighted challenges due to absence of accessible tests, leading HCPs to solely rely on the assessment of verbal subtests, mainly of the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) or making adaptations to the assessment of performance tasks for observational purposes. Approaches to administering tests varied widely. ConclusionBoth literature and interviews with HCPs indicate that no specific intelligence tests tailored for adults with VI have been developed in the past decade, making accurate Total Intelligence Quotient (TIQ) measurement currently impossible. There is an urgent need for tailored tests with corresponding norm-groups and/or standardized protocols to ensure validity and consistency. Until then, HCPs should select predominantly verbal subtests tailored to the individual, observe performance closely, and explicitly report considerations. Strengths and limitations of this studyO_LIMixed-methods design combining an exploratory literature review with qualitative interviews enabled methodological triangulation and a comprehensive understanding of current practices. C_LIO_LISystematic and transparent review procedures, including dual independent screening, use of JBI critical appraisal tools, and PROSPERO registration, enhanced methodological rigor. C_LIO_LIA final strength was the use of established qualitative data collection and analysis approaches (semi-structured interviews, reflexive thematic analysis, and double coding), which enhanced the depth and credibility of the findings. C_LIO_LIThe exploratory (non-systematic) nature of the literature review, including broad database searches and absence of a fully reproducible search strategy, may limit reproducibility and increase the risk of selection bias. C_LIO_LILastly, qualitative sampling through snowball recruitment within a single national context (Dutch LVS) and a relatively small sample size may limit transferability and increase the risk of selection bias. C_LI Key messages- Recent literature on intelligence testing in adults with Visual Impairment (VI) provides no evidence of valid and reliable tools for accurately measuring Total Intelligence Quotient (TIQ); - Healthcare professionals (HCPs) working with adults with VI primarily administer verbal subtests from the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV); - More research should be performed on the development of specific intelligence tests and adapted norm-groups tailored to adults with VI to assess valid TIQ.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0-97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

Wolfram syndrome is a rare genetic disorder characterized by antibody-negative early-onset atypical diabetes mellitus, optic nerve atrophy, sensorineural hearing loss, diabetes insipidus (arginine vasopressin deficiency), and progressive neurodegeneration, with significant variability in disease severity. We assessed the accuracy of a genotype-based severity scoring system to predict the onset of cardinal symptoms in Wolfram syndrome. This system is based on the type of WFS1 variants (in-frame or out-of-frame) and their location relative to transmembrane domains. Severity scores were assigned to 324 patients with documented onset ages for diabetes mellitus, optic atrophy, hearing loss, and diabetes insipidus. Our analysis revealed a clear correlation between severity scores and earlier onset of diabetes mellitus and optic atrophy. Patients with in-frame variants outside transmembrane domains exhibited milder symptoms, especially WFS1 c.1672C>T (p.Arg558Cys) variant, whereas those with out-of-frame variants showed the earliest onset. Severity scores 3 and 4 did not follow the expected progression, suggesting that transmembrane domain involvement in both alleles may result in greater severity. These findings suggest that this scoring system provides valuable insights into the progression of Wolfram syndrome and may guide clinical care. Further refinement may improve its utility for predicting the onset of non-diabetic symptoms.

BackgroundApproximately 300 million people worldwide live with a rare disease, and the majority of rare diseases manifest in childhood. For families, the period before diagnosis is often protracted and distressing, marked by repeated consultations, inconclusive investigations, conflicting medical opinions, and the absence of a recognisable name for their childs condition. While the clinical and epidemiological dimensions of the diagnostic odyssey have been documented, the narrative and experiential dimensions of how parents live through and make sense of prolonged diagnostic uncertainty remain underexplored, particularly in low- and middle-income country contexts. AimTo explore the narrative experiences of parents navigating diagnostic uncertainty for children with rare diseases in Brazil. MethodsA narrative inquiry informed by the three-dimensional narrative space framework of Clandinin and Connelly was conducted. Sixteen parents (twelve mothers and four fathers) of children who had experienced a diagnostic delay of at least two years were recruited from two rare disease referral centres in Sao Paulo and Belo Horizonte. Data were collected through two narrative interviews per participant, supplemented by participant-produced timelines and family photographs. Analysis followed a narrative analytical approach attending to temporality, sociality, and place. FindingsThree narrative threads were woven across the parents stories: (a) "Living in the space before the name," capturing the disorienting experience of caring for a child whose suffering could not be categorised, explained, or predicted; (b) "Fighting to be believed," describing the relentless advocacy required to sustain medical attention in a system that struggled to accommodate conditions falling outside familiar diagnostic categories; and (c) "Rewriting the story," illuminating how the eventual arrival (or non-arrival) of a diagnosis reshaped parents understanding of their child, their family, and themselves. ConclusionDiagnostic uncertainty for parents of children with rare diseases is not a passive waiting period but an active, effortful, and identity-transforming experience. The findings highlight the need for healthcare systems to provide structured psychosocial support during the pre-diagnostic period and for clinicians to develop communication practices that acknowledge, rather than dismiss, the legitimacy of undiagnosed suffering.

BackgroundCongenital heart defects (CHDs) contribute to approximately 220,000 childhood deaths globally each year, with most occurring in low- and middle-income countries. Despite advances in diagnosis and management, survival remains poor in sub-Saharan Africa due to delayed diagnosis and limited access to specialized care. In Uganda, an estimated 16,000 children are born with CHDs annually, many requiring urgent intervention. Despite this burden, evidence on survival and its determinants in Uganda remains limited. This study aimed to investigate socio-demographic and clinical factors associated with survival among children born with CHDs at the Uganda Heart Institute. MethodsA retrospective cohort study was conducted using electronic patient records of children diagnosed with congenital heart defects at the Uganda Heart Institute between January 2014 and December 2018. Survival analysis was performed using the log-rank test to assess differences across groups, and the Cox proportional hazards regression model was used to identify independent predictors of mortality. ResultsChildren residing in rural areas had a significantly higher hazard of death compared to those in urban areas (HR = 1.33; 95% CI: 1.06-1.66; p = 0.013). Underweight children had more than twice the hazard of death compared to those with normal BMI (HR = 2.07; 95% CI: 1.60-2.69; p < 0.001). Defect severity was significantly associated with survival, with moderate defects showing increased hazard relative to critical defects (HR = 1.98; 95% CI: 1.25-3.13; p = 0.004), while non-critical defects were not statistically significant. Timing of diagnosis was a strong predictor of mortality (HR = 1.67; 95% CI: 1.30-2.14; p < 0.001), indicating that delayed diagnosis increases the risk of death. Oxygen level was not significantly associated with survival. ConclusionSurvival among children with congenital heart defects is significantly influenced by nutritional status, place of residence, defect severity, and timing of diagnosis. Underweight children, those from rural areas, and those diagnosed later have a higher risk of mortality. Early detection and improved nutritional support are essential to enhance survival outcomes. Strengthening early screening programs and improving access to timely diagnosis and specialized care, particularly in rural settings, are critical to reducing mortality.

BackgroundFunctional neurological disorder (FND) is one of the most common, but least researched, conditions in neurology. Debate exists as to whether the clinical entity referred to as FND is truly a single disorder or is in fact multiple entities which have been erroneously amalgamated into the same condition. We sought to provide empirical evidence on this question by treating it as a problem of model comparison. MethodsWe formulated statistical models equivalent to: (1) FND being a single entity with variation in phenotype, represented by latent trait (binary factor/item response theory) models, and (2) FND being multiple discrete entities, represented by latent class analysis (LCA) models. We fitted these models to data on the symptoms experienced by 697 people with FND from the FND Research Connect database (fnd-research.org) and used Bayesian model comparison methods to compare them. ResultsAll but one of the latent trait models, representing FND as a single entity with heterogeneous phenotype, fit the data better than all the LCA models. Secondary analysis of the LCA models showed results compatible with the models capturing discretisation of continuous variation rather than true discrete categories. DiscussionOur results suggest that the symptom structure of FND is the result of a single pathophysiological process, either as a single entity, or a common pathway preceded by multiple causative processes where the common pathway is solely responsible for the phenotype of the condition.

BackgroundDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which encodes dystrophin in skeletal muscle cells. Although the role of dystrophin as a structural protein is well known, the cellular processes underlying myofiber degeneration are still not fully understood. Despite advances from studies in murine models, these models do not fully replicate the human pathology. MethodsWe investigated sarcolemmal integrity, membrane repair capacity, and annexin protein expression in DMD patient muscle biopsies and human skeletal muscle cell lines using immunohistochemistry, both shear stress-based and laser irradiation injury assays, western blotting, and live-cell imaging of GFP-tagged annexins. ResultsWe identified defective membrane repair in DMD skeletal muscle cells, independent of increased membrane fragility, by evaluating resealing capacity in control and DMD derived-patient cell lines using both a shear stress assay (N = l2, p < 0.000l) and a laser irradiation assay (N = 3, p < 0.000l). Analyses performed on human DMD muscle biopsies (N = l0) further confirmed this defect, demonstrating massive intracellular IgG uptake (p < 0.000l) together with altered annexin expression profiles. While mechanical stress induces the upregulation of annexin A5 (ANXA5, p < 0.0l) and A6 (ANXA6, p < 0.05) in healthy skeletal muscle cells - suggesting an adaptive response to membrane damage, given the annexin familys central role in membrane repair - we observed dysregulated expression patterns of these proteins in DMD cells. Notably, ANXAl (p < 0.05) and ANXA2 (p < 0.0l) were not only significantly overexpressed but also aberrantly localized to the extracellular space, a putative consequence of defective membrane repair. Since extracellular ANXA2 has been associated with adipocyte accumulation in the muscle tissue of patients with dysferlinopathy, a similar pathological mechanism may be at play in DMD. ConclusionsOur findings propose that ANXA2 contributes to muscle degeneration in DMD and highlight it as a potential therapeutic target to prevent adipogenesis and muscle loss.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.