Orphanet Journal of Rare Diseases

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).

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.

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.

Background: Hereditary transthyretin amyloidosis (hATTR) manifests as cardiomyopathy and/or polyneuropathy. The V142I variant predominantly causes cardiac disease in African Americans, though neurological involvement may be underrecognized. We characterized neuropathy documentation and treatment patterns in a predominantly V142I cohort. Methods: Retrospective review of 54 hATTR patients at a major academic medical center. Neuropathy was classified as: objective (abnormal EMG), possible polyneuropathy (documented symptoms suggestive of polyneuropathy), symptoms only (neuropathic symptoms without specialist evaluation), or unclear. Treatment with stabilizers (tafamidis, acoramidis, diflunisal) and gene silencers (patisiran, vutrisiran, eplontersen) was assessed. Results: Of 54 patients (88.9% African American, 85.2% V142I), 51 (94.4%) had confirmed cardiac involvement. Among cardiac patients, 40/42 eligible (95.2%) received stabilizers. Overall, 16 patients (29.6%) received gene silencers, with 13 (24.1%) receiving both a stabilizer and gene silencer concurrently. Possible neuropathy (objective, possible polyneuropathy, or symptoms) was documented in 30 patients (55.6%). Gene silencer use was highest among those with objective neuropathy (8/17, 47.1%) versus symptoms only (1/10, 10.0%). All three patients without confirmed cardiac disease received gene silencers. Conclusions: In this V142I-predominant cohort with 94.4% cardiac involvement, stabilizer use was high (95.2%) among eligible patients. Over half had possible neuropathy based on clinical documentation, though EMG completion was limited (57.4%). Gene silencer use was associated with objective neuropathy documentation and non-cardiac phenotype. These findings support systematic neurological assessment in hATTR, even when cardiac disease predominates.

Background and objectivesSTXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. MethodsIn this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. ResultsEighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). DiscussionQuantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

PIK3CA-related overgrowth spectrum (PROS) comprises a heterogeneous group of disorders caused by postzygotic activating variants in PIK3CA, leading to mosaic activation of the PI3K pathway. PROS natural history is highly variable across patients and depends on the timing and distribution of the somatic mutation. To better characterize this natural history, we analyzed a cohort of patients with PROS. This multicenter study was conducted at Hopital Femme Mere Enfant (Lyon, France) and Hopital Necker-Enfants Malades (Paris, France). We included pediatric and adult patients with PROS who had a documented PIK3CA variant and at least two MRI examinations performed at least 2 months apart. Patients undergoing interventional surgical or radiological procedures, or receiving targeted therapies were excluded. In all patients, target lesions were identified on baseline MRI scans, and assessed on follow-up scans according to the RECIST criteria. Among 67 PROS patients screened from 2008 to 2021, 30 met the inclusion criteria, including 43.3% female patients. The median age at first MRI was 19 years (interquartile range, 5 to 34) and the median interval between the two scans was 75.7 months (range, 2.1 to 160.3 months). Recurrent localizations included the face (n = 6; 20%), ear, nose and throat region (n = 3; 10%), upper limbs (n = 5; 16.7%), thorax (n = 3; 10%), abdomen (n = 4; 13.3%), pelvis (n = 5; 16.7%), and lower limbs (n = 10; 33.3%), with some patients presenting multisite involvement. During the observation period, 86.6% (n = 26) of patients exhibited an increase in target lesion volume, with a median progression of 37.8% (range, 2.6 to 233.0%) and a mean progression of 52% (standard error of the mean, 7.2%), reflecting a right-skewed distribution driven by a subset of rapidly enlarging lesions. In conclusion, this study provides the first radiological description of the natural history of PROS, demonstrating that tissue malformations most often enlarge over time, with sustained progression persisting into adulthood.

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.

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.

BackgroundExome sequencing (ES) has become a key diagnostic tool for rare diseases (RDs). However, most evidence on ES performance comes from high-income countries and patients from European ancestry. In countries such as Chile, limited access to next generation sequencing amplifies health disparities and highlights the need to identify which patients are most likely to benefit from ES. MethodsThis study presents the second phase of the Chilean DECIPHERD project, in which we performed ES in a new group of patients with RDs presenting with multiple congenital anomalies (MCA), neurodevelopmental disorders (NDD), and/or suspected inborn errors of immunity. To identify clinical and demographic factors associated with an increased probability of obtaining an informative ES result, we conducted a logistic regression analysis, combining the results of the first and second phases of the project. We also objectively evaluated global ancestry measured using ADMIXTURE, as a potential factor. ResultsSixty-seven patients participated in this second phase of DECIPHERD with a median age of 6 years (range: 0-27); 55.2% were female, with an average ({+/-} s.d.) proportion of Native American ancestry of 0.615 {+/-} 0.18. Clinically, 52.2% presented with both MCA and NDD, and the rest had other phenotype combinations. An informative result, including pathogenic or likely pathogenic variants in genes consistent with the patients phenotype, was identified in 34.3% of the cohort; 61% of these variants had not been previously reported in databases such as ClinVar. By combining the two phases of the study, we reached a total of 167 patients, in whom the presence of NDD and/or MCA significantly increased the probability of achieving an informative ES outcome. In contrast, previous use of gene panel testing was associated with a decreased likelihood of receiving an informative result. Ancestry was not associated with diagnostic yield. ConclusionsThis study demonstrates the utility of ES in achieving a diagnosis in a clinically diverse cohort of Chilean patients with RDs, and characterized features associated with a higher diagnostic yield. These findings may contribute to evidence-based patient prioritization strategies in settings with limited access to NGS resources.

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.

BackgroundMultiple long-term conditions (MLTC) are increasingly common and place significant strain on healthcare systems designed around single-organ conditions, often resulting in fragmented and reactive care for people living with MLTC. There is limited understanding of how health care professionals (HCPs) make decisions for and with individuals with MLTC at the point of hospital presentation. This study examined how HCPs in emergency and acute settings make decisions around pathways and places of care for people with MLTC, exploring the factors that shape clinical judgement, the challenges HCPs navigate in practice and structures that influence clinical decision-making. MethodsWe conducted semi-structured, individual interviews with 40 NHS professionals working in emergency departments (EDs) and acute assessment units across multiple regions, roles, and specialties. Participants included consultant physicians, resident doctors, senior nursing staff and allied health professionals. Interviews focused on how decisions were made around referrals, admissions, and care planning for people with MLTC. Data were analysed thematically using an inductive approach. ResultsFour themes were identified: A journey of uncertainty, Within and beyond limitations, Structures of care and Implementing relational care. Clinical decision-making is shaped by clinical uncertainty, limited resources, care approaches, and interpersonal relationships and communication. Fragmented services and single-disease pathways complicate care, but participants highlighted the value of continuity, communication, and relational approaches. Challenges include resource limitations, rigid pathways and limited community support. Key enablers of clinical decision-making include integrated care, ownership, and early conversations about priorities. ConclusionsClinical decision-making by HCPs in hospitals for patients with MLTC is complex and shaped by systemic misalignment, where clinical realities clash with health system structures. Improving clinical decision-making around referrals, admissions and care planning for people with MLTC will require adapting systems and training to reflect the realities of MLTC. Potentially beneficial adaptations include strengthening relational and multidisciplinary approaches and expanding intermediate care to reduce avoidable admissions.

BackgroundWhile pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. ObjectiveWe investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. DesignWe analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. ResultsMutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with HNF1B and NPHP3 mutations. ConclusionWe describe a previously unrecognized pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft. What is already known on this topicO_LICiliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. C_LIO_LIPancreatic cysts have been sporadically reported in syndromic ciliopathies. C_LIO_LIThe pancreas is not currently recognized as a major target organ of ciliary dysfunction. C_LIO_LIA clear link between ciliary gene mutations and pancreatic anomalies is still unknown. C_LIO_LIAnimal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. C_LI What this study addsO_LIIdentifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). C_LIO_LIDemonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. C_LIO_LIReveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. C_LIO_LIShows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. C_LIO_LIDefines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. C_LI How this study might affect research, practice or policyO_LIEstablishes the pancreas as a novel and clinically relevant target of ciliopathies. C_LIO_LIExpands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. C_LIO_LISuggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. C_LIO_LIHighlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. C_LIO_LIOpens new research avenues into the role of primary cilia in pancreatic homeostasis and disease. C_LI

BackgroundSickle cell disease (SCD) is a common inherited genetic disorder and contributor to global childhood mortality and morbidity. In the Democratic Republic of the Congo, nearly 40,000 newborns, approximately 2% of all newborns, are estimated to be affected each year. Despite progress in the treatment and care of the disorder, its detection and management in lower-resource settings remain challenging. MethodsWe collected 308 front facing photos of patients and their age-and sex-matched controls aged from 5 months to 19 years in the Democratic Republic of the Congo. Facial features were extracted and categorized into geometric and texture-based descriptors. A support vector machine ranked features according to their relevance for distinguishing SCD patients from controls. ResultsThe facial analysis algorithm identified eight geometric and six texture discriminative features that were significantly different between the cohorts. An explainable machine learning model identified sickle cell disease with 79.5% accuracy using a combination of six geometric features: distance between medial and lateral canthi, angle at nasal ala, distance from nasion to philtrum, distance from medial canthi to the columella, distance from columella to the lower lip, and distance between nasal alae. SCD related features were identified to become increasingly discriminative with age. ConclusionThese findings demonstrate the potential machine learning based methodologies to be leveraged to inform point-of-care tools in the screening and management of sickle cell disease. The discriminative facial features identified here may provide further opportunities into Artificial-Intelligence based diagnostics and personalized care strategies of sickle cell disease.

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.

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.

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.

IntroductionFibrosis can affect organs throughout the body and is present in a wide range of diseases. Recent research has suggested that there could be shared biological mechanisms that lead to fibrosis in different organs. MethodsWe performed genome-wide association studies using UK Biobank for fibrosis in 12 different organ-systems and meta-analysed results with previously published studies of fibrotic diseases. We considered genetic associations that colocalised across [&ge;]3 organs as those likely to be involved in general fibrotic mechanisms and also identified novel genetic variants not previously reported as associated with fibrosis. Genetic correlation of fibrosis between organs was calculated using linkage disequilibrium score regression (LDSC). Discovery analyses were performed using European ancestry individuals and results were tested further in African, South Asian and East Asian ancestry groups. ResultsWe identified eight genetic loci that colocalised across three or more organs. One of these signals, located near the SH2B3 and ATXN2 genes, showed evidence of a shared causal variant for fibrosis across five organs. We also identified two novel fibrotic associations, one implicating alternative splicing of TFCP2L1 for urinary fibrosis and another implicating a missense variant in FAM180A for intestinal-pancreatic fibrosis. We observed significant genetic correlations for all organs, particularly for liver and skeletal fibrosis. ConclusionWe found evidence of shared genetic associations for fibrosis across organs, both at individual genetic loci and genome-wide. This highlights specific genes that may contribute to fibrosis across organs and diseases, which may facilitate the development of new therapies.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.