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.

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.

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).

There is currently no FDA approved treatment for Batten disease CLN1, a rapidly progressive, fatal, and rare pediatric neurodegenerative disease. In this article, we aimed to collect retrospective clinical data from the families to identify CLN1 patients for a future patient facing natural history study and clinical trial. We have therefore developed and launched an institutional review board approved Batten disease CLN1 registry (https://cln1registry.collaborationspharma.com). We implemented a range of clinically relevant questions for the caregiver to answer in the registry created using the Django 5.0 web framework. Authenticated users provide profile data as well as patient and caregiver information, which is collected, stored in an encrypted SQLite database and deidentified before export and analysis. The registry application is deployed on an in-house private server using Docker with the database file and decryption key stored outside of the docker image and managed independently. We analyzed the collected data from 23 individuals with CLN1 Batten disease, including geographic distribution, age of diagnosis, onset of disease including motor and language declines. Although CLN1 is well known as infantile onset (<18 months), on average the diagnosis was not identified until 25 months which indicates a delay in diagnosis. We identified how the onset of disease is similar with most occurring before 25 months while infantile and late infantile patients had earlier onset and more frequent seizures in comparison to juvenile onset patients. Antiepileptic medications were the most heavily represented. Our findings provide new insights for CLN1 clinical care, enabling readiness for future natural history and clinical trials.

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

BackgroundAcrodysostosis type 2 (ACRDYS2) is a rare autosomal dominant disease characterized by skeletal defects and cognitive deficit, with clinical symptoms observed in multiple other tissues including the skin. It is caused by mutations in a phosphodiesterase, PDE4D, a key regulator of cAMP/PKA (cyclic adenosine monophosphate / protein kinase A) signalling. Despite its well-defined genetic causes, the molecular mechanisms underlying the disease remain poorly understood, with studies based largely on engineered cellular models reaching conflicting interpretations. MethodsTo investigate how endogenous dynamics are affected by PDE4D mutations in unmanipulated cells, we studied PDE4D transcript and protein expression, activity and downstream signalling in native dermal fibroblast from ACRDYS2 patients and healthy controls. ResultsSignificant reduction in total PDE4D expression in patient cells was observed both at the transcript and protein level, with marked decreases in the long isoforms PDE4D4 and PDE4D7; a reduction in PDE4D9 mRNA was also observed. PDE4D enzymatic activity was reduced in ACRDYS2 fibroblasts, though total PDE activity was largely preserved. Reduced PDE4D expression was associated with an increase in the phosphorylated form of the cAMP-responsive transcription factor CREB and elevated PRKAR1A (PKA type 1 regulatory subunit alpha) transcript levels, suggesting altered downstream signalling. Interestingly, expression of the related phosphodiesterase family member PDE4B was increased, consistent with a compensatory response to reduced PDE4D function. ConclusionsThis is the first study demonstrating reduced PDE4D expression and isoform-specific dysregulation in native ACRDYS2 cells. Together, our results support a model in which reduction in PDE4D activity and compensatory changes in other PDE4 family members contribute to the molecular pathology of ACRDYS2, providing new insights into the molecular mechanisms underlying this disorder.

We sequenced nine trios in which the probands in an underserved population were affected by a rare and undiagnosed disorder with neurological features. Sequencing was performed with one trio per flowcell on a benchtop sequencing instrument, leveraging the design of sequencing the proband at twice the coverage of the parents. The reduced coverage in the parents led to sequencing efficiencies while retaining the benefits of trio sequencing: the ability to discover de novo variants and the ability to trace inheritance patterns of rare variants. Once the sequencing data was generated, our two teams used independent informatics pipelines for variant calling and interpretation. In five of the nine cases, both teams found a single SNV or small indel that was deemed causal pending clinical validation. In three of the nine cases, neither team had a significant finding. In the final case, an additional scan for large CNVs performed by one of the teams identified a de novo deletion and duplication in the proband which is the likely cause of the underlying disease. The results across cases with significant findings showed a variety of affected genes (CFAP52, DYNC1H1, FANCE, TCF4, and TOP3A), variant types, and inheritance patterns. All findings were clinically validated, after which the families were counseled about disease management, current research studies (i.e. gene therapy), and family planning. With six of nine families receiving findings, the study demonstrated an efficient and effective trio sequencing design strategy.

Background. Three disease-modifying therapies (DMTs) for spinal muscular atrophy (SMA) have been approved since 2016, yet many adults remain untreated. Identifying them depends on ICD-10 codes that capture SMA but do not reliably distinguish it from other related conditions. We examined, in one U.S. health system, both patients' engagement with therapy and the accuracy of the codes used to find them. Methods. We conducted a retrospective chart review of adults in an academic health system identified by SMA-associated ICD-10 codes, with manual adjudication of diagnosis and DMT status. Confirmed SMA-positive, DMT-naive patients were invited to a structured telephone interview on treatment awareness and barriers. Results. Of 60 charts, 22 (36.7%; 95% CI 25.6-49.3%) were appropriately coded for SMA or a related disorder; only 16 (26.7%) had molecularly confirmed SMA. The other 38 (63.3%) were miscoded, spanning spinal and bulbar muscular atrophy, asymptomatic carriers, prenatal screening, and conditions unrelated to SMA. Ten of the 16 confirmed patients (62.5%) were DMT-naive; one was interviewed, one declined, and eight could not be reached. The non-response is itself a finding: the patients least visible to administrative data are the hardest to reach. Conclusions. ICD-10 ambiguity is a barrier to treatment access in adult SMA, as is loss to follow-up. We make two recommendations: continuous documentation-coding alignment that uses natural language processing to verify the genetic precondition, and type-specific SMA codes (subcodes for Types 0-4) anchored on molecular SMN1 confirmation. Together these would support cohort identification, outreach, and evidence generation without adding to clinician burden.

BackgroundNeurological disorders affect approximately 3 billion people globally, yet clinical trial success is often hindered by poorly selected outcome measures, impacting trial design, compliance, and interpretation. Over the past 25 years, Core Outcome Sets (COS) have emerged as standardized tools to enhance outcome selection, ensuring comparability across studies and reflecting the priorities of both researchers and patients. Despite the success of COS initiatives in other fields, their development in neurology remains limited, leaving many trialists without disease-specific guidance. ObjectivesThis study aimed to develop a COS framework for neurological disorders with the assistance of artificial intelligence (AI) by analysing the frequency and scope of outcomes previously reported in existing COS to identify common themes applicable to neurological research. MethodsCOS-Neuro was developed using AI-assisted thematic framework analysis, complemented by expert review. A modified five-step thematic analysis was conducted without pre-determined codes: O_LIDataset Gathering - Data was collected from the COMET database, and COS domains for neurological disorders were coded. C_LIO_LIPrompt Design & Testing - Large language models (LLMs), including ChatGPT 3.5, Google Gemini 1.5 Flash and Meta Llama-2-70b, were trialled, and prompts refined based on their outputs. C_LIO_LIThematic Analysis - LLMs categorised domains into core areas. C_LIO_LIHuman Refinement - Experts reviewed LLM-generated core areas and selected those most appropriate for further interpretation. C_LIO_LIClinical Validation - Experts validated the domains, core areas, and concepts. C_LI This approach integrated AI with expert oversight to develop a standardised COS framework for neurological disorders. ResultsUtilising LLMs, particularly ChatGPT, a robust conceptual framework for COS in neurological disorders was developed, based on the existing 112 existing COS. Through adaptation of the OMERACT model, the final framework comprised four concepts, 13 core areas, and 75 domains, as determined by expert consensus. ConclusionCOS-Neuro establishes AI-assisted framework for developing COS in neurological disorders. This project provides a foundational resource for future COS research and serves a reference for designing trials in areas where established COS are lacking. Furthermore, it sets a precedent for the integration of AI in qualitative analysis in medicine, demonstrating the scalability of approaches like OMERACT for the development of COS of COS across various specialties.

ObjectiveWolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. ApproachPatient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants and statistical analysis was performed using unpaired and paired t-tests and one- and two-way ANOVA with Tukeys or Dunnetts tests. ResultsA greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by optic atrophy emerging significantly earlier in patients with 2 nonsense/frameshift alleles compared with 0 missense transmembrane variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy. Summary / ConclusionsThe results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.

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

BackgroundThe prevalence of symptomatic COVID-19 in children remains low to date. In just a few months, COVID-19 has affected millions of people worldwide, and as of the date of this publication, the pandemic continues. Based on the current available evidence, children do not appear to be at higher risk of contracting COVID-19 than adults. However, children with neurological and neuromuscular conditions are vulnerable to the respiratory complications of other viral infections. ObjectivesTo assess whether children with brain-based developmental disabilities were more likely to develop COVID-19 and have complications or poorer outcomes following infection. MethodsWe conducted a two-week rapid review on studies with primary data regarding children aged between zero and 18 years old with brain-based developmental disabilities, or who were at risk of developing such disabilities, with confirmed or suspected COVID-19. We performed our literature searches on April 18, 2020. ResultsOur search strategy identified 538 individual records, of which four were included in our review. Of the 50 COVID-19 pediatric patients reported in the included studies, a total of seven children were at risk of developing brain-based disabilities. Symptoms ranged in severity. However, generally, patients were discharged or saw improvements in their symptoms by the end of the study period. No deaths were reported. DiscussionOur study highlights a knowledge gap regarding the impact of COVID-19 in children with brain-based developmental disabilities.

ObjectiveWe sought to evaluate outcomes for clinical management following a genetic diagnosis from the Deciphering Developmental Disorders (DDD) Study. DesignIndividuals in the DDD study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n=5010). Clinical notes from regional clinical genetics services notes were reviewed to assess pre-defined clinical outcomes relating to interventions, prenatal choices, and information provision. ResultsOutcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centres across the UK and Ireland. Additional diagnostic or screening tests were performed in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped/avoided as no longer necessary in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 (2%) probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups. ConclusionsOur results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups.

BackgroundAlthough individually rare, collectively rare diseases are more common than diabetes mellitus. The diagnostic odyssey for rare diseases is typically prolonged. AimWe aimed to hear the voice of rare disease stakeholders to provide evidence for strategies to improve rare disease care in Tasmania, Australia. MethodsMixed methods research with surveys, focus groups, and interviews captured the voice of healthcare consumers with rare disease, their families, and their caregivers, as well as consumer advocates, community reference group, rare disease researchers, and healthcare professionals. ResultsWe undertook 1,014 stakeholder consultations. Participants described elements of the diagnostic pathway that worked well, as well as barriers to diagnosis. Those affected by rare disease and their caregivers emphasised the need for healthcare providers to listen and respond to consumer concerns. Collectively, stakeholders reported that challenges in rare disease diagnosis in Tasmania include difficulties accessing timely primary and specialist health care, low awareness of rare disease among health professionals in Tasmania (including how to identify people with possible rare disease and what to do next), difficulty in accessing diagnostic testing, cost and geographic barriers in accessing diagnostic care, a lack of epidemiologic information on rare disease in Tasmania and the breakdown in care and support from the health system when transitioning from paediatric to adult services. DiscussionMany participant concerns that fall under the system responsibility of the Tasmanian Government could be addressed by establishing a Tasmanian Rare Care Centre. The centre could adopt principles from cancer care, such as patient-centred care, safe and quality care, multidisciplinary care, supportive care, care coordination, communication, and research and clinical trials. Other concerns, such as the equitable implementation of emerging diagnostic technologies and the education and training of non-genetics practitioners, will require national leadership and interjurisdictional cooperation to address. O_TEXTBOXSUMMARY BOXThe Known Rare diseases are a global health priority. The diagnostic odyssey is often prolonged, affecting rare disease care. The New Stakeholder consultation revealed that individuals affected by rare diseases and their families and caregivers often feel that they are not listened to, that their care is fragmented, and that non-genetics healthcare providers have limited awareness and understanding of rare disease. The Implications Many concerns raised by rare disease stakeholders could be addressed by establishing a Tasmanian Rare Care Centre. C_TEXTBOX

The Na+ leak channel NALCN regulates the resting membrane potential and consequently cell excitability of several cell types, including neurons. Studies of animal models demonstrated that NALCN is involved in fundamental physiological functions such as respiratory rhythm, circadian rhythm, sleep, locomotor behavior and pain perception. Pathogenic variants of NALCN have been associated with ultra-rare developmental disorders characterized by a wide range of symptoms with variable severity. We and others previously showed that pathogenic variants of NALCN can be categorized in 2 groups. The first group corresponds to inherited biallelic loss-of-function variants with patients suffering from the IHPRF1 syndrome (OMIM #615419). The second one corresponds to de novo gain-of-function variants that cause the CLIFAHDD syndrome (OMIM #616266). In this study, we provide a standardized phenotypic description of a large group of 35 individuals with de novo pathogenic variants of NALCN. In addition, we performed functional studies of several of these variants using the patch clamp technique in a recombinant system. We highlight a large heterogeneity in terms of both expressed symptoms and their severity. By contrast with previous reports only showing a pure gain-of-function effect of de novo pathogenic variants, we found that de novo variants of NALCN differentially impact the biophysical properties of the NALCN current and likely influence cell excitability. To conclude, de novo variants of NALCN differentially impact the biophysical properties of the NALCN current. We hypothesize that this may at least partly explain the phenotypic diversity observed in patients.

PurposeIn recent years, the advent of high throughput sequencing techniques has led to the identification of a number of genetic variants across different genes that are associated with movement disorders. However, the under-appreciation of the variant spectrum in movement disorders and the lack of consolidated and systematic evidence-based annotation of these variants has long undermined the true potential of genomic approaches to expedite precision medicine. MethodsWe manually curated the genetic variants from a panel of 118 genes that have been associated with monogenic causes of movement disorders and systematically annotated them according to ACMG & AMP (American College of Medical Genetics and the Association of Molecular Pathologists) guidelines. ResultsData integration after systematic classification of variants according to ACMG & AMP guidelines showed 5118 pathogenic/likely pathogenic variants accounting for 18.03% of the total unique variants being annotated. This data and annotations are available in a comprehensive online compendium DystoGen. ConclusionTo the best of our knowledge, this is the most comprehensive compendium of genetic variants in movement disorders annotated as per the ACMG & AMP guidelines for pathogenicity. The compendium indexes 28377 variants along with a wide array of information including the geographical origin of the variant, global distribution, and population allele frequency. The resource has been made available in the URL https://clingen.igib.res.in/dystogen/.

BackgroundA genetic neurodevelopmental diagnosis (GND) impacts all aspects of a child and familys life. GNDs are rare; most have limited natural history data. We aimed to understand parents experiences around data acquisition about their childs GNDs which can help inform clinical practice. Design and participantsThis analysis is part of the UK multicentre GenROC study. We conducted 17 semi-structured interviews with parents of children with GNDs (aged 0-15 years). Data were analysed following the principles of thematic analysis. ResultsFive main themes are reported: Impact on the family around a genetic diagnosisDistress results from diagnosis wait, the act of receiving it, associated irreversibility (loss of hope) and family/reproductive implications. GNDs and Uncertainty: Lack of data and rareness causes uncertainty for the future. Relationships with health professionalsPositive where parents are empowered and feel part of the team; Negative -parents feel not heard/believed or lack of expertise/understanding. Parent mental healthGNDs can be a significant burden to family life. Need for advocating for services is a negative impact. Isolation through rareness is a factor - this can be helped by support networks which mostly consist of gene specific Facebook groups. Development of positive parent identitiesincluding that of advocate, professional and educator. ConclusionsGNDs represent a major challenge for families, clinicians and service providers. Distressed parents are struggling to cope with challenges and suffer poor mental health. Psychosocial support, better signposting, and health professional education may help. Patient contributionPPI group contributed to topic guide development and commented on findings.

Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.), highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.

Background and ObjectivesCerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006. MethodsWe conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes. ResultsOf 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term "non-progressive" (48/164, 29%). The vast majority of respondents (157/164, 96%) answered Yes to the question: Do you think we should revise the 2006 consensus definition of CP? DiscussionWe propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.