AIM: Exploring the association between SETD1B variants and absence seizures (ASs). METHODS: We engaged a small cohort of four pediatric epilepsy patients with identified SETD1B variants and conducted a comprehensive revi...AIM: Exploring the association between SETD1B variants and absence seizures (ASs). METHODS: We engaged a small cohort of four pediatric epilepsy patients with identified SETD1B variants and conducted a comprehensive review of 50 documented instances. Clinical profiles were meticulously compiled, and genetic screening was executed via trio-based whole-exome sequencing. Our literature survey centered on AS manifestations linked to SETD1B alterations, utilizing descriptive statistics for analysis. RESULTS: The quartet of new cases presented with developmental impediments, cognitive deficits, and epileptic manifestations. Pathogenicity was established in the detected SETD1B variants. Among the 54 individuals, 26 (accounting for 48.1 %) presented with AS during the course of the disease. The median seizure onset age stood at 44.8 months, with a majority displaying cognitive challenges and autistic traits. Anti-epileptic drug therapies proved efficacious in 70.8 % of the instances. Notably, variants within the N-SET, SET, and post-SET domains of SETD1B were prevalent in 46.2 % of the AS-afflicted cohort. DISCUSSION: Our findings accentuate the potential influence of SETD1B variants in AS pathogenesis, these variants may perturb neuronal excitability, possibly via modulation of histone methylation landscapes. The insights garnered here deepen our grasp of AS's genetic architecture. CONCLUSION: Our study identified four novel SETD1B variants, highlighting that the importance of AS as part of the phenotype among individuals with SETD1B, demonstrated by 3 novel cases, and supported by review of the literature. Our findings also suggest that the SET domains may play a potential role in the pathogenesis of AS, providing a clue for future mechanistic research.
BACKGROUND: CACNA1A-related disorders are rare and progressive; to date, there is no approved treatment. Trials with N-acetyl-leucine (NAL) demonstrated efficacy in disorders featuring ataxia, cognitive impairment, and e...BACKGROUND: CACNA1A-related disorders are rare and progressive; to date, there is no approved treatment. Trials with N-acetyl-leucine (NAL) demonstrated efficacy in disorders featuring ataxia, cognitive impairment, and epilepsy. Accordingly, we hypothesized that NAL may be effective in CACNA1A-associated disorders. CASES: Four patients (1 boy, age 15 years, 3 girls, age 5, 9, and 14) received NAL as individualized off-label treatment and were assessed using the SARA Score, SCAFI and CGI-I. In all children NAL resulted in rapid improvement of ataxia, (gait, balance, fine motor and speech - mean SARA improvement at first follow-up: 3.25 points). Improvement was sustained up to 3 years (mean long-term SARA improvement: 5.13 points). SCAFI and CGI-I showed similar improvement. NAL was well-tolerated, without adverse reactions. CONCLUSIONS: N-acetyl-leucine is a novel potential treatment for a so far untreatable rare disease spectrum of CACNA1A-disorders. The sustained benefit may reflect neuroprotective effects seen in other populations. Clinical trials are needed to control the results.
BACKGROUND: Therapeutic apheresis (TA) are promising treatment option for neuroimmunological disorders. In paediatrics, the available data is limited, particularly for the use of IA. The aim of this study was to analyse...BACKGROUND: Therapeutic apheresis (TA) are promising treatment option for neuroimmunological disorders. In paediatrics, the available data is limited, particularly for the use of IA. The aim of this study was to analyse the use of PE and IA in children and adolescents, with emphasis on outcome and neurological course after treatment as well as the safety of the two modalities. METHODS: Clinical data from paediatric patients with neuroimmunological disorders treated with TA in two German university children's hospitals between 2015 and 2022 were retrospectively analysed. RESULTS: In total, 39 patients underwent 322 sessions of TA, of which 184 were IA and 138 PE. The most common diagnosis was autoimmune encephalitis in 39 % (n = 15) of the patients. Other indications were central nervous system inflammatory demyelinating disorders in 21 % (n = 8), Guillain-Barré syndrome in 18 % (n = 7), Myelin Oligodendrocyte Glycopeptide-antibody associated syndromes in 8 % (n = 3), Myasthenia gravis in 5 % (n = 2) and other neurological disorders in 10 % (n = 4). Overall, there was an improvement in 76 % of patients (81 % with IA, 70 % with PE; p = 0.41) immediately after treatment and an improvement in 88 % of patients (90 % with IA, 85 % with PE; p = 0.63) one month after treatment. Complications occurred in 13 % of all sessions (13 % with IA and 13 % with PE; p = 1). Most complications were considered as moderate. CONCLUSION: Both, IA and PE, are effective treatment options in the therapy of neuroimmunological disorders in children and adolescents, with no major differences in terms of efficiency or safety.
OBJECTIVE: Early diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) are crucial for a favorable prognosis. Detecting the causative autoantibodies can be challenging. Probable diagnostic c...OBJECTIVE: Early diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) are crucial for a favorable prognosis. Detecting the causative autoantibodies can be challenging. Probable diagnostic criteria are useful in adults less so in children. We aimed to develop a novel diagnostic score for pediatric NMDARE using cohort data. METHODS: We retrospectively analyzed pediatric participants (0-18 years) with suspected autoimmune encephalitis who underwent cerebrospinal fluid analysis for antineuronal antibodies (Abs) between January 2015 and March 2023. Clinical data, including symptoms and laboratory findings, were analyzed. Symptoms were selected through univariate analysis and then analyzed with multivariate logistic regression model. Resulting odds ratios were used to calculate scores. Scoring systems were developed and evaluated with five-fold validation and univariate logistic regression. One scoring system was selected to create a diagnostic prediction score for pediatric NMDARE. RESULTS: Of the 504 patients, 264 met the inclusion criteria, and 39 tested positive for NMDAR Abs. Comparing clinical symptoms between cohorts and identified 15 variables significantly different (p < 0.05) to create a pediatric NMDARE prediction score. This score showed 82.1 % sensitivity and 82.2 % specificity, with an 8-point cutoff. The area under the curve was 0.888 (95 % confidence interval: 0.838-0.939). A five-fold cross-validation showed a sensitivity of 95.6 %, specificity of 71.4 %, and kappa coefficient of 0.670. CONCLUSION: We developed a novel evidence-based diagnostic prediction score for pediatric NMDARE that incorporates specific clinical features and laboratory findings. This score may improve diagnostic accuracy and guide early therapy in children with suspected autoimmune encephalitis.
BACKGROUND: Intra-thecal Nusinersen has been approved for the treatment of Spinal muscular atrophy (SMA). Limited data is available regarding the efficacy and safety of Nusinersen in children with SMA type 2 and 3 from N...BACKGROUND: Intra-thecal Nusinersen has been approved for the treatment of Spinal muscular atrophy (SMA). Limited data is available regarding the efficacy and safety of Nusinersen in children with SMA type 2 and 3 from North India. OBJECTIVE: To study the efficacy and safety of Nusinersen among children with SMA type 2 and 3 from North India compared to standard of care (SOC) over 12 months. METHODS: Children with a genetically confirmed diagnosis of SMA and ≥2 copies of the SMN2 gene were screened for enrolment in prospective study design. Revised Hammersmith score (RHS) and revised upper limb module (RULM) were assessed every three months. Compound muscle action potentials (CMAPs) at median and ulnar nerves and quality of life (QOL) were performed at baseline and 12 months. Intra-thecal procedure-related and treatment-emergent side effects in children receiving Nusinersen therapy were recorded. Outcome measures at 6 and 12 months were compared between the Nusinersen and SOC groups. RESULTS: Forty-two children with SMA, mean age of 85 ± 6 months, including 16 in the Nusinersen group and 26 in the SOC group, were enrolled. The mean RHS score in the Nusinersen group increased from the baseline of 35 ± 18 to 38.9 ± 19, and 39.9 ± 17 at 6 and 12 months (p value-0.001), in the SOC group increased from the baseline of 28.8 ± 15, to 29.6 ± 16, and 29.9 ± 17 at 6 and 12 months respectively (p value-0.35). The mean gain in the RHS score over 12 months in the Nusinersen group was significantly higher compared to the SOC group (p-value 0.02). RULM showed significant gain in the Nusinersen group compared to the SOC group over 12 months (p value 0.03). The median and ulnar nerve CMAPs, and QOL were similar in both the groups. A total of 119 intrathecal injections of Nusinersen were given. Most adverse events were mild and related to the intra-thecal procedure. CONCLUSION: Intra-thecal Nusinersen therapy among children with late-onset SMA from North India over 12-month duration was associated with improvement in motor abilities as measured by RHS compared to SOC. Intra-thecal Nusinersen was safe and tolerated well.
A wide phenotypic spectrum exists among DMD patients, with genetic modifiers seen as a putative cause of this variability. The main aim was to evaluate the effect of 4 genetic modifiers and the location of DMD variants o...A wide phenotypic spectrum exists among DMD patients, with genetic modifiers seen as a putative cause of this variability. The main aim was to evaluate the effect of 4 genetic modifiers and the location of DMD variants on disease severity in a DMD Argentine cohort. A secondary objective was to provide a summary of the current state of knowledge and association of the tested loci with DMD's phenotype. Two groups of patients with extreme phenotypes (Severe/Mild) were defined based on the age at loss of ambulation. SNVs in SPP1, LTBP4, CD40, and ACTN3 were genotyped, and their distribution was compared between groups using Chi-square or Fisher exact tests. Concurrent effects with glucocorticoids treatment, DMD mutation location (proximal/distal) and the other loci were evaluated by multivariate logistic regression. Additionally, we performed a systematic literature review to summarize and interpret the impact of modifiers on various DMD traits. ACTN3-rs1815739 was the only modifier loci of DMD progression in our cohort. A concurrent damaging effect between DMD mutation and ACTN3 was detected, identifying a possible interaction between distal variants and ACTN3 TT-genotype that need to be validated in a larger cohort. The systematic review showed agreement in the results when significant differences were reported. The employment of extreme DMD phenotypic groups was an innovative approach for identifying risk loci for disease severity. The interaction between DMD mutation location and ACTN3, if confirmed, could help to avoid confounding elements in assembling study cohorts for clinical trials. Finally, this report's major highlight is being the first study conducted on an Argentine and Latin-American population.
Yılmaz Ü, Gücüyener K, Yavuz M
… +16 more, Ibrahim Oncel, Canpolat M, Saltık S, Ünver O, Çıtak Kurt AN, Tosun A, Yılmaz S, Özgör B, İlknur Erol, Öztoprak Ü, Elitez DA, Çobanoğulları Direk M, Bodur M, Teber S, Anlar B, Turkish Pediatric Multiple Sclerosis Study Group
BACKGROUND: To assess the efficacy, safety, and tolerability of full-spectrum cannabis oil (FSCO) (CBD:THC ratio of 10:1) for the treatment of spasticity in individuals with spastic cerebral palsy (CP) grades IV and V. M...BACKGROUND: To assess the efficacy, safety, and tolerability of full-spectrum cannabis oil (FSCO) (CBD:THC ratio of 10:1) for the treatment of spasticity in individuals with spastic cerebral palsy (CP) grades IV and V. METHOD: A pilot trial to assess the feasibility of FSCO in seven CP patients was followed by a prospective double-blind, placebo-controlled parallel trial, with 53 participants aged 5-25 years, randomised in a 1:1 ratio. The double-blind phase lasted six weeks, followed by the open-label phase of six weeks' duration. The primary endpoint was a change in spasticity measured by the modified Ashworth Scale. Secondary outcomes were changes in motor function (Gross Motor Function Measure 88 scale), quality of life, safety, and tolerability. RESULTS: There was no significant difference in spasticity, motor function, and quality of life parameters between patients receiving FSCO or placebo. Patients in the FSCO group were significantly drowsier compared to the placebo group. Adverse events were mild to moderate; there were no life-threatening events. INTERPRETATION: This trial suggests FSCO treatment in children with CP is generally well tolerated and safe. It might have benefits on quality of life. No significant change in spasticity was demonstrated with FSCO treatment compared to the placebo.
De Falco A, De Dominicis A, Trivisano M
… +21 more, Specchio N, Digilio MC, Piscopo C, Capra V, Scala M, Iacomino M, Accogli A, Romano F, Salpietro V, Mancardi M, Striano P, Operto FF, Gburek-Augustat J, Perrin L, Capri Y, Lupo V, Elia M, Manti F, Pisani F, Brunetti-Pierri N, Terrone G
Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance. To date, no distinctive neurological, psych...Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance. To date, no distinctive neurological, psychiatric, electroencephalographic, and neuroimaging features have been identified in this condition. We expand the clinical phenotype of SETD5-related disorder by describing 28 previously unreported patients, 26 carrying single nucleotide variants, and 2 with copy number variations involving SETD5 gene, focusing on neurological, psychiatric, EEG, and brain MRI data. In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %). Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures. Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient. Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms. Finally, we conduct a comprehensive review of the available literature, suggesting a possible genotype-phenotype correlation.
BACKGROUND: Acute neuropsychiatric disorders are heterogeneous conditions resulting from interaction between genetic and environmental features. Among these, post infectious forms like Pediatric Acute-onset Neuropsychiat...BACKGROUND: Acute neuropsychiatric disorders are heterogeneous conditions resulting from interaction between genetic and environmental features. Among these, post infectious forms like Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) are common. Preclinical studies suggest a role of CNS T-helper-17/interleukin-17 (IL-17) inflammatory mediated response in the pathogenesis of these disorders. We analyze serum and cerebral-spinal fluid (CSF)-IL-17 concentrations in a cohort of patients with acute neuropsychiatric disease. METHODS: We retrospectively included patients <14 years with acute neuropsychiatric symptoms from 2016 to 2020. IL-17 was determined on serum and CSF by means of quantitative sandwich enzyme immunoassay technique, and values were compared to serum and CSF controls. Variables were identified using univariate analysis with Pearson's regression test and X test. RESULTS: 58 subjects were included (67.8 % males, average age: 8.5 years). 50.8 % were classified as PANDAS, 11.8 % as PANS. Mean concentrations of serum IL-17 were higher in the study group compared to controls (p < 0.0001). We observe a trend of increasing IL-17 in post-pubertal children both on serum (p = 0.05) and on CSF (p = 0.04). Coupled IL-17 concentration were higher in the CSF than in serum (p = 0.003), with a marked significance in the PANDAS and PANS group (p < 0.001). CONCLUSION: IL-17 is elevated in children and adolescents with acute neuropsychiatric conditions, both on serum and CSF. IL-17 could be involved in the pathogenesis of acute neuropsychiatric disorders in childhood. Further studies are necessary to validate its potential role as a diagnostic or prognostic biomarker.
The association of recognisable neurological conditions with an underlying malignancy is well described. In this review we explore the complex interplay of genetic, environmental and tumour factors which contribute to au...The association of recognisable neurological conditions with an underlying malignancy is well described. In this review we explore the complex interplay of genetic, environmental and tumour factors which contribute to autoimmunity and paraneoplastic conditions. We review the current understanding of the pathogenesis of well recognised paraneoplastic conditions in children including Opsoclonus myoclonus ataxia syndrome, N-Methyl-D Aspartate receptor encephalitis and limbic encephalitis, and the broad approaches to treatment. Rapid advances in oncological treatment has expanded the arsenal of therapeutic modalities. We explore the broad spectrum of immune therapies in childhood cancer, and the potential neurological complications of these novel therapies, and discuss the fine balance of risk and benefit that these bring.
AIM: To determine the effectiveness of integrated hip surveillance pathways on pain, function and quality of life (QOL) in children with Cerebral Palsy (CP). METHOD: A systematic literature review, designed, conducted an...AIM: To determine the effectiveness of integrated hip surveillance pathways on pain, function and quality of life (QOL) in children with Cerebral Palsy (CP). METHOD: A systematic literature review, designed, conducted and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. INCLUSION CRITERIA: confirmed CP diagnosis, management under recognised international hip surveillance pathways, outcome measures of hip displacement plus at least one other relevant to pain, function or QOL. RESULTS: 100 articles were identified. 12 full text articles were screened, and four were included. Reduced range of movement was associated with hip pain in children with CP. Increasing age, Gross Motor Function Classification Score (GMFCS) and migration percentage (MP) were associated with increased hip pain. General health declined with increased age. Increased MP and GMFCS level were associated with interruption to activities of daily living. INTERPRETATION: Outcomes relating to function and QOL are under-researched in the current integrated hip surveillance pathway evidence-base. Wider outcomes related to function and QOL need to be included to capture the wider impact on children who are at risk of hip dislocation. WHAT THIS PAPER ADDS: Increased pain was associated with reduced joint range and increased migration percentage. Pain also increased with greater age and Gross Motor Function Classification Score. Early orthopaedic intervention for hip displacement may not successfully mitigate pain. Effectiveness of integrated pathways on function and quality of life is under-evidenced. Studies investigating integrated pathways and holistic outcomes are needed to inform practice.
In this study, we investigated the prevalence of mental disorders and the use of psychopharmacologic drugs among individuals with cerebral palsy (CP). We studied how the association between CP and mental illness develops...In this study, we investigated the prevalence of mental disorders and the use of psychopharmacologic drugs among individuals with cerebral palsy (CP). We studied how the association between CP and mental illness develops over the life course (between ages 5 and 65 years), and how it varies across disability specific factors (intellectual disability, gross motor function and communicative ability). We used logistic regression models on a longitudinal matched case-control data material on all persons with CP in Sweden linked to several administrative registers including, the national patient registers and the pharmaceutical registers. Our results showed that the probability of being diagnosed with mental disorders and being dispensed psychopharmacologic drug was significantly higher among persons with CP compared to persons without CP across the different outcomes [OR = 1.52-4.7]. For some mental and neurodevelopmental disorders including sleep disorders, autism, and ADHD, and for the use of anxiolytics and sedatives, there was a sizeable gap already in childhood. However, the excess burden of mental illness appeared to grow over the life course, indicating that adults with CP may be a particularly disadvantaged group. Diagnosis for mental disorders and dispensation for psychopharmacologic drugs were not consistent with respect to disability specific factors, especially communicative and intellectual function, which indicates the need for systematic approaches in the mental health care of individuals with CP.
BACKGROUND AND OBJECTIVES: Dravet Syndrome is a severe developmental and epileptic encephalopathy with significant care needs for affected individuals and families. Our objective was to characterise the caregiver burden...BACKGROUND AND OBJECTIVES: Dravet Syndrome is a severe developmental and epileptic encephalopathy with significant care needs for affected individuals and families. Our objective was to characterise the caregiver burden and therapeutic needs of families caring for an individual with Dravet Syndrome from child to adulthood, to examine age related differences in co-morbidities, and identify current gaps in health and social care. METHODS: Cross-sectional national survey conducted by the patient advocacy group Dravet Syndrome UK (DSUK) emailed to registered families caring for an individual with a confirmed diagnosis of Dravet syndrome. To characterise the sample, quantitative data on demographics, diagnostic journey, co-morbidities, therapies, healthcare utilisation, social care and funding, and impact on family life were collected. Qualitative data were analysed using grounded theory to develop a model of impact and service need. RESULTS: 165 out of 381 families (43 %) responded. 90 % of adult Dravet syndrome patients waited >12 months to receive a diagnosis, compared to 25 % families with a young child (p < 0.001). 96 % reported intellectual disability as co-morbidity, more frequently observed in older Dravet syndrome individuals (p < 0.001), alongside autism/autistic-like symptoms (χ = 15.3, df = 3 p = 0.001) and scoliosis (χ = 28.4, df = 3, p < 0.001). Sleep problems are associated with greater impact on caregiver's mental well-being (χ = 13.2, df = 2, p < 0.001). 77 % of families wished more discussions about sudden unexpected death in epilepsy (SUDEP) and 50 % rated the paediatric to adult transition experience as 'poor'. 90 % of caregivers were unable to continue working as normal with negative impact on their quality of life (p = 0.024) and mental well-being (p = 0.007). DISCUSSION: Families are profoundly impacted by Dravet syndrome. Their experience changes over time as people with Dravet syndrome become older and present with increasing levels of health, cognitive and behavioural comorbidities. Families will benefit from improved communication with health care professionals, psychosocial interventions and better access to social care.
Neal EG, Whiteley VJ, van der Louw E
… +15 more, Devlin AM, Eltze C, Pujar S, Simpson Z, Hardy I, Palmer A, Szmurlo A, Parker AP, Mills N, Ord R, Lagae L, Kerckhove KV, van den Berg S, Cross JH, Schoeler NE
We aimed to develop a registry ('Keto-Reg') for individuals with epilepsy referred for ketogenic dietary therapy (KDT) and to test feasibility of its implementation. The purpose of the registry is to provide a platform f...We aimed to develop a registry ('Keto-Reg') for individuals with epilepsy referred for ketogenic dietary therapy (KDT) and to test feasibility of its implementation. The purpose of the registry is to provide a platform for collaborative research to answer specific research questions regarding long-term clinical and safety outcomes and to identify the most suitable candidates for KDT. Registry data items were determined via an international Delphi survey of KDT healthcare professionals, and then entered into an electronic platform. Three UK and two other European KDT centres entered data for 10 'patients' and reported on its acceptability and feasibility of use via questionnaire. 25 % of data was validated against medical records. A national survey was distributed and 19 parents and four young people were interviewed about a potential future patient/family section to the registry. Healthcare professionals from six continents responded to the Delphi (n = 153 round 1, n = 79 round 2); 70 items reached the agreement threshold. Registry data entry was accurate (0.3 % errors identified) and reported to be feasible and acceptable in the short-term. Lack of time was identified as the main barrier to longer-term implementation, with funded hours required. 87 % of the 53 survey responders and all interviewees viewed a patient/family section to be positive and feasible. We have shown healthcare professional involvement in Keto-Reg to be feasible in the short-term, and have identified what is necessary for the next stage: prospective longitudinal data entry from a larger number of international centres.
NorthStar Ambulatory Assessment (NSAA) total score (TS) is an ordinal scale to evaluate disease progression and treatment response in ambulatory Duchenne Muscular Dystrophy individuals. Clinical management according to s...NorthStar Ambulatory Assessment (NSAA) total score (TS) is an ordinal scale to evaluate disease progression and treatment response in ambulatory Duchenne Muscular Dystrophy individuals. Clinical management according to standard of care could be enhanced by understanding how changes in the TS could inform standards of care. Here we describe the associated item performance patterns in the NorthStar Database for ranges of NSAA TS and its timed tests (10 m walk/run and rise from floor). We then compare these patterns depending on whether a participant is on an improving/stable (≤2-point loss in the prior year) or declining (>2-point loss in the prior year) trend. These TS and trends are subsequently linked and referenced to therapy standards of care. We included 761 participants from the UK NorthStar observational clinical database between 5 and 16 years, who were on steroids. Differences and trends in item ability, compensations, and times can suggest specific disease complications and lead towards anticipatory therapy recommendations. Families and therapists can benefit from using the TS and trend to guide therapy management.