Brain communications最新文献

{"title":"Niacin ameliorates Charcot-Marie-Tooth 4B1 neuropathy without interfering with nerve regeneration.","authors":"Silvia Cipriani, Emanuela Porrello, Matteo Cerea, Andrea Gazzaniga, Roberta Di Guardo, Amanda Heslegrave, Serena Valenzano, Ubaldo Del Carro, Phu Duong, John Svaren, Stefano Carlo Previtali, Alessandra Bolino","doi":"10.1093/braincomms/fcaf039","DOIUrl":"10.1093/braincomms/fcaf039","url":null,"abstract":"<p><p>Charcot-Marie-Tooth (CMT) neuropathies represent a broad and very heterogeneous group of disorders for which no therapies are yet available. Due to the huge genetic heterogeneity, therapeutical approaches that can benefit several forms independently of the unique pathogenetic mechanism have been sought. Niacin, nicotinic acid, is a vitamin used for many decades as anti-dyslipidaemic and anti-cholesterol drug product under the commercial name of Niaspan^®, the extended-release formulation of niacin. Of note, niacin can have other effects depending on the dose, formulation and physiology and it has been used to reduce inflammation, to promote angiogenesis and to protect neurons, muscle and axons by boosting nicotinamide adenine dinucleotide (NAD⁺) levels. Niacin also activates TNF-alpha convertase enzyme (TACE) secretase, which negatively regulates Neuregulin type I-mediated signalling in the peripheral nervous system and myelination. We previously postulated that niacin-mediated TACE activation can be effective in reducing aberrant excessive myelin associated with different CMT forms. Here, we explored efficacy of this strategy by performing a long-term preclinical trial and we provided evidence that a novel niacin-based long-lasting formulation ameliorates neurophysiology and reduces fibre degeneration in a model of Charcot-Marie-Tooth type 4B1 (CMT4B1) neuropathy, characterized by aberrant myelin. We also sought to determine whether this strategy might interfere with nerve regeneration, which is dependent on Neuregulin type I signalling. Surprisingly, we found that the <i>Mtmr2</i> knockout mice, a model of CMT4B1, have a defect in nerve regeneration and that niacin-based treatment is not detrimental to nerve regeneration.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf039"},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting individual long-term prognosis of spatial neglect based on acute stroke patient data.","authors":"Lisa Röhrig, Daniel Wiesen, Dongyun Li, Christopher Rorden, Hans-Otto Karnath","doi":"10.1093/braincomms/fcaf047","DOIUrl":"10.1093/braincomms/fcaf047","url":null,"abstract":"<p><p>One of the most pressing questions after a stroke is whether an individual patient will recover in the long term. Previous studies demonstrated that spatial neglect-a common cognitive deficit after right hemispheric stroke-is a strong predictor for poor performance on a wide range of everyday tasks and for resistance to rehabilitation. The possibility of predicting long-term prognosis of spatial neglect is therefore of great relevance. The aim of the present study was to test the prognostic value of different imaging and non-imaging features from right hemispheric stroke patients: individual demographics (age, sex), initial neglect severity and acute lesion information (size, location). Patients' behaviour was tested twice in the acute and the chronic phases of stroke and prediction models were built using machine learning-based algorithms with repeated nested cross-validation and feature selection. Model performances indicate that demographic information seemed less beneficial. The best variable combination comprised individual neglect severity in the acute phase of stroke, together with lesion location and size. The latter were based on individual lesion overlaps with a previously proposed chronic neglect region of interest that covers anterior parts of the superior and middle temporal gyri and the basal ganglia. These variables achieved a remarkably high level of accuracy by explaining 66% of the total variance of neglect patients, making them promising features in the prediction of individual outcome prognosis. An online tool is provided with which our algorithm can be used for individual outcome predictions (https://niivue.github.io/niivue-neglect/).</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf047"},"PeriodicalIF":4.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain connectivity in individuals with migraine resets during the headache phase: a whole-brain connectivity study.","authors":"Enrico Schulz, Astrid Mayr, Pauline Jahn, Anne Stankewitz","doi":"10.1093/braincomms/fcaf045","DOIUrl":"10.1093/braincomms/fcaf045","url":null,"abstract":"<p><p>Episodic migraine is reflected by cyclic changes in behavior and cortical processing. We aimed to identify how functional connectivity changes over the entire migraine cycle. By using longitudinal neuroimaging and a whole-brain connectivity analysis approach, we tested 12 episodic migraine patients across 82 functional MRI recordings during spontaneous migraine headaches with follow-up measurements over the pain-free interval without any external stimulation. We found that the functional connectivity linearly increased over the interictal interval. In the prodromal phase, we observed the strongest connections between the anterior agranular insula and the posterior orbitofrontal cortex with sensory, motor and cingulate areas. The strength of the connections dropped during the headache. Peak connectivity during the prodromal phase and its collapse during the headache can be regarded as a mechanism of normalizing cortical processing. We speculate about a malfunction at the molecular level in agranular frontal and insular regions, which needs to be addressed in subsequent studies.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf045"},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF production rate, resistance to reabsorption, and intracranial pressure: a systematic review and meta-analysis.","authors":"Ihsane Olakorede, Stefan Y Bögli, Zofia Czosnyka, Marek Czosnyka, Peter Smielewski","doi":"10.1093/braincomms/fcaf044","DOIUrl":"10.1093/braincomms/fcaf044","url":null,"abstract":"<p><p>Davson's equation relates the state of stable intracranial pressure (ICP) to the production rate of CSF (I_F) and resistance to CSF outflow (R_OUT). Both parameters are assumed to be independent of ICP, but results are conflicting. The objective is to define the relationship between ICP, I_F and R_OUT using a systematic literature review. Medline and Embase were searched from inception up to 12 February 2024. Experimental studies exploring the association between ICP, I_F, and R_OUT were included. Individual measurements of ICP, I_F and/or R_OUT were extracted from tables or graphs, alongside descriptive parameters (population, ICP measurement site, disease, and computational method). Linear regression and mixed effects models were applied. From 1304 references, 25 articles were included in our meta-analysis. I_F is approximately constant across all pathologies independent of the ICP level, population, disease, ICP measurement site and the measurement/estimation method. Conversely, ICP was positively correlated with R_OUT. The intercorrelation, however, differed by population, disease, ICP measurement site and estimation method. Additionally, I_F derived from Davson's Equation compared with the measured I_F were similar for patients with hydrocephalus but differed for patients with acute brain injury. Davson's Equation describes the various components of cerebrospinal fluid dynamics. The results underline important caveats for its use in patients with acute brain injury wherein the estimated values differ from the measured ones. Overall, additional metrics describing the cerebrovascular system or the underlying disease have to be taken into account for more accurate estimations.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf044"},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia.","authors":"Judith Cossins, Imre Kozma, Claudia Canzonetta, Al Hawkins, David Beeson, Patricio Sepulveda, Yin Yao Dong","doi":"10.1093/braincomms/fcaf046","DOIUrl":"10.1093/braincomms/fcaf046","url":null,"abstract":"<p><p>Congenital myasthenic syndromes are a group of inherited disorders characterized by defective neuromuscular transmission and fatigable muscle weakness. Causative mutations have been identified in over 30 genes, including <i>DOK7</i>, a gene encoding a post-synaptic protein crucial in the formation and stabilization of the neuromuscular junction. Mutations in this gene are one of the leading three most prevalent causes of congenital myasthenia in diverse populations across the globe. The majority of DOK7 congenital myasthenic patients experience varying degrees of disability despite receiving optimized treatment (usually salbutamol), necessitating the development of improved therapeutic approaches. Here, we executed a dose escalation pre-clinical trial using a DOK7 congenital myasthenic syndrome mouse model to assess the efficacy of AMP-101, an innovative recombinant adeno-associated viral gene replacement therapy. This mouse model harbours a duplication in the <i>Dok7</i> gene that corresponds to the mutation most commonly found in DOK7 congenital myasthenia patients, c.1124-1127dupTGCC. The model has a much more severe phenotype than patients, and lives for only a few days. AMP-101 is based on AAVrh74 and contains human <i>DOK7</i> cDNA under the control of a muscle-restricted promoter. Three doses of AMP-101 (2 × 10¹³ vg/kg, 6 × 10¹³ vg/kg or 1 × 10¹⁴ vg/kg) were administered intraperitoneally at 4 days of age. We show that the two higher doses of 6 × 10¹³ vg/kg and 1 × 10¹⁴ vg/kg generated enlarged neuromuscular junctions and rescued the very severe phenotype of the model. Treated mice became at least as strong as wild-type littermates, as demonstrated by using an inverted screen hang test, a rotarod test and a grip strength test. EMG showed that the treated model mice had decrement of compound muscle action potential on repetitive nerve stimulation, which indicates defective signalling at the neuromuscular junction. However, male models treated with 1 × 10¹⁴ vg/kg showed the least decrement that was not statistically different from wild-type littermates. Western blot analysis demonstrated robust expression of DOK7 in the diaphragm and tibialis anterior muscles. These data show that AMP-101 is an effective treatment in a mouse model for DOK7 congenital myasthenia, and suggests that AMP-101 is a promising candidate to move forward to clinic trials as a gene therapy for patients.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf046"},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory analysis of biological age measures in a remyelination clinical trial.","authors":"Christopher E McMurran, Ermelinda de Meo, Nick G Cunniffe, J William L Brown, Ferran Prados, Baris Kanber, James H Cole, Alasdair J Coles, Sara Hägg, Declan T Chard","doi":"10.1093/braincomms/fcaf032","DOIUrl":"10.1093/braincomms/fcaf032","url":null,"abstract":"<p><p>Enhancing CNS myelin repair (remyelination) is a promising strategy to prevent neurodegeneration and associated progressive disability in multiple sclerosis. Remyelination becomes inefficient with older chronological age, but the relationship between measures of biological age and remyelination has not been previously described in a clinical cohort. Here, we investigated two measures of biological age amongst participants of the Cambridge Centre for Myelin Repair One trial of bexarotene: MRI brain age (BA_MRI) and a blood-based biological age (BA_Blood). In people with radiologically stable multiple sclerosis (<i>n</i> = 44 of 49 total participants), we found that treatment with bexarotene, along with promoting remyelination, was associated with significant decrease in MRI brain age [-1.98 years, 95% confidence interval (CI) [-3.75, -0.21 years] versus placebo over 6 months, <i>P</i> = 0.034]. Whilst BA_MRI increased as expected during the trial in the placebo group (+0.92 years, CI [-0.41, 2.26]), the brain MRIs of participants treated with bexarotene appeared on average 11 months younger at the end compared to the start of the trial (-0.93 years, CI [-2.02, 0.17]). The effect of bexarotene on BA_MRI was associated with its remyelinating activity in cortical grey matter lesions (<i>β</i> = 0.25% units (pu)/year, CI [0.03, 0.46], <i>P</i> = 0.023) and brainstem lesions (<i>β</i> = 0.24 pu/year, CI [0.09, 0.39], <i>P</i> = 0.003). We also observed some regional trends that the remyelinating response to bexarotene was linked with measures of biological age at baseline. For example, after adjustment for chronological age, remyelination of brainstem lesions assessed by magnetization transfer ratio was reduced by 0.06 pu for each year increase in BA_MRI (CI [0.00, 0.13], <i>P</i> = 0.058) and 0.02 pu for each year increase in BA_Blood (CI [-0.01, 0.05], <i>P</i> = 0.17). This is, to the best of our knowledge, the first demonstration that MRI brain age can be therapeutically modulated by a drug in people with a neurological disorder. Overall, these findings highlight that beyond chronological age, biological age may also influence the potential for repair and should be considered when developing treatments for multiple sclerosis.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf032"},"PeriodicalIF":4.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unmasking paramagnetic rim multiple sclerosis lesions: the advantages of quantitative susceptibility mapping over phase imaging.","authors":"Àlex Rovira, Deborah Pareto","doi":"10.1093/braincomms/fcaf037","DOIUrl":"10.1093/braincomms/fcaf037","url":null,"abstract":"<p><p>This scientific commentary refers to 'Quantitative susceptibility mapping is more sensitive and specific than phase imaging in detecting chronic active multiple sclerosis lesion rims: pathological validation', by Gillen <i>et al</i>. (https://doi.org/10.1093/braincomms/fcaf011).</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf037"},"PeriodicalIF":4.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical involvement of lateral trunk flexion and verticality misperception in Parkinson's disease.","authors":"Masayuki Kohsaka, Tomoko Oeda, Shigetoshi Takaya, Satoshi Tomita, Kwiyoung Park, Kenji Yamamoto, Hidenao Fukuyama, Hideyuki Sawada","doi":"10.1093/braincomms/fcaf040","DOIUrl":"10.1093/braincomms/fcaf040","url":null,"abstract":"<p><p>Lateral trunk flexion is a common form of postural abnormality in Parkinson's disease and could be associated with verticality misperception. However, the mechanisms underlying lateral trunk flexion and verticality misperception in Parkinson's disease remain unclear. In the current study, we examined whether lateral trunk flexion is associated with verticality misperception in patients with Parkinson's disease. We also identified the brain regions involved in lateral trunk flexion and altered verticality perception. In this cross-sectional study, we evaluated the verticality perception using the subjective visual vertical test in 81 patients with Parkinson's disease and 14 age-matched healthy controls. According to the 97.5th percentile upper reference limit of the body tilt angle in the healthy controls, patients with Parkinson's disease were grouped into 37 patients with lateral trunk flexion and 44 patients without lateral trunk flexion. The mean of absolute subjective visual vertical angles was compared between patients with Parkinson's disease with lateral trunk flexion, those without lateral trunk flexion, and the healthy controls, and the impact of verticality misperception on lateral trunk flexion was evaluated using multivariate logistic regression models. We further performed a voxel-wise comparison of regional cerebral blood flow using N-isopropyl-p-[¹²³I] iodoamphetamine single-photon emission computed tomography (height threshold of <i>P</i> < 0.001, uncorrected for multiple comparisons, extent threshold of 100 voxels) to identify the brain regions associated with lateral trunk flexion, and to investigate the relationship between verticality misperception and regional hypoperfusion. The mean of absolute subjective visual vertical angles was larger in patients with Parkinson's disease with and without lateral trunk flexion than in healthy controls (<i>P</i> < 0.001 and <i>P</i> < 0.001). Additionally, the subjective visual vertical angle was associated with the presence of lateral trunk flexion (odds ratio 2.25, 95% confidence interval 1.51-3.36, <i>P</i> < 0.001). The regional cerebral blood flow in patients with Parkinson's disease with lateral trunk flexion was decreased in the right inferior parietal lobule, right superior parietal lobule, right superior temporal gyrus, and right dorsal posterior cingulate cortex compared with those without lateral trunk flexion. The subjective visual vertical angle was inversely correlated with regional cerebral blood flow in these regions, except for the dorsal posterior cingulate cortex. Our study reveals that hypofunction in the right temporoparietal association cortices is involved in verticality misperception and the development of lateral trunk flexion in patients with Parkinson's disease. These results provide insights into potential therapeutic targets for addressing lateral trunk flexion.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf040"},"PeriodicalIF":4.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myths and facts about alcohol use disorder: a Delphi consensus study.","authors":"Sophie Hytner, Daphne Josselin, David Belin, Owen Bowden Jones","doi":"10.1093/braincomms/fcaf035","DOIUrl":"10.1093/braincomms/fcaf035","url":null,"abstract":"<p><p>Educational interventions that counter myths about alcohol use disorder with facts have the potential to reduce public stigma. Few such interventions have hitherto been rigorously developed. Using a Delphi expert consensus method, this study identified myths and facts to include in an intervention targeting the public stigma of alcohol use disorder. Sixteen UK-based experts (four academics, five clinicians and seven experts-by-experience) completed three sequential online survey rounds. The first round was used alongside a systematic review of the literature on public alcohol use disorder stereotypes to develop 13 myth-fact pairs, which participants quantitively scored in subsequent rounds to determine their importance for inclusion. Pairs reaching consensus (>70% agreement) on high importance (mean score, 7-9) challenged beliefs that alcohol use disorder '<i>only affects certain groups'</i>, and that people with alcohol use disorder '<i>cannot recover'</i>, are '<i>to blame'</i> for, and '<i>able to control'</i>, their drinking. The myth-fact pairs scored as most important relate to responsibility- and recovery-based themes and provide a basis for future educational interventions for public alcohol use disorder stigma.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf035"},"PeriodicalIF":4.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genetic landscape and classification of infantile epileptic spasms syndrome requiring surgery due to suspected focal brain malformations.","authors":"Matthew Coleman, Min Wang, Penny Snell, Wei Shern Lee, Colleen D'Arcy, Cristina Mignone, Kate Pope, Greta Gillies, Wirginia Maixner, Alison Wray, A Simon Harvey, Cas Simons, Richard J Leventer, Sarah E M Stephenson, Paul J Lockhart, Katherine B Howell","doi":"10.1093/braincomms/fcaf034","DOIUrl":"10.1093/braincomms/fcaf034","url":null,"abstract":"<p><p>Infantile epileptic spasms syndrome is a severe epilepsy of infancy that is often associated with focal malformations of cortical development. This study aimed to elucidate the genetic landscape and histopathologic aetiologies of infantile epileptic spasms syndrome due to focal malformations of cortical development requiring surgery. Fifty-nine children with a history of infantile epileptic spasms syndrome and focal malformations of cortical development on MRI were studied. Genetic testing of resected brain tissue was performed by high-coverage targeted panel sequencing or exome sequencing. Histopathology and MRI were reviewed, and integrated clinico-pathological diagnoses were established. A genetic diagnosis was achieved in 47 children (80% of cohort). Germline pathogenic variants were identified in 27/59 (46%) children, in <i>TSC2</i> (x19), <i>DEPDC5</i> (x2), <i>CDKL5</i> (x2), <i>NPRL3</i> (x1), <i>FGFR1</i> (x1), <i>TSC1</i> (x1), and one child with both a <i>TUBB2A</i>/<i>TUBB2B</i> deletion and a pathogenic variant in <i>COL4A1</i> (x1). Pathogenic brain somatic variants were identified in 21/59 (36%) children, in <i>SLC35A2</i> (x9), <i>PIK3CA</i> (x3), <i>AKT3</i> (x2), <i>TSC2</i> (x2), <i>MTOR</i> (x2), <i>OFD1</i> (x1), <i>TSC1</i> (x1) and <i>DEPDC5</i> (x1). One child had 'two-hit' diagnosis, with both germline and somatic pathogenic <i>DEPDC5</i> variants in trans. Multimodal data integration resulted in clinical diagnostic reclassifications in 24% of children, emphasizing the importance of combining genetic, histopathologic and imaging findings. Mammalian target of rapamycin pathway variants were identified in most children with tuberous sclerosis or focal cortical dysplasia type II. All nine children with somatic <i>SLC35A2</i> variants in brain were reclassified to mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Somatic mosaicism was a major cause of focal cortical dysplasia type II/hemimegalencephaly (81%) and mild malformation of cortical development with oligodendroglial hyperplasia (100%). The genetic landscape of infantile epileptic spasms syndrome due to focal malformations comprises germline and somatic variants in a range of genes, with mTORopathies and <i>SLC35A2</i>-related mild malformation of cortical development with oligodendroglial hyperplasia being the major causes. Multimodal data integration incorporating genetic data aids in optimizing diagnostic pathways and can guide surgical decision-making and inform future research and therapeutic interventions.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"7 1","pages":"fcaf034"},"PeriodicalIF":4.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}