Rachel J Boyd, A Ra Kho, Sarah A McClymont, Stacie K Loftus, Han Seok Ko, Andrew S McCallion
Parkinson's disease (PD) is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body (LB) aggregates, neuronal loss, and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic PD. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of PD, including insoluble LB aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbors variation associated with PD risk and demonstrated its role as a neuronal cis-regulatory element (CRE). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils (PFF) was used to seed PD pathology (or PBS vehicle) in these mice. Cohorts of mice harboring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, LB acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn PFF, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against PD-relevant histopathology, including DA neurodegeneration, LB acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduce the onset, severity and progression of PD pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for PD.
{"title":"Neuronal titration of Snca via enhancer disruption mitigates disease onset in a Parkinson's disease mouse model.","authors":"Rachel J Boyd, A Ra Kho, Sarah A McClymont, Stacie K Loftus, Han Seok Ko, Andrew S McCallion","doi":"10.1093/brain/awag007","DOIUrl":"10.1093/brain/awag007","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body (LB) aggregates, neuronal loss, and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic PD. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of PD, including insoluble LB aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbors variation associated with PD risk and demonstrated its role as a neuronal cis-regulatory element (CRE). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils (PFF) was used to seed PD pathology (or PBS vehicle) in these mice. Cohorts of mice harboring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, LB acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn PFF, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against PD-relevant histopathology, including DA neurodegeneration, LB acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduce the onset, severity and progression of PD pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for PD.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"On the practice of video documentation and representation in movement disorders.","authors":"Christos Ganos,Michael P H Stanley,Anthony E Lang","doi":"10.1093/brain/awag005","DOIUrl":"https://doi.org/10.1093/brain/awag005","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"44 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The CD5-CK2-STAT3 axis in Th17 cell polarization: implications for multiple sclerosis.","authors":"Luisa M Villar","doi":"10.1093/brain/awaf469","DOIUrl":"https://doi.org/10.1093/brain/awaf469","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"24 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Geoffrey K Ganter, Hope C Reveche, Lindsey A Fitzsimons, Eugen V Khomula, Jon D Levine, Kerry L Tucker
The primary cilium, a single microtubule-based organelle protruding from the surface of cells, utilizes intraflagellar transport (IFT) to establish and maintain its structure and function. It is well-established to guide development and function of the nervous system through signaling pathways identified by expression of molecular markers such as ADP-ribosylation factor-like protein 13 (ARL13B) and type 3 adenylyl cyclase (AC3). Its dysregulation results in ciliopathies, clinical syndromes affecting a broad range of organ systems. Recently it has been established in several species that nociceptors have a primary cilium, which regulates their excitability, contributing to acute and chronic pain. Since primary cilium-dependent signaling, such as Hedgehog (Hh) and Wingless (Wnt) pathways, have been implicated in nociceptor excitability and pain syndromes, interventions targeting this organelle may provide novel treatments for pain.
{"title":"The nociceptor primary cilium","authors":"Geoffrey K Ganter, Hope C Reveche, Lindsey A Fitzsimons, Eugen V Khomula, Jon D Levine, Kerry L Tucker","doi":"10.1093/brain/awag004","DOIUrl":"https://doi.org/10.1093/brain/awag004","url":null,"abstract":"The primary cilium, a single microtubule-based organelle protruding from the surface of cells, utilizes intraflagellar transport (IFT) to establish and maintain its structure and function. It is well-established to guide development and function of the nervous system through signaling pathways identified by expression of molecular markers such as ADP-ribosylation factor-like protein 13 (ARL13B) and type 3 adenylyl cyclase (AC3). Its dysregulation results in ciliopathies, clinical syndromes affecting a broad range of organ systems. Recently it has been established in several species that nociceptors have a primary cilium, which regulates their excitability, contributing to acute and chronic pain. Since primary cilium-dependent signaling, such as Hedgehog (Hh) and Wingless (Wnt) pathways, have been implicated in nociceptor excitability and pain syndromes, interventions targeting this organelle may provide novel treatments for pain.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"42 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While there has been a considerable increase in the understanding of glioblastoma and investigations into the therapeutic utility of several novel putative active compounds, the prognosis of glioblastoma patients remains dismal. This paradox makes glioblastoma a unique disease in which the availability of key molecular and biological insight does not translate into therapeutic discovery or improved outcomes. Much of the challenge in glioblastoma treatment is due to a dearth of tools capable of accurately selecting patients who may benefit from current standard-of-care or targeted therapies. Moreover, the lack of reliable circulating biomarkers also delays treatment initiation and hampers therapeutic response evaluation. However, the emergence of a personalized medicine paradigm employing extracellular vesicles has the potential to revolutionize cancer treatment, bringing renewed hope for patients with glioblastoma. In this review, we provide a brief overview of the clinical outlook of current standard-of-care, immunotherapy, and their drawbacks, introduce the need for a personalized model, and finally discuss the conceptual underpinnings of how extracellular vesicle cargo as superior liquid biopsy tools can be utilized for a new personalized therapeutic approach in glioblastoma.
{"title":"Extracellular vesicles as liquid biopsy tools for personalized therapeutic goals in glioblastoma","authors":"Camille Menaceur Vandenbroucke, Kavitha Unnikrishnan, Michael Itak Ita, Ulrik Niels Lassen, Mattias Belting, Anders Rosendal Korshoej, Carsten Reidies Bjarkam, Vineesh Indira Chandran","doi":"10.1093/brain/awag003","DOIUrl":"https://doi.org/10.1093/brain/awag003","url":null,"abstract":"While there has been a considerable increase in the understanding of glioblastoma and investigations into the therapeutic utility of several novel putative active compounds, the prognosis of glioblastoma patients remains dismal. This paradox makes glioblastoma a unique disease in which the availability of key molecular and biological insight does not translate into therapeutic discovery or improved outcomes. Much of the challenge in glioblastoma treatment is due to a dearth of tools capable of accurately selecting patients who may benefit from current standard-of-care or targeted therapies. Moreover, the lack of reliable circulating biomarkers also delays treatment initiation and hampers therapeutic response evaluation. However, the emergence of a personalized medicine paradigm employing extracellular vesicles has the potential to revolutionize cancer treatment, bringing renewed hope for patients with glioblastoma. In this review, we provide a brief overview of the clinical outlook of current standard-of-care, immunotherapy, and their drawbacks, introduce the need for a personalized model, and finally discuss the conceptual underpinnings of how extracellular vesicle cargo as superior liquid biopsy tools can be utilized for a new personalized therapeutic approach in glioblastoma.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"11 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johanna R Roller, Ashraf Yahia, Giovanni Stevanin, Ammar E Ahmed, Amna M T Alawadhi, Mohammed Almannai, Maryam Y Busehail, Alexander H Choi, Ali A Elhassan, Liena E O Elsayed, Christina Goode, Lauren H Hammer, Christina Laukaitis, Amber Begtrup, Rachel A Paul, Jasmin Roohi, Hoda Y Tomoum, Peter Bauer, Ludger Schöls, Jorge P Basto, Matthis Synofzik, Holger Hengel
{"title":"The RAB3A hot spot variant R83W causes spasticity as part of the ataxia-spasticity spectrum.","authors":"Johanna R Roller, Ashraf Yahia, Giovanni Stevanin, Ammar E Ahmed, Amna M T Alawadhi, Mohammed Almannai, Maryam Y Busehail, Alexander H Choi, Ali A Elhassan, Liena E O Elsayed, Christina Goode, Lauren H Hammer, Christina Laukaitis, Amber Begtrup, Rachel A Paul, Jasmin Roohi, Hoda Y Tomoum, Peter Bauer, Ludger Schöls, Jorge P Basto, Matthis Synofzik, Holger Hengel","doi":"10.1093/brain/awaf482","DOIUrl":"https://doi.org/10.1093/brain/awaf482","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frida Lona-Durazo, Ross P Byrne, Marc-Olivier Pilon, Michael D Greicius, Marie-Pierre Dubé, Michael E Belloy, Russell L McLaughlin, Sarah A Gagliano Taliun
Sex differences, in terms of prevalence, symptoms and disease progression, are established in the etiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence, through genetic and functional analyses, affirming the role of the immune system in such diseases, but a thorough assessment of sex differences linking the immune system and neurodegenerative diseases is understudied. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10,895 cases, 57,062 controls; males = 15,547 cases, 50,145 controls), Parkinson’s disease (females = 7,947 cases, 90,662 controls; males = 13,020 cases, 89,660 controls) and Alzheimer’s disease (females = 18,822 cases, 281,415 controls; males = 17,293 cases, 213,339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (FDR cutoff < 0.01) from a large sex-combined plasma protein dataset (N = 33,477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (N = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson’s disease, and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer’s disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson’s disease and of GRN, SERPINF2 and TREM2 on Alzheimer’s disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson’s disease and of CD33 on Alzheimer’s disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer’s disease and Parkinson’s disease, some of which may be considered as potential candidates for drug development.
{"title":"Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases","authors":"Frida Lona-Durazo, Ross P Byrne, Marc-Olivier Pilon, Michael D Greicius, Marie-Pierre Dubé, Michael E Belloy, Russell L McLaughlin, Sarah A Gagliano Taliun","doi":"10.1093/brain/awaf474","DOIUrl":"https://doi.org/10.1093/brain/awaf474","url":null,"abstract":"Sex differences, in terms of prevalence, symptoms and disease progression, are established in the etiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence, through genetic and functional analyses, affirming the role of the immune system in such diseases, but a thorough assessment of sex differences linking the immune system and neurodegenerative diseases is understudied. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10,895 cases, 57,062 controls; males = 15,547 cases, 50,145 controls), Parkinson’s disease (females = 7,947 cases, 90,662 controls; males = 13,020 cases, 89,660 controls) and Alzheimer’s disease (females = 18,822 cases, 281,415 controls; males = 17,293 cases, 213,339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (FDR cutoff &lt; 0.01) from a large sex-combined plasma protein dataset (N = 33,477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (N = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson’s disease, and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer’s disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson’s disease and of GRN, SERPINF2 and TREM2 on Alzheimer’s disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson’s disease and of CD33 on Alzheimer’s disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer’s disease and Parkinson’s disease, some of which may be considered as potential candidates for drug development.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inna Radzishevsky, Lama Harb, Maali Odeh, Inon Maoz, Aseel Saeed, Ankita Lahkar, Bella Agranovich, Ifat Abramovich, Farrukh A Chaudhry, Avi Avital, Daniel J Liebl, Herman Wolosker
Biallelic mutations in SLC38A3 lead to postnatal progressive microcephaly, epilepsy, and intellectual disability. However, the underlying pathophysiology remains unknown. Here, we identified Slc38a3 expressed at the vascular endothelium as a critical glutamine transporter that mediates blood-to-brain influx of glutamine through the blood-brain barrier (BBB). Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the BBB and decreased brain glutamine levels in mouse pups. This was associated with lower transfer of glutamine carbons to glutamate and GABA, suggesting impairment of the glutamine-glutamate/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly as well as behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups fail to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower TCA cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly, and normalized motor behavior in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype. In contrast to the dogma that all glutamine is produced locally in the brain, our data show that Slc38a3 provides blood-derived glutamine for neurotransmitter synthesis, energy metabolism, and synaptogenesis. Our findings suggest that SLC38A3 mutations cause a glutamine-related BBB aminoacidopathy and developmental disorder, which may be amenable to glutamine supplementation therapy.
{"title":"SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development","authors":"Inna Radzishevsky, Lama Harb, Maali Odeh, Inon Maoz, Aseel Saeed, Ankita Lahkar, Bella Agranovich, Ifat Abramovich, Farrukh A Chaudhry, Avi Avital, Daniel J Liebl, Herman Wolosker","doi":"10.1093/brain/awaf473","DOIUrl":"https://doi.org/10.1093/brain/awaf473","url":null,"abstract":"Biallelic mutations in SLC38A3 lead to postnatal progressive microcephaly, epilepsy, and intellectual disability. However, the underlying pathophysiology remains unknown. Here, we identified Slc38a3 expressed at the vascular endothelium as a critical glutamine transporter that mediates blood-to-brain influx of glutamine through the blood-brain barrier (BBB). Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the BBB and decreased brain glutamine levels in mouse pups. This was associated with lower transfer of glutamine carbons to glutamate and GABA, suggesting impairment of the glutamine-glutamate/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly as well as behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups fail to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower TCA cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly, and normalized motor behavior in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype. In contrast to the dogma that all glutamine is produced locally in the brain, our data show that Slc38a3 provides blood-derived glutamine for neurotransmitter synthesis, energy metabolism, and synaptogenesis. Our findings suggest that SLC38A3 mutations cause a glutamine-related BBB aminoacidopathy and developmental disorder, which may be amenable to glutamine supplementation therapy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"22 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Real world treatments for 5q-spinal muscular atrophy (SMA) have evolved rapidly following the sequential approval of three disease-modifying treatments (DMT): nusinersen, onasemnogene abeparvovec (OA) and risdiplam. The aim of this study was to accurately map the sequence and timing of SMA treatments using the SMArtCARE registry, a disease-specific registry for patients with SMA across 84 participating centers in Germany, Austria, and Switzerland. All patients registered in SMArtCARE were included in the analysis. Patients were grouped based on their treatment regimen: those who remained on the first DMT versus those who switched DMT. The impact of clinical and genetic factors on treatment decisions were evaluated, including age at initiation of treatment, SMN2 copy number, motor function status, the need for ventilator support or tube feeding, and the presence of scoliosis. A total of 2,140 patients were included. Of these, 1,294 patients (60.5%) initiated treatment with nusinersen, 514 patients (24.0%) with risdiplam, 243 patients (11.4%) with OA. Overall, 1,366 patients (63.8%) remained on the first DMT. Most treatments switches occurred shortly after approval of a new DMT. Notably, most patients who switched, showed no change in motor milestone status between the start of the first and the second DMT. In this large real-world cohort, we present the first comprehensive analysis of SMA treatment patterns across all age groups and disease severities. While most patients remained on the first DMT, switches were mainly observed after DMT approvals. Decisions to switch appear multifactorial and are not directly related to motor function effectiveness.
{"title":"Treatment evolution in spinal muscular atrophy: insights from the SMArtCARE registry.","authors":"Cornelia Voigt-Müller,Michelle Pfaffenlehner,Günther Bernert,Hakan Cetin,Tim Hagenacker,Heike Kölbel,Hanns Lochmüller,Christian Pfeuffer,Katharina Vill,Maggie C Walter,Janbernd Kirschner,Astrid Pechmann","doi":"10.1093/brain/awaf472","DOIUrl":"https://doi.org/10.1093/brain/awaf472","url":null,"abstract":"Real world treatments for 5q-spinal muscular atrophy (SMA) have evolved rapidly following the sequential approval of three disease-modifying treatments (DMT): nusinersen, onasemnogene abeparvovec (OA) and risdiplam. The aim of this study was to accurately map the sequence and timing of SMA treatments using the SMArtCARE registry, a disease-specific registry for patients with SMA across 84 participating centers in Germany, Austria, and Switzerland. All patients registered in SMArtCARE were included in the analysis. Patients were grouped based on their treatment regimen: those who remained on the first DMT versus those who switched DMT. The impact of clinical and genetic factors on treatment decisions were evaluated, including age at initiation of treatment, SMN2 copy number, motor function status, the need for ventilator support or tube feeding, and the presence of scoliosis. A total of 2,140 patients were included. Of these, 1,294 patients (60.5%) initiated treatment with nusinersen, 514 patients (24.0%) with risdiplam, 243 patients (11.4%) with OA. Overall, 1,366 patients (63.8%) remained on the first DMT. Most treatments switches occurred shortly after approval of a new DMT. Notably, most patients who switched, showed no change in motor milestone status between the start of the first and the second DMT. In this large real-world cohort, we present the first comprehensive analysis of SMA treatment patterns across all age groups and disease severities. While most patients remained on the first DMT, switches were mainly observed after DMT approvals. Decisions to switch appear multifactorial and are not directly related to motor function effectiveness.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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