TOC Summary R. Mark Richardson argues that, in an era where sensing-enabled devices can provide effective therapy when applied to appropriate seizure networks, treating thalamic implantation as research by default may be...TOC Summary R. Mark Richardson argues that, in an era where sensing-enabled devices can provide effective therapy when applied to appropriate seizure networks, treating thalamic implantation as research by default may be overly conservative. He views hypothesis-driven thalamic SEEG as indispensable for optimizing neuromodulation strategies.
Mutations in the SNCA gene encoding α-synuclein (α-syn) underlie familial early-onset Parkinson's disease (PD). Pathological α-syn deposition may commence decades prior to the emergence of cardinal motor symptoms. Long-t...Mutations in the SNCA gene encoding α-synuclein (α-syn) underlie familial early-onset Parkinson's disease (PD). Pathological α-syn deposition may commence decades prior to the emergence of cardinal motor symptoms. Long-term investigation of brain and behavioral development in an SNCA-A53T transgenic macaque model offers critical insights into PD progression. In this study, we systematically characterized SNCA-A53T transgenic rhesus monkeys through multimodal assessments. Our results showed that these transgenic monkeys exhibited phosphorylated α-syn aggregation patterns and dopaminergic degeneration resembling PD patients. Progressive motor and cognitive deficits were observed in transgenic monkeys with aging. Polysomnographic analysis revealed REM sleep behavior disorder manifestations in transgenic animals. Four-year longitudinal MRI tracking demonstrated abnormal developmental patterns of cortical surface area alongside thickness and volume alterations. Single-cell transcriptome revealed that astrocyte-specific gene dysregulation and cell loss contribute to brain atrophy in transgenic monkeys. Cortical and subcortical gray matter regions showing volume reduction were functionally associated with behavioral deficits and differentiated transgenic animals from wild-type controls. Collectively, this comprehensive study provides evidence that SNCA-A53T transgenic monkeys recapitulate PD pathophysiology while demonstrating the utility of longitudinal monitoring in genetically engineered nonhuman primates for tracking neurodegenerative disease progression.
Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity...Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson's disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta-alpha and low beta coupling did not show significant associations with DBS response (theta-alpha: βstd = -0.02, P = 0.805; low beta: βstd = -0.08, P = 0.426). The 'optimal' high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10-5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.
Soni argues that modern seizure classifications change too often, confusing clinicians and patients. By contrasting them with the stable, descriptive approaches of Hippocrates, Galen, and Ibn Sina, she calls for simpler,...Soni argues that modern seizure classifications change too often, confusing clinicians and patients. By contrasting them with the stable, descriptive approaches of Hippocrates, Galen, and Ibn Sina, she calls for simpler, enduring language to improve epilepsy care.
Spinal Muscular Atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease modifying treatments have greatly improved...Spinal Muscular Atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. Skeletal muscle tissue and the Muscle Stem Cells (MuSC) that sustain its postnatal growth and regenerative capacity, are affected by SMN deficit. While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established. Using SMA type II patient muscle biopsies and several mutant mouse models, we performed an accurate study of SMN role in MuSC function during postnatal growth and adulthood. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ MuSC. In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that deletion of a single Smn allele is sufficient to induce quiescent MuSC apoptosis in adult muscle, showing that high levels of SMN are required for the maintenance of the quiescent MuSC reservoir. We further established that depletion of MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of part of the alpha motor neurons (MN) in the long term. Overall, our findings demonstrate an interdependence between quiescent MuSC and the MN reservoirs, supporting that MuSC may be important therapeutic targets for the long-term treatment of SMA. Moreover, we provide important insights into the specific SMN requirements of MuSC, which could be valuable for to the development of next generation combinatorial therapies.
Facioscapulohumeral dystrophy (FSHD) is primarily associated with contraction of the D4Z4 macrosatellite array at the 4q35 locus. Unaffected individuals carry 11-150 D4Z4 repeats, whereas ∼95% of FSHD patients (FSHD1) ex...Facioscapulohumeral dystrophy (FSHD) is primarily associated with contraction of the D4Z4 macrosatellite array at the 4q35 locus. Unaffected individuals carry 11-150 D4Z4 repeats, whereas ∼95% of FSHD patients (FSHD1) exhibit a contraction to 1-10 units, along with reduced DNA methylation. In another ∼3% of patients (FSHD2), the disease results from a digenic mechanism associated with the presence of a pathogenic variant in the SMCHD1 gene, leading to the epigenetic deregulation of the 4q35 locus. However, 1%-2% of clinically diagnosed patients lack a defined genetic cause, highlighting diagnostic gaps. In prior work, we identified >70 patients, clinically diagnosed with FSHD and carrying a complex structural variant of the 4q35 or 10q26 loci. A potential pathogenicity of these structural variants was evoked in some cases, in the absence of other FSHD-associated genetic features. Given their diagnostic relevance, here we performed detailed structural analyses of these rearrangements in seven representative cases carrying different structural variants of the 4q35 or 10q26 loci using high-resolution long-read sequencing technologies (Oxford Nanopore and PacBio) and suspected of FSHD. By comparing the advantages and limitations of several methodological long-read sequencing strategies, we resolved the architecture and methylation patterns across the 4q35 and 10q26 loci at the nucleotide level. We show that duplicated alleles arise from intrachromosomal recombination between LSau elements contained within D4Z4 and distal subtelomeric β-satellite elements, producing variable deletions within the proximal D4Z4 region, with breakpoints differing among patients. These complex structural variants are not detectable using standard technologies, such as Bionano Optical Genome Mapping, and require manual curation for identification during routine molecular diagnosis procedures. Importantly, determining the pathogenic relevance of these rearrangements necessitates integration of structural and epigenetic features typically associated with FSHD. Our results underscore the importance of in-depth molecular characterization for patients with clinical FSHD who test negative for FSHD1/FSHD2 by conventional diagnostic methods. We also show that structural variants might be considered as likely to be pathogenic, in the absence of an SMCHD1 variant. Overall, as structural variants at 4q35 are increasingly identified in patients clinically diagnosed with FSHD, their comprehensive analysis is crucial to refine diagnosis, guide genetic counselling and, ultimately, improve clinical care for individuals clinically suspected of FSHD but presenting with an atypical molecular profile.
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neuroinflammatory disease with no effective treatment. In this study, we investigated...Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neuroinflammatory disease with no effective treatment. In this study, we investigated whether dimethyl fumarate (DMF), an immunomodulatory agent approved for treating multiple sclerosis, exerts therapeutic effects relevant to HAM/TSP. Peripheral blood mononuclear cells (PBMCs) from 16 people living with HAM/TSP were used to evaluate the effects of DMF on cell viability, spontaneous proliferation, inflammatory cytokine production and HTLV-1 proviral load (PVL). DMF significantly inhibited lymphocyte proliferation in a concentration-dependent manner, with reductions of 42.1% at 10 µM, 56.3% at 25 µM, 60.6% at 50 µM and 69.9% at 100 µM. This suppressive effect was particularly evident in CD8+ T cells, CD4+ T cells and HTLV-1-infected CD4+ T cells. Furthermore, DMF reduced the production of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) released from these proliferating cells. A reduction in PVL was also observed in a subset of ex vivo PBMC cultures derived from individuals with HAM/TSP exhibiting high viral proliferative activity. These results suggest that DMF suppresses pathogenic immune activation in HAM/TSP and may therefore represent a promising therapeutic candidate for this disabling neuroinflammatory disorder.
Schierbaum L, Gonzalez Saez-Diez E, Tam A
… +17 more, Rong J, Zubair U, Bernardi K, Yang K, Quiroz V, Zaman Z, Saffari A, Carty S, Agianda HAP, Alexandrescu S, Eichler F, Sveden A, Chopra M, Calame DG, Danzi MC, Zuchner S, Ebrahimi-Fakhari D
Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants...Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM, and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.
It is not known what the relapse risk is after immunomodulatory treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Evidence suggests "at least" 3 months of oral corticos...It is not known what the relapse risk is after immunomodulatory treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Evidence suggests "at least" 3 months of oral corticosteroids reduces the relapse risk after a single attack and that it may be possible to stop maintenance treatment in relapsing stable disease but the optimal duration of treatment is unknown. We therefore aimed to investigate relapse outcomes following maintenance treatment discontinuation. We conducted a cohort study of MOGAD patients seen in the Oxford Neuromyelitis Optica Highly Specialised Service between January 2010 and May 2025. Patients with MOGAD, at least 12 months follow-up, and who commenced and then discontinued maintenance treatment were included. Associations of factors including treatment duration prior to discontinuation, disease course at discontinuation (after a single attack/monophasic or relapsing course) and MOG IgG1 status on live cell-based assay were investigated. Primary outcome was time-to-relapse following treatment discontinuation. Cox regression was used. We included 190 MOGAD patients with 236 discontinued treatment intervals. 150 (63.6%) discontinuations were after a single attack and before a first relapse when disease course was monophasic, and 86 (36.4%) discontinuations occurred in patients who had a relapsing disease course. Most patients used corticosteroids alone (84.7% IT intervals), and non-steroid IT were used in 15.2% of IT intervals either alone or in combination with steroids. Post-discontinuation relapse occurred after 92 (39.0%) discontinuations at a median time of 5.4 (interquartile range 1.4-20.1) months after treatment cessation. Those who relapsed were more likely to have a relapsing course at time of discontinuation (50% vs 27.8%, P=0.001) and a positive/low positive pre-discontinuation MOG IgG1 result (89.8% vs 71.5%, P=0.005). In multivariable analysis, a relapsing course at time of discontinuation was associated with an elevated relapse risk (hazard ratio 1.95, 95% confidence interval 1.25-3.06, P=0.003). Overall, prolonged treatment durations prior to discontinuation beyond 3 months significantly reduced relapse risk. Optimal treatment durations were estimated as at least 10-18 months for patients treated after their onset attack and 20-30 months for relapsing patients, following which treatment discontinuation could be considered in patients who were relapse-free on treatment. Identifying the relapse risk when discontinuing maintenance immunomodulatory treatment in MOGAD should aid management decisions in patients presenting with their first attack and also in those on longer-term treatment for relapsing disease. Our findings, from a cohort predominantly treated with steroids, provide evidence to inform joint decision-making for stable patients who are considering treatment cessation.
Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in...Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We have previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures in mice, whereas the loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and their relationship to the seizure phenotype, Arx conditional mutant mouse lines were interrogated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that the abrogation of ARX results in cIN density and distribution defects as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence (CGE) to medial ganglionic eminence (MGE) identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation (ChIP)-seq revealed ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation, guidance cues and receptors, as well as other transcription factors. Interrogation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates cIN number and distribution in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX and diagnosed with developmental epileptic encephalopathy. Together our data provide novel insights into how ARX and its target genes regulate cIN development and migration and the pathogenic mechanisms of a spectrum of neurodevelopmental disorders linked to loss of ARX.
Ramdas S, Dong YY, Munot P
… +15 more, Natera de Benito D, Nascimento Osorio A, Maggi L, Bönnemann CG, McAnally M, Schara-Schmidt U, Della Marina A, Kostera-Pruszczyk A, Milone M, Evoli A, Jungbluth H, Lochmüller H, Beeson D, Reddel S, Palace J