small molecules

2026-09-14 | Hyperactive KIF5A in Neurodegeneration.

The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin-1 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.

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2026-09-08 | Efficacy and safety of memantine in adults with amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.

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2026-09-03 | When the Electromyography (EMG) and the Patient Disagree: Unraveling a Motor Neuron Disease Mimic With Small-Fiber Dysfunction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor neuron dysfunction.Electromyography (EMG) is central to its evaluation, but neurogenic abnormalities and fasciculations are not specific to ALS and must be interpreted within the clinical phenotype and disease trajectory.This study reports a 52-year-old man with an approximately eight-year history of intermittent muscle twitching, bilateral upper-limb tremor, muscular tightness and warmth, and asymmetric cutaneous hypersensitivity.An initial electrodiagnostic evaluation raised concern for diffuse motor neuron disease, despite preserved strength, normal gait, absence of muscle wasting, and lack of clear upper motor neuron signs.Extensive evaluation for inflammatory, autoimmune, metabolic, toxic, infectious, paraneoplastic, neuromuscular junction, and peripheral nerve hyperexcitability disorders was unrevealing.Serum creatine kinase was mildly and variably elevated, while aldolase and a comprehensive myositis panel were normal.Brain magnetic resonance imaging (MRI) demonstrated no supportive features of ALS.Sudomotor testing showed reduced electrochemical skin conductance (ESC) in the hands, supporting smallfiber/autonomic dysfunction in the context of prominent sensory symptoms.Repeat EMG, performed after interval follow-up with broad muscle sampling, demonstrated focal neurogenic abnormalities involving bilateral ulnar distributions and left L5-S1 radiculopathy but found no electrophysiological evidence of a neurodegenerative disorder.The patient was treated symptomatically with gabapentin and vitamin E and reported approximately 80% improvement after six weeks.This case highlights the importance of clinicophysiological correlation, disease trajectory, sensory phenomenology, and repeat electrophysiology when an initial EMG suggests motor neuron disease but the longitudinal clinical picture is discordant.It also illustrates how small-fiber dysfunction and focal neurogenic abnormalities may coexist and mimic a progressive motor neuron syndrome.

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2026-08-27 | ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?

Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.

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2026-08-27 | High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons, driven by converging mechanisms including glutamatergic excitotoxicity, mitochondrial dysfunction, oxidative stress, calcium dyshomeostasis, impaired RNA metabolism, and neuroinflammation. In the absence of effective disease-modifying therapies, high-dose methylcobalamin has emerged as a candidate intervention based on its pleiotropic neurobiological effects. A structured literature search was conducted in PubMed/MEDLINE and ScienceDirect to identify peer-reviewed studies published between January 2017 and December 2025 addressing the mechanistic, preclinical, and clinical effects of methylcobalamin in ALS. Preclinical evidence suggests that methylcobalamin modulates homocysteine metabolism, supports S-adenosylmethionine-dependent methylation pathways, preserves mitochondrial integrity, attenuates oxidative stress, and promotes axonal regeneration. Experimental and translational findings further indicate that its therapeutic effects may be strongly dose dependent, particularly under ultra-high-dose regimens capable of overcoming limitations in central nervous system delivery. Clinical trials evaluating ultra-high-dose methylcobalamin demonstrate a potential attenuation of functional decline in patients treated during early disease stages, although effects on survival and respiratory outcomes remain inconsistent. This narrative review integrates molecular mechanisms, experimental evidence, biomarker research, and clinical trial data to examine the translational relevance, stage dependency, and therapeutic implications of high-dose methylcobalamin in ALS.

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proteins

2026-09-24 | Natural history of 441 cases of bulbar onset motor neuron disease (MND) in China: a single-center retrospective study.

To describe the natural history and identify prognostic factors of bulbar onset motor neuron disease (MND). Bulbar onset MND patients with regular follow-up between January 2014 and December 2023 were included. Clinical features at initial evaluation, duration from onset to next region and time to death or tracheotomy were retrospectively collected. Survival analysis was performed by Kaplan-Meier method and Cox regression model. A total of 441 patients were included. Disease progression occurred most frequently from bulbar region to upper limbs (77.1%), followed by lower limbs (16.4%) and respiratory muscles (6.5%), with a median time interval of 6.0 (1.0, 48.0) months. 215 patients died or underwent tracheotomy. The median duration to death or tracheotomy was 43.0 (95% CI 39.1-46.9) months, the 1-year, 2-year, 3-year, 4-year and 5-year survival rates (95%CI) were 96.6% (94.9-98.3), 79.9% (76.0-83.9%), 59.1% (54.0-64.7), 42.2% (36.6-48.6) and 29.9% (24.3-36.7), respectively. Younger onset age, slower ALSFRS-R decreasing rate, longer diagnostic delay, longer duration to next region and pure upper motor neuron involvement at initial evaluation were associated with favorable prognosis. Upper limbs involvement secondly to bulbar region was independently associated with better outcomes compared with respiratory muscles spreading. The natural history of bulbar-onset ALS exhibits substantial heterogeneity. Patients with only upper motor neuron involvement in bulbar region at onset and subsequent upper limbs involvement as the second region tend to have a favorable prognosis.

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2026-09-24 | Protecting Against Cytoplasmic Protein Aggregates With Cytoplasmic PML Variants.

Cytoplasmic protein aggregation is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and certain forms of motor neuron disease. Recent evidence indicates that promyelocytic leukemia protein (PML) and engineered PML-derived variants can act as versatile aggregate-remodeling factors. In particular, cytoplasmically redirected PML variants recognize pathological cytoplasmic inclusions and promote their clearance. Here, we describe a protocol to generate and validate two engineered cytoplasmic PML variants: full-length mPML, which is redirected to the cytoplasm by disruption of its nuclear localization sequence, and the truncated mPMLΔRBC variant, which lacks the RING, B-box, and coiled-coil domain but retains aggregate-reducing activity. The protocol integrates fluorescence-based imaging, bimolecular fluorescence complementation, detergent-soluble/insoluble fractionation, and validation in primary rat cortical neurons. This workflow provides a practical platform for assessing cytoplasmic aggregate burden and for comparing the aggregate-remodeling activities of PML-derived constructs. It can also be adapted to other disease-associated aggregation-prone proteins, including TDP-43, SOD1, FUS, tau, polyGA, and polyQ-expanded proteins. Key features • Describes the generation and validation of two complementary cytoplasmic PML variants: full-length mPML and truncated mPMLΔRBC. • Provides fluorescence-based and BiFC-based assays to visualize pathological cytoplasmic protein assemblies. • Includes detergent-soluble/insoluble fractionation for biochemical assessment of aggregate burden. • Establishes a primary rat cortical neuron workflow to evaluate the effect of mPML on TDP-43-CTF aggregates. • Can be adapted to other aggregation-prone proteins and additional PML-derived aggregate-remodeling candidates.

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2026-08-19 | Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.

Amyotrophic lateral sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene is recognized for phenotypic variability, yet cerebellar ataxia as a presenting feature has been reported only in isolated cases. We describe four unrelated patients: three men and one woman, aged 35 to 49 years at symptom onset, who carried the SOD1 D91A (p.Asp91Ala) mutation. Two patients were heterozygous and two homozygous for the D91A variant. Clinical, neuroimaging, electrophysiological and genetic data were reviewed. All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS. Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years. Cerebellar signs included gait and limb ataxia, dysmetria, intention tremor, and oculomotor abnormalities; neuroimaging revealed mild cerebellar atrophy only in one case, and electrophysiological evidence of lower motor neuron involvement was often limited at initial assessment. To our knowledge, this is the largest reported case series of patients homogeneous for a single SOD1 mutation and a shared cerebellar ataxia-onset ALS phenotype. The findings expand the clinical spectrum of SOD1-associated ALS and underscore the importance of SOD1 genetic testing in patients with progressive adult-onset ataxia of undetermined origin, particularly given the emerging availability of SOD1-targeted therapies.

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2026-07-07 | PathMap Experiment #000007 - Tags: #Axonal Transport #Motor Neuron Disease #C9orf72 Repeat Expansion #Dipeptide Repeats #VAPB protein, human

Interactive Data Viewer: Read, View, and Print from Day 1 Use our fully interactive viewer to view, read, and print this research data right from Day 1: https://pathmap.org/viewer.php?id=7 Artificial General Intelligence LLC Claim Evaluated: Simply put, we still don't know why neurons are dying in ALS, and why motor neurons die while other types of neurons don't. Even for genetic forms c9orf72 familial ALS, why is it that the mutation is in every cell but the motor neurons are dying ie have increased susceptibility? This dataset contains the raw JSON execution trace, verified verbatim quotes, and MeSH-aligned logic gates generated by PathMap Studio's Veridical Enforcement engine. 🧪 Extracted Custom Datapoints 📊 Suggested Experiments Perform single-nucleus RNA sequencing on resilient (OMN) vs. vulnerable (SMN) motor neurons in C9orf72 carriers to identify differential gene networks associated with VAPB or miRNA stability. Test if overexpression of VAPB in C9orf72-iPSC-derived spinal motor neurons prevents the accumulation of DPRs and restores axonal transport. 📊 Suggested Studies Longitudinal imaging study of ALS patients tracking the transition of CST MRI markers alongside neurofilament light chain to validate the 'synaptic compartmentalization failure' model. Comprehensive screening for septin multimer autoantibodies in larger ALS cohorts to determine if autoimmune mechanisms contribute to the 'focal onset' observed in systemic genetic carriers. 📊 Swansons Literature Based Discovery Candidates Cystatin C (Bunina bodies) sequestration in ALS motor neurons may be a direct consequence of localized HDAC6-mediated tubulin deacetylation and microtubule destabilization. HDAC6 dysregulation disrupts axonal transport by deacetylating alpha-tubulin, causing microtubule destabilization (ID: 42261159). Bunina bodies contain cystatin C, which normally provides neuroprotective protease inhibition; their formation suggests a breakdown in autophagy (ID: 42373582). HDAC6/Microtubule-dependent autophagic flux. Since HDAC6 is required for the formation of aggresomes and stress granules for autophagic clearance, the destabilization of microtubules by HDAC6 dysfunction likely impedes the delivery of cystatin C to degradation pathways, leading to its accumulation in Bunina bodies. 📊 Contradictions Between Evidences There is a slight tension between studies characterizing HDAC6 as purely 'degenerative' (due to microtubule destabilization) and 'neuroprotective' (due to its role in autophagic clearance of toxic aggregates). 📊 Repurposed Solutions The use of IRE1 activators (ID: 42341041) to improve translational quality control of TDP-43 and carboplatin (ID: 42134762) to inhibit NF-κB in astrocytes are promising repurposed therapeutic strategies to restore neuronal homeostasis. 🔖 Tags Attractor Table Extracted Keywords & Entities Axonal Transport, _gates_from_axonal_transport, Motor Neuron Disease, _gates_to_motor_neuron_disease, C9orf72 Repeat Expansion, _gates_from_c9orf72_repeat_expansion, Dipeptide Repeats, _gates_to_dipeptide_repeats, _gates_from_dipeptide_repeats, VAPB protein, human, _gates_to_vapb_protein,_human, _gates_from_vapb_protein,_human, Autophagy, _gates_to_autophagy, Autophagy-Related Proteins, _gates_from_autophagy-related_proteins, C9orf72 Expansion, _gates_from_c9orf72_expansion, _gates_from_autophagy, _gates_to_axonal_transport 🚀 Run Your Own Analysis PathMap is a patent-pending universal AI workbench designed to eliminate LLM hallucinations in medical research. Generate your own autonomous discovery reports at PathMap.org.

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2026-06-30 | Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.

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gene therapies

2026-09-19 | TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.

Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.

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2026-09-15 | Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.

In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.

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2026-09-02 | The survival motor neuron protein: structure, functions, stability, and therapeutic targeting.

The survival motor neuron (SMN) protein is an essential and highly versatile assembly factor that coordinates RNA metabolism and ribonucleoprotein (RNP) complex formation across multiple cellular compartments. Although SMN is required for the survival of virtually all cell types, its deficiency disproportionately affects α-motor neurons, causing their selective degeneration and giving rise to spinal muscular atrophy (SMA). Once viewed primarily as a motor neuron disease, SMA is now understood to be a multi-systemic disorder in which cell-intrinsic dysfunction extends to skeletal muscle, inflammatory glial cells, and metabolic organs. This review examines the regulatory mechanisms that control SMN protein stability, collectively termed proteostasis, with a focus on how post-translational modifications coordinate with the ubiquitin-proteasome system and the autophagy-lysosomal pathway to govern protein turnover and clearance. We also address the emerging concept of gene dosage sensitivity, including the underappreciated paradox that therapeutic SMN overexpression can be as harmful as deficiency, producing distinct toxicities in both neuromuscular and peripheral tissues. Finally, we highlight the need for next-generation combination therapies that integrate genetic modifiers, targeted degradation strategies, and post-translational regulators to maintain SMN levels within the narrow physiological range required for safety and efficacy.

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2026-06-19 | Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.

A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, fewer motor neurons, glial activation, sparse phosphorylated TDP-43 pathology, and increased cryptic TDP-43 splicing. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.

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2026-06-13 | Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.

Tofersen is a gene-targeted therapy for individuals with superoxide dismutase 1 (SOD1) (+) amyotrophic lateral sclerosis (ALS). Prior to U.S. Food and Drug Administration (FDA) approval, tofersen was made available through expanded access protocol. This study describes the clinical and operational experience of administering tofersen through expanded access protocols at a single academic medical center in the U.S. Individuals with symptomatic SOD1(+) ALS (≥ 18 years), who were ineligible for traditional ALS clinical trials, received tofersen via bedside lumbar punctures at Massachusetts General Hospital. Treatment was provided through single-patient and intermediate-sized expanded access protocols prior to FDA approval. Demographic and clinical characteristics, referral-to-treatment timelines, safety outcomes, and operational costs were collected. Eleven individuals with SOD1(+) ALS received monthly intrathecal tofersen over a two-year period (July 2021 to July 2023). Most participants were female, and 81.8% had leg-onset ALS. The mean (SD) referral-to-first dose duration was 36 (22.4) days. A total of 120 doses were administered over a two-year period. Tofersen was safe and well tolerated, with no treatment-related serious adverse events. Operational costs totaled $336,620, supported by philanthropy and insurance. The company provided the drug for free. This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies.

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oligonucleotides

2026-08-19 | SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.

Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce. Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region. Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy. This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.

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2026-08-15 | Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view.

Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. Although most ALS cases occur sporadically, without a known family history of the disease, genetic factors play a major role in its pathogenesis through monogenic, oligogenic, or polygenic mechanisms. It is estimated that 10-15% of ALS cases occur in a familial setting; however, a specific monogenic cause cannot always be identified. Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. Over the years, differing opinions have existed regarding the role of genetic testing in individuals diagnosed with ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice.

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2026-08-04 | Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).

To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.

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2026-07-29 | Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.

The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.

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2026-06-25 | Clinical and literature insights into the frontotemporal dementia and motor neuron disease spectrum.

Frontotemporal dementia represents a heterogeneous group of neurodegenerative disorders primarily affecting the frontal and temporal lobes. The overlap between FTD and motor neuron disease is increasingly recognized, presenting a complex clinical syndrome characterized by progressive cognitive, behavioral, and motor decline. We describe a 69-year-old patient with a 4-year history of excessive ambulation. Over the last year, behavioral changes including disorganized conduct, irritability, spitting, and cold water foot immersion developed. The patient experienced compelling auditory hallucinations driving her to walk continuously for up to 10 h per day. Four months prior to admission, gait impairment with frequent falls, along with hyperorality developed. Neurological examination revealed asymmetric mild weakness, marked muscle atrophy of facial and limb muscles, hyperreflexia, and impaired postural control. Brain MRI showed diffuse cerebral atrophy; electrophysiological studies indicated probable motor neuron disease; and TRODAT SPECT demonstrated impaired presynaptic dopaminergic function bilaterally, consistent with parkinsonism. Final diagnosis was frontotemporal dementia with probable motor neuron disease. A review of the literature highlights the clinical, radiological, and molecular features of FTD-MND overlap, emphasizing the role of TDP-43 pathology, C9orf72 mutations, and the need for multidisciplinary management. Current strategies are symptomatic, though novel therapies such as antisense oligonucleotides and biomarkers like neurofilament light chain (NfL) show promise. This case highlights the diagnostic complexity of FTD with MND overlap syndrome, emphasizing the need for comprehensive clinical, neuroimaging, and electrophysiological evaluation. Multimodal treatment approaches focusing on behavioral symptoms and functional support are essential for optimizing patient outcomes.

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2026-08-06 | The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 106 and <10 × 106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.

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2026-06-08 | Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease.

Severe neuropathies with predominant involvement of motor fibers can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibers. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays, and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n=86, Guillain-Barré syndrome n=37, multifocal motor neuropathy n=18, diabetic neuropathy n=30, other inflammatory neuropathies n=10), amyotrophic lateral sclerosis (n=50), multiple sclerosis (n=50), and healthy controls (n=50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over four years. Among 3,543 total samples tested, three patients (two male, one female) - diagnosed with the LMND variant of amyotrophic lateral sclerosis (ages 65, 72, and 79, respectively) - showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt-Lanterman incisures (SLIs), paranodes, and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs ("incisuropathy"). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over three years. The other two patients died of rapid disease progression: One of them received no immunotherapy while the other had ineffective treatments with single administrations of IVIG and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome, and responses to immunotherapy in larger cohorts.

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2026-05-11 | Efficacy and safety of pharmacological and biological therapies for amyotrophic lateral sclerosis: a network meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder for which disease-modifying treatment options remain limited. This study aimed to systematically assess the efficacy and safety of pharmacological and biological therapies for ALS via a network meta-analysis (NMA). PubMed, EMBASE, Cochrane, and Web of Science were searched until February 25, 2025. Randomized controlled trials (RCTs) evaluating any pharmacological or biological intervention in ALS were eligible. Risk of bias was assessed using the Cochrane RoB 2 tool. A Bayesian NMA was performed in R (gemtc package). Effect estimates were expressed as mean differences (MDs) or risk ratios (RRs) with 95% credible intervals (CrIs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA). Publication bias was explored with funnel plots (Stata 18.0). Subgroup analyses were conducted for drug classes demonstrating significant efficacy and including at least three RCTs. 109 trials involving 16,353 participants were included. The primary outcome was the ALS Functional Rating Scale-Revised (ALSFRS-R); secondary outcomes included forced vital capacity (FVC), mortality, and serious adverse events (SAEs). Compared with placebo, the combination of cell therapy and neuroprotective agents produced the greatest attenuation of ALSFRS-R decline (MD: 3.65, 95% CrI: 1.27-6.05) and was associated with the lowest SAE risk. Receptor agonists ranked highest for preservation of FVC, whereas alkaloids ranked first for mortality reduction; however, no intervention demonstrated a statistically significant survival benefit versus placebo. Within-class subgroup analyses further identified several specific agents, such as masitinib, talampanel, and EH301, as demonstrating relatively consistent efficacy, although substantial heterogeneity remained among enzyme inhibitors. Cell therapy combined with neuroprotective agents may slow functional decline in ALS. Receptor agonists may help preserve respiratory function. Survival benefits remain inconclusive, underscoring the continued importance of comprehensive supportive care. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000672, identifier CRD420251000672.

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2026-04-29 | Amyotrophic lateral sclerosis and chronic inflammatory demyelinating polyneuropathy coexistence in a patient with a C9orf72 variant: case report.

The C9orf72 variation has been strongly implicated in the inheritance of familial ALS, frontotemporal dementia (FTD), and combined ALS-FTD cases. Increasing evidence implicates immune changes and inflammation in some ALS patients. Several studies demonstrated that ALS coexists with CIDP or polyneuropathy. Mouse models of C9orf72 loss-of-function mutations exhibit fatal immune dysregulation. A 62-year-old Caucasian man developed right foot drop, and he underwent fibular nerve release without significant improvement. At the same time, he developed progressive weakness and numbness in his bilateral hands. MRI revealed cervical canal stenosis and neuroforaminal narrowing that prompted neurosurgical decompression without clinical improvement. Subsequently, he developed left foot drop. At the clinic presentation, he exhibited dysarthria, tongue fasciculations, weakness in all extremities, muscle atrophy, widespread fasciculations, and upper extremity hyperreflexia, meeting clinical criteria for ALS. Genetic testing identified a pathogenic variant in the C9orf72 gene, confirming a C9orf72 variant, commonly linked to familial ALS. Brain MRI demonstrated the motor band sign. Although EMG/NCS findings were consistent with lower motor neuron disease, he also had signs of demyelinating polyneuropathy based on conduction parameters. Neuromuscular ultrasound showed significant multifocal nerve enlargement typical of immune-mediated neuropathy. CSF studies revealed albuminocytologic dissociation (protein: 112 mg/dL, with normal cell count) and high albumin quotient and index. He fulfilled the 2021 EAN/PNS criteria for possible typical CIDP. He was treated with intravenous immunoglobulin in addition to riluzole with temporary improvement. This is the first case of the co-existence of CIDP and ALS in the setting of a pathogenic C9orf72 variant.

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2026-03-14 | Motor Neuron Disease with Guillain-Barré Syndrome? Motor Band Sign with Anti-GQ1b Antibodies.

A 79-year-old former marathoner, with memory impairment since age 78, developed increasing stumbling and progressively worsening waddling gait. Three months after gait disturbance onset, she noted mild dysphagia. With declining walking distance and endurance, she presented to our hospital six months after onset, exhibiting frontal signs, Parkinsonism with marked trunk rigidity, and hyperreflexia of the jaw and limbs. L-dopa challenge tests showed no improvement. At seven months post-onset, she had difficulty rising. By nine months, she relied on a walker, and speech disturbance appeared. At 10-11 months, both dysarthria and dysphagia rapidly worsened, she became bed-ridden, and upper limb weakness developed (though she could still use chopsticks). Neurological examination at one year revealed severe dysarthria/dysphagia, four extremity fasciculations and muscle weakness (grade 2 in upper limbs, grade 1 in lower limbs), trunk-dominant rigidity, and hyperreflexia in the jaw and limbs. Brain MRI, specifically susceptibility-weighted imaging, revealed motor band signs. Cerebrospinal fluid study revealed albuminocytological dissociation. Needle electromyography revealed acute denervation and chronic reinnervation in the cranial nerve, cervical, and lumbar areas, which was suggestive of motor neuron disease (MND). Serum anti-GQ1b antibodies were detected. Immunotherapy was followed by mild improvement, which might suggest a reversible component, although definitive pathological overlap remains unconfirmed. This case highlights a diagnostic challenge where an acute immune-mediated neuropathy could potentially be superimposed on a chronic neurodegenerative process. Anti-GQ1b antibodies should be interpreted with caution, as they may reflect either a true clinicopathological overlap with Guillain-Barré syndrome or a secondary phenomenon (epiphenomenon) related to the primary neurodegenerative process.

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