European Journal of Neurology

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA1, SMA2, and SMA3. We performed a longitudinal measurement of the main dopamine-related catabolites - 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) - in cerebrospinal fluid (CSF) samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in CSF DOPAC and HVA levels across SMA types or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy and tracheostomy, and were associated with reduced improvement on the CHOP-INTEND scale. These findings suggest that reduced central dopaminergic turnover reflects disease progression in SMA1 and is associated with more severe clinical impairment and limited functional recovery.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.

Nusinersen was the first disease modifying treatment approved for 5q spinal muscular atrophy (SMA). Long-term results of broad populations, particularly for adolescents and adults, remain limited. We conducted a population-based, ambispective observational study of all SMA patients living in the Valencian Community (Spain) between September 2017 and December 2022 and follow-up until December 2025. Demographic, clinical and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. The risk for nusinersen discontinuation was assessed with a Bayesian model, and SMA-FCR trajectories with mixed linear regression. Of 72 patients included, 18 were <12 years old (all treated with nusinersen) and 54 were [&ge;]12 years (28 treated; 26 untreated) at the baseline visit. After a median of 7 years, all patients <12 years were classified as responders versus 68% of patients [&ge;]12 years. Discontinuation rates were 11% in children compared to75% in the older cohort. In patients [&ge;]12 years, reasons for discontinuation included: treatment burden (71%), and loss(53%) or lack of benefit (43 %). Lower baseline SMA-FCR (expEstimate= 0.84 [0.718,0.93], prob:1) and older age (expEstimate=1.028 [1.011,1.055], prob:1) independently predicted higher discontinuation risk. Sustained nusinersen treatment was independently associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration over time. In this long-term population-based study, nusinersen use and persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy. However, a proportion of adolescents and adults (those younger and with higher baseline function) experienced sustained benefit.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

BackgroundChitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases. MethodsTF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp-duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR. ResultsNo group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls (p = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1-values compared to females (p = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls. ConclusionsChitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non-invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementary by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.

Background and objectivesSTXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. MethodsIn this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. ResultsEighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). DiscussionQuantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

INTRODUCTIONCore cognitive deficits in iNPH include slowed information processing, psychomotor slowing and executive dysfunction. However, the cognitive benefits of iNPH treatment with shunt surgery are not well understood. This review synthesised evidence on cognitive assessment methods and outcomes following shunt surgery in iNPH. METHODSPubMed, Scopus, PsycINFO and Web of Science were searched for peer-reviewed studies including adults with iNPH who underwent shunt surgery and had within-subject cognitive evaluations pre- and post-operatively. Key data were extracted and study quality was assessed. Random-effects meta-analyses were performed on pooled baseline and post-shunt difference scores for frequently reported cognitive tests with comparable data. RESULTSOf 1,876 records, 195 met the inclusion criteria, comprising 11,445 patients. Cognitive evaluation methods ranged from subjective reports and NPH grading scales to brief screening tools and comprehensive test batteries. Over 193 distinct tests were reported and 54.4% of studies did not formally assess any core iNPH cognitive deficits. Post-shunt improvement rates, follow-up times and criteria for defining improvement varied widely. Eighty-five studies contributed data to meta-analyses of ten outcomes. Pooled estimates indicated post-shunt cognitive improvement, with Trail Making Test-A, Grooved Pegboard-Dominant and Trail Making Test-B showing changes exceeding thresholds for clinically significant improvement. CONCLUSIONSCognitive assessment in iNPH is highly heterogeneous and frequently omits core domains, limiting detection of treatment effects. When domain-relevant cognitive measures are used, shunt surgery is associated with statistically and clinically significant cognitive improvement. These findings highlight the need for standardised iNPH-specific cognitive evaluation tools with validated criteria for detecting clinically meaningful change and have direct implications for clinical assessment, interpretation of shunt response and the selection of cognitive endpoints in future interventional studies. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSCognitive outcomes after shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) have been inconsistently reported, with cognitive improvement reported less reliably than gait outcomes, in the context of highly variable assessment practices across centres. What this study addsThis systematic review of 195 studies (11,445 patients) shows substantial heterogeneity in iNPH cognitive assessment and demonstrates that when tests sensitive to frontal-subcortical dysfunction are used, shunt surgery is associated with statistically and clinically meaningful cognitive improvement. Widely used dementia screening tools, including the MMSE and MoCA, show changes largely within expected practice-effect ranges and do not adequately capture core iNPH cognitive deficits. How this study might affect research, practice or policyThese findings demonstrate the need to standardise cognitive assessment in iNPH using appropriate iNPH-specific tools with validated metrics for determining clinically meaningful improvement. This will enable robust trial endpoints and accurate evaluation of cognitive benefits of shunting in routine clinical practice.

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim light conditions at six predefined time points around habitual sleep onset (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-2025). Standardized demographic and clinical data were collected. ResultsA total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2{+/-}7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardsons syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported [&le;]25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. ConclusionThis largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0-97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

BackgroundPeri-synaptic astrocyte processes (PAPs) play a fundamental role in synapse formation and function. Central afferent synapse loss and astrocyte dysfunction greatly impede sensory-motor circuitry in spinal muscular atrophy (SMA) disease progression, however mechanisms underpinning tripartite synapse dysfunction remains to be fully elucidated. The aims of this study were to further define PAP and motor neuron synaptic defects in human SMA disease pathology and implement a therapeutic intervention strategy to improve motor neuron function. MethodsWe derived astrocyte monocultures and motor neuron astrocyte co-cultures from healthy and SMA patient induced pluripotent stem cell (iPSC) lines to assess intrinsic astrocyte filopodia defects and phenotypes occurring at the synapse-PAP interface, respectively, using cell surface capture mass spectrometry proteomics, confocal and super resolution microscopy, synaptogliosome isolation, and electrophysiology. ResultsSMA astrocytes demonstrated intrinsic filopodia actin defects featuring low abundance of actin-associated cell surface N-glycoproteins, and decreased filopodia density and CDC42-GTP levels after actin remodeling stimulation. This phenotype is likely driven by the significant reduction of CD44 and phosphorylated ezrin, radixin and moesin ERM proteins (pERM) within SMA astrocyte filopodia. The dual combination of SMN1 gene therapy and forskolin treatment, an adenylyl cyclase activator leading to increased cyclic adenosine monophosphate (cAMP) levels and actin signaling pathway stimulation, led to extensive branching and increased filopodia density of SMA astrocytes during actin remodeling. SMA patient-derived motor neuron and astrocyte co-cultures, particularly samples derived from male patient iPSC lines, demonstrated a significant decrease in synapse number, actin-associated pre-synaptic neurotransmitter release protein, synapsin I (SYN1), and PAP-associated expression of pERM and glutamate transporter, EAAT1. Our astrocyte-targeted SMN1 augmentation and forskolin treatment paradigm restored SYN1 protein levels within the SMA synaptogliosome, resulting in significant increases in motor neuron synapse formation and function, but did not fully restore PAP-associated proteins levels at the synapse. ConclusionsSMA astrocytes demonstrate intrinsic actin-associated defects within filopodia, which correlates with decreased pERM levels at tripartite motor neuron synapses. We also define a SMN- and cAMP-targeted treatment paradigm that significantly increases pre-synaptic neurotransmitter release protein levels to improved SMA motor neuron synapse formation and function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/714618v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1257ab8org.highwire.dtl.DTLVardef@19c0010org.highwire.dtl.DTLVardef@c84552org.highwire.dtl.DTLVardef@3f1e62_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background: Clinical evidence on the contemporary management and functional outcomes of patients with Wernicke encephalopathy remains limited. This study aimed to clarify the nationwide patterns of thiamine administration and functional outcomes at discharge. Methods: Using the Japanese nationwide inpatient Diagnosis Procedure Combination database, we identified patients hospitalized with Wernicke encephalopathy between July 2010 and March 2024. Initial intravenous thiamine doses were categorized as low ([&le;]300 mg/day), medium (301-900 mg/day), or high (>900 mg/day). Outcomes included in-hospital mortality and functional status (Barthel Index) at discharge. Results: We identified 7856 patients with Wernicke encephalopathy. Over the 13-year study period, the proportion of patients receiving initial high-dose thiamine increased markedly from 5.4% to 49.0%, while the frequency of low-dose therapy decreased from 83.0% to 37.9%. Despite prompt intervention [median time to initial administration: 0 days (interquartile range, 0 to 0 days)], 56.1% of patients were discharged with impaired activities of daily living (Barthel Index <90), and the in-hospital mortality rate was 3.8%. Conclusions: High-dose thiamine treatment is increasingly implemented for Wernicke encephalopathy in Japan. Although in-hospital mortality was relatively low, the high prevalence of functional impairment at discharge, despite early treatment initiation, indicates substantial burden of Wernicke encephalopathy. Given the limited clinical evidence, further research investigating the optimal thiamine dose and develop effective primary prevention strategies for Wernicke encephalopathy is needed.

IRF2BPL-related disorder is a neurodevelopmental disorder caused by heterozygous variants in the IRF2BPL (Interferon Regulatory Factor 2 Binding Protein-Like) gene. The few reports available in the literature suggest that common symptoms include developmental delay, intellectual disability and developmental regression. There are no reports of genotype-phenotype correlations. We developed a retrospective and prospective patient-reported survey to assess diagnostic information, presenting symptoms and longitudinal follow-up of neurological symptoms for up to two years. Clinical information was available for all 32 participants and was highly variable in regards to age at symptom onset, severity of neurologic manifestations, and progressivity. For 27 of the 32 participants, diagnostic genetic test results were available. Genetic mutation analysis revealed 22 individuals with truncating variants and five participants with unique missense variants in IRF2BPL. The study data support the hypothesis that IRF2BPL missense variants are associated with a less severe disease presentation and progression than participants with truncating variants. The purpose of this study is to further define IRF2BPL-related disorder and provide more clinical and molecular insight into this ultra-rare disease. Highlights- Patient-reported clinical history at diagnosis and up to two years of follow up - The clinical spectrum is increasingly heterogeneous - We report 32 patients, 27 with noted IRF2BPL variants, 14 being novel to literature. - Data supports the notion that IRF2BPL missense variants may be associated with less severe disease than truncations (nonsense/frameshifts).

Protocadherin-12 (PCDH12), a cell-adhesion protein belonging to the non-clustered protocadherin family, plays a crucial role in the establishment and regulation of neuronal connections and communication. Bi-allelic loss-of-function (LoF) variants in the PCDH12 gene have been associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic junction dysplasia syndrome, cerebral palsy, and cerebellar ataxia, often accompanied by ocular abnormalities. However, genotypes exhibit variable expressivity. Affected individuals sharing the same PCDH12 variant presenting differing phenotypic severities have posed major challenges towards identification of the underlying pathogenic mechanisms. Here, we report three affected individuals from two families, each harbouring non-truncating pathogenic missense variants in PCDH12. The patients are compound heterozygous, with each individual carrying one extracellular [c.1742T>G (p.Val581Gly) and c.1861_2del/insCA (p.Ile621His)] and one intracellular variant [c.3370C>T (p.Arg1124Cys) and c.3445G>A (p.Asp1149Asn] on each allele. The children present with a range of phenotypes similar to those associated with LoF variants. One child exhibited microcephaly and seizures, while the two siblings displayed developmental delays and severe behavioral disorders. All three children experienced some degree of visual impairment. The missense variants provided new insights into the neurodevelopmental consequences of compromised PCDH12 function by distinguishing the specific consequences associated with dysfunction in the extracellular versus intracellular domains of PCDH12. All identified missense variants are predicted to be deleterious and destabilizing. The expression of PCDH12 in HEK293T and HeLa cells demonstrated that PCDH12 is expressed effectively, regardless of the presence of missense variants. However, the extracellular variants p.Val581Gly and p.Ile621His compromised the stability of PCDH12s homophilic adhesion. Additionally, we found evidence of an interaction between PCDH12 and the extracellular domain of the epilepsy-associated PCDH19 protein. PCDH12 extracellular missense variants also affect PCDH19 stability. Our study provides evidence that PCDH12 mediates both homophilic and heterophilic interactions. Our findings also highlight the importance of stable PCDH12-mediated adhesion, emphasizing the need to further study the functional consequences of PCDH12 missense variants on brain and visual system development.

Waldenstrom macroglobulinemia (WM) is a rare indolent neoplasm characterized by presence of more than 10% lymphoid cells in BM that exhibit plasmacytoid or plasma cell differentiation that secretes an IgM monoclonal protein. This is a retrospective analysis of 89 patients of WM that describes the clinical and laboratory characteristics, treatment patterns and outcome of patients of WM. The median age of the entire cophort was 66 years with male predominance (67.4%). Most common presentations were symptoms pertaining to anemia (77.5%) and constitutional symptoms (33.7%). Median bone marrow lymphoplasmacytic cells were 41%. Positivity for MYD88 and CXCR4 mutations were seen in 81.8% and 2.4% cases. BR was the most common regimen used (52.8%). Overall response rates were seen at 87.8%. Median overall survival, progression free survival and time to next treatment is 8.49 years, 2.15 years and 3.88 years. BR regimen was associated with highest event free survival.

Twenty percent of familial amyotrophic lateral sclerosis (fALS) cases are linked to mutations in the Superoxide Dismutase 1 (SOD1) gene and accumulation of misfolded SOD1 aggregates. SOD1 misfolding from the broader ALS population without SOD1 mutations is less clear. Here, we report SOD1 seeding activity in antemortem cerebrospinal fluid (CSF) from ALS participants with and without SOD1 mutations during ALS progression. Antemortem CSF from controls, SOD1-ALS, and sporadic ALS (sALS) patients was subjected to SOD1 seed amplification real-time quaking induced conversion (RT-QuIC) assays. SOD1-ALS CSF exhibited shorter lag phase and increased ThioflavinT (ThT) fluorescence amplitude compared to healthy controls and those with spinal muscular atrophy. CSF from sALS participants, who had no mutations in SOD1 or nine other ALS risk genes, also displayed SOD1 seeding activity, indicating wild-type SOD1 is aggregate-prone in the broader ALS population. Longitudinal CSF data indicated that SOD1 seeding activity correlates with ALS progression via the ALS Functional Rating Scale Revised (ALSFRS-R) slope decline and CSF neurofilament light. Our sALS CSF cohort primarily comprised of participants less than 2 years from symptom onset, suggesting that SOD1 seeding activity is an early biomarker that may enable inclusion in clinical trials. With the FDA-approval of tofersen (Qalsody), a SOD1-lowering antisense oligonucleotide, new SOD1 diagnostic, prognostic and pharmacodynamic biomarkers may enable SOD1-targeting strategies that could benefit the broader ALS population.

BackgroundPersons with epilepsy are at increased risk of depression/anxiety. Older antiseizure medications (ASMs) had drug-drug interactions that complicated pharmacotherapy of depression/anxiety; newer ASMs lack this drawback but can have psychiatric side effects. Anxiety/depression are increasingly recognized and treated pharmacologically. We hypothesized that the likelihood of treatment with selective serotonin uptake inhibitors (SSRI) would have increased in adult-onset epilepsy when prescription habits shifted towards newer ASMs. MethodsWe linked national health registers and included 28569 persons with epilepsy incident in 2006-2020 and 68509 age- and sex matched controls. We assessed the risk of starting SSRI treatment compared to age- and sex-matched controls across three incidence periods: 2006-2010, 2011-2015, and 2016-2020. Cox regression was used to estimate adjusted hazard ratios (HRs), and subgroup analyses explored age, sex, and comorbidities. Specialist psychiatric care was also assessed as a measure of more severe depression. Analysis including persons with SSRI-use before the epilepsy diagnosis were used for sensitivity analyses. FindingsPersons with epilepsy had higher risks of starting SSRIs compared to controls; 1986/9561 (20.8%) received SSRI during follow-up after epilepsy in 2006-2010 and 2020/9165 (22.0%) in 2016-2020; adjusted HRs were 1.92 (95%CI:1.79 - 2.06) in 2006-2010, 1.84 (95%CI:1.72-1.97) in 2011-2015, and 1.81 (95%CI:1.69 - 1.94) in 2016-2020. Among individuals aged 18-30 years at their epilepsy diagnosis, the proportion receiving SSRIs remained the same between the first and last calendar periods (18.2%). Because of increased treatment of controls, the adjusted HRs of SSRI-treatment decreased from 2.33, (95% CI:1.96 - 2.78) to 1.63, (95% CI 1.39 to 1.91). The HR of specialist psychiatric care was not significantly different between the time periods. Most comorbidities were consistently associated with increased likelihood of SSRI treatment, whereas intellectual disability decreased the likelihood in some periods. InterpretationWe found no evidence of overall increased SSRI initiation or psychiatric care after the shift to newer ASMs. Person with epilepsy remain more likely to receive SSRI treatment, but probably not to a level matching the higher prevalence of depression. Increased SSRI treatment of younger age adults has not been matched by increased treatment of young adults with epilepsy. This suggests a potentially widening treatment gap and a need for increased recognition of depression in young adults with epilepsy. FundingSwedish Research Council (2023-02816), Swedish state through the ALF-agreement (ALFGBG-1006343), Knut och Ragnvi Jacobsson foundation, Swedish Society for Medical Research (S18-0040), Swedish Society of medicine (SLS-881501), Epilepsifonden, Rune och Ulla Amlovs stiftelse.

OBJECTIVETo assess differences in the severity of Alzheimers disease neuropathological changes in disease epicenters of patients with logopenic variant PPA (lvPPA) with a history of learning differences/developmental dyslexia (LD) versus lvPPA patients without such history (non-LD). BACKGROUNDLearning differences, including developmental dyslexia, are overrepresented in the lvPPA population. It is not known whether a history of developmental differences is associated with a more severe phenotypic expression of Alzheimers disease pathology. DESIGN/METHODSWe quantified the cortical area fraction of phospho-tau immunohistochemistry (IHC) and beta-amyloid IHC in the angular gyrus and superior temporal gyrus of postmortem brains of 15 cases of lvPPA secondary to Alzheimers disease of which 9 non-LD cases (2 males and 7 females), and 6 LD cases (2 males and 4 females). Histological sections were digitally acquired, and foreground IHC-signal was automatically separated and thresholded to quantify the respective tau and beta-amyloid area fractions in each region. RESULTSThere were no differences in the mean age at death between the two groups. Disease duration was longer in the LD group (10.7 {+/-} 1.2 years) than in the non-LD group (8.1 {+/-} 0.8 years), p=0.09. When corrected for sex, age at death and Apo E4 carrier status, the LD group showed higher tau pathology burden in the superior temporal gyrus compared to the non-LD group (0.91% {+/-} 0.37, p=0.03). No differences in tau pathology burden between the groups were observed in the angular gyrus (0.39% {+/-} 0.41, p=0.37). There were no statistically significant differences in the area fraction of beta-amyloid between the two groups of patients in both the angular gyrus and the superior temporal gyrus. CONCLUSIONSOur data suggest that patients with lvPPA secondary to Alzheimers disease and a history of developmental differences have higher tau-pathology burden in the superior temporal gyrus compared to lvPPA-AD patients without such history.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.