Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study

C5 inhibitor; Myasthenia gravis; ZilucoplanInhibidor de C5; Miastenia gravis; ZilucoplanInhibidor de C5; Miastènia gravis; ZilucoplanBackground: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11–4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline −6.06 [−7.09, −5.03]) and were sustained through to Week 60 (−6.04 [−7.21, −4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (−6.46 [−8.19, −4.72]), and were sustained through to Week 60 (−6.51 [−8.37, −4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871)The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by UCB Pharma. The funding source contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication

Post-polio syndrome is not a dysimmune condition

Post-polio syndrome; Dysimmune conditionSíndrome post-polio; Condició disimmuneSíndrome pospolio; Condición disinmuneBACKGROUND: Poliomyelitis is a global disabling disease affecting 12-20 million of people. Post poliomyelitis syndrome (PPS) may affect up to 80% of polio survivors: increased muscle weakness, pain, fatigue, functional decline. It relies on aging of an impaired neuro-muscular system with ongoing denervation processes. A late involvement of humoral or cellular pro-inflammatory phenomena is also suspected. AIM: To assess the dysimmune hypothesis of PPS by comparing lymphocyte subpopulations and humoral immune factors between PPS patients and controls. DESIGN: Cross-sectional study. SETTING: Montpellier University Hospital. POPULATION: Forty-seven PPS and 27 healthy controls. METHODS: PPS patients and controls were compared on their lymphocyte subpopulations and humoral immune factors (IL-1β, IL-6, IL-8, IL-17, IL-21, IL-22, IL-23, IFN-γ, TNF-α, GM-CSF, RANTES, MCP1, MIP-3a, IL-10, TGF-β, IL4, IL13). Patients were further compared according to their dominant clinical symptoms. Sample size guaranteed a power >90% for all comparisons. RESULTS: PPS patients and controls were comparable in gender, age and corpulence. Most patients had lower limb motor sequelae (N.=45, 95.7%), a minority had upper limb motor impairment (N.=16, 34.0%). Forty-five were able to walk (94%), 35/45 with technical aids. The median of the two-minute walking test was 110 meters (interquartile range 55; 132). Eighteen (38%) required help in their daily life. Their quality of life was low (SF36). All described an increased muscular weakness, 40 (85%) a general fatigue, and 39 (83%) muscular or joint pain. Blood count, serum electrolytes, T and B lymphocyte subpopulations and cytokines were comparable between patients and controls, except for creatine phospho kinase that was significantly higher in PPS patients. None of these variables differed between the 20/47 patients whose late main symptoms were pain or fatigue, and other patients. CONCLUSIONS: Our results suggest that PPS is not a dysimmune disease. CLINICAL REHABILITATION IMPACT: Our results do not sustain immunotherapy for PPS. Our work suggest that PPS may be mostly linked to physiological age-related phenomena in a disabled neuromuscular condition. Thus, our results emphasize the role of prevention and elimination of aggravating factors to avoid late functional worsening, and the importance of rehabilitation programs that should be adapted to patients’ specific conditions

The Hexokinase 1 5′-UTR Mutation in Charcot–Marie–Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering

Hexokinase I; MitochondriaHexoquinasa I; MitocondrisHexoquinasa I; MitocondriasDemyelinating Charcot–Marie–Tooth 4G (CMT4G) results from a recessive mutation in the 5′UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.This work was supported by the EpiGenMed program, the European Research Council grant (FP7-IDEAS-ERC 311610), and an INSERM—AVENIR grant to N.T

Survey on the management of Pompe disease in routine clinical practice in Spain

Antibodies; Diagnosis; Pompe diseaseAnticuerpos; Diagnóstico; Enfermedad de pompeAnticossos; Diagnòstic; Malaltia de pompeBackground Despite the availability of several clinical guidelines, not all health professionals use their recommendations to manage patients with Pompe disease, a rare genetic disorder involving high-impact therapy. Through several discussion meetings and a survey, the present study aimed to learn about the management of Pompe disease in routine clinical practice in Spain, to improve clinical care in a real-life situation. Results The survey was sent to 42 healthcare professionals who manage patients with Pompe disease in their clinical practice. Although most respondents followed the clinical guidelines, clinical practice differed from the expert recommendations in many cases. Approximately 7% did not request a genetic study to confirm the diagnosis before starting treatment, and 21% considered that only two dried blood spot determinations suffice to establish the diagnosis. About 76% requested anti-GAA antibodies when there is a suspicion of lack of treatment efficacy, though a significant percentage of respondents have never requested such antibodies. According to 31% of the respondents, significant impairment of motor function and/or respiratory insufficiency is a requirement for authorizing medication at their hospital. Up to 26% waited for improvements over the clinical follow-up to maintain treatment and withdrew it in the absence of improvement since they did not consider disease stabilization to be a satisfactory outcome. Conclusions The results highlight the lack of experience and/or knowledge of some professionals caring for patients with Pompe disease. It is necessary to develop and disseminate simple guidelines that help to apply the expert recommendations better or centralize patient follow-up in highly specialized centers.Sanofi has sponsored this project without participating in the article’s design, data analysis, or writing

Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy

Protein gene; Multisystem proteinopathyGen de proteína; Proteinopatía multisistémicaGen de proteïna; Proteinopatia multisistèmicaBackground and Objectives Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. Methods A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. Results All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. Discussion This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.Two grants from the National Institute of Health (R01AG031867 and K24R073317 to C.W.) and a grant from Academy of Medical Sciences (APR04/007 to J.D.-M.)

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

Amyotrophic lateral sclerosis; Biomarker; PrognosisEsclerosi lateral amiotròfica; Biomarcador; PronòsticEsclerosis lateral amiotrófica; Biomarcador; PronósticoAmyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the “fit-for-purpose” concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.This study has been funded by Instituto de Salud Carlos III through the project “PI19/0593” (co-funded by European Regional Development Fund: “A way to make Europe “)

Plum pudding random medium model of biological tissue toward remote microscopy from spectroscopic light scattering

Biological tissue has a complex structure and exhibits rich spectroscopic behavior. There is \emph{no} tissue model up to now able to account for the observed spectroscopy of tissue light scattering and its anisotropy. Here we present, \emph{for the first time}, a plum pudding random medium (PPRM) model for biological tissue which succinctly describes tissue as a superposition of distinctive scattering structures (plum) embedded inside a fractal continuous medium of background refractive index fluctuation (pudding). PPRM faithfully reproduces the wavelength dependence of tissue light scattering and attributes the "anomalous" trend in the anisotropy to the plum and the powerlaw dependence of the reduced scattering coefficient to the fractal scattering pudding. Most importantly, PPRM opens up a novel venue of quantifying the tissue architecture and microscopic structures on average from macroscopic probing of the bulk with scattered light alone without tissue excision. We demonstrate this potential by visualizing the fine microscopic structural alterations in breast tissue (adipose, glandular, fibrocystic, fibroadenoma, and ductal carcinoma) deduced from noncontact spectroscopic measurement

Immunological, Clinical, and Epidemiological Features of Guillain-Barré Syndrome Associated with SARS-CoV-2 Infection

Guillain-Barré Syndrome; SARS-CoV-2 InfectionSíndrome de Guillain-Barré; Infección por SARS-CoV-2Síndrome de Guillain-Barré; Infecció per SARS-CoV-2Objectives. There is a growing interest in understanding the association between Guillain-Barré syndrome (GBS) and SARS-CoV-2 infection. The aim of this study was to analyse various characteristics of GBS before and after the pandemic outbreak and thus identify possible distinctive features of GBS associated with SARS-CoV-2 (GBS-S). Material and Methods. In our centre, we retrospectively reviewed the records of patients diagnosed with GBS between January 2018 and March 2022. Epidemiological, clinical, and immunological data were analysed and compared between patients with GBS according to the time of diagnosis and antecedent events. Results. Thirty-nine patients with GBS were included: nine (23.1%) were diagnosed with GBS-S. GBS-S was most frequent in 2020 (6/13, 46.1%). Most of these patients developed a postinfectious classic demyelinating variant (4/9, 44.4%) with frequent bilateral facial paralysis (4/9, 44.4%). Serum antiganglioside antibodies (AGAs) were found in 1/9 patients with GBS-S. Serum anti-SSA/Ro60 antibodies were highly prevalent in GBS-S (7/9 (77.8%) vs. 3/11 (27.3%), ). Three cases associated with SARS-CoV-2 vaccination (GBS-V) were detected. Of note, two had bilateral facial paralysis and anti-SSA/Ro60 antibodies. Conclusion. Our findings suggest that SARS-CoV-2 has become an important antecedent event associated with GBS in our setting. GBS-S shows a postinfectious demyelinating immune-mediated profile with negative serological testing for AGAs. Serum anti-SSA/Ro60 antibodies were found frequently in these patients. Bilateral facial paralysis stands out as a possible characteristic clinical feature both in GBS-S and GBS-V. Larger, prospective studies are needed for a better understanding of its immunopathogenesis

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

Juvenile amyotrophic lateral sclerosis; Predominant disorderEsclerosi lateral amiotròfica juvenil; Trastorn predominantEsclerosis lateral amiotrófica juvenil; Trastorno predominanteAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants