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BACKGROUND: Comorbidity between myasthenia gravis (MG) and other autoimmune diseases is well-documented. However, concurrent MG and Parkinson's disease (PD) have rarely been described. This concurrence has mostly been considered coincidental in cases reported to date. MATERIAL/METHODS: We characterized patients with concurrent MG and PD within a cohort of 631 MG patients by gender, age, MGFA class, quantitative MG score at diagnosis, UPDRS score at diagnosis, and the DaTSCAN uptake pattern, to determine the frequency and the phenotype of individuals with these two concurrent entities. Meta-analysis of cases in the literature was used for comparison with our series. RESULTS: Eighteen cases were identified in which the two diseases were concurrent. The major characteristics of the phenotype are male prevalence, late-onset MG, and frequent initial symptoms of dropped head and oculobulbar involvement. DAT confirmed reduced bilateral uptake in eleven patients and reduced unilateral uptake in the others. CONCLUSIONS: To our knowledge, this is the largest reported series of concurrent MG and PD. This concurrence is more common than expected (2.85%). Either MG or PD may appear first. We found no iatrogenic relationship for the order of appearance. The overlapping of symptoms sometimes leads physicians to overlook the second disease, instead viewing it as a deterioration of the first. This study describes patients with well-documented diagnoses of both MG and PD, thus providing further indications of a shared etiology of these two diseases. Prospective studies including genetic, immunological, and environmental analysis are necessary to identify possible common pathogenic mechanisms.
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Miastenia Gravis , Enfermedad de Parkinson , Humanos , Miastenia Gravis/epidemiología , Miastenia Gravis/complicaciones , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/complicaciones , Masculino , Femenino , Anciano , Persona de Mediana Edad , España/epidemiología , Estudios de Cohortes , Anciano de 80 o más Años , Comorbilidad , AdultoRESUMEN
BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.
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Actividades Cotidianas , Miastenia Gravis , Humanos , Miastenia Gravis/tratamiento farmacológico , Anticuerpos Monoclonales , Autoanticuerpos , PacientesRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.
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Degeneración Lobar Frontotemporal , Enfermedad de la Neurona Motora , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Degeneración Lobar Frontotemporal/patología , Degeneración Lobar Frontotemporal/genética , Estudios Retrospectivos , Enfermedad de la Neurona Motora/patología , Enfermedad de la Neurona Motora/genética , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/patología , Demencia Frontotemporal/genética , Encéfalo/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.
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Adrenoleucodistrofia , Adulto , Masculino , Humanos , Resultado del Tratamiento , Adrenoleucodistrofia/tratamiento farmacológico , Francia , Método Doble Ciego , Progresión de la EnfermedadRESUMEN
AIMS: The study's aim is to investigate the efficacy and safety of SOM3355 (bevantolol hydrochloride), a ß1 -adrenoreceptor antagonist with recently identified vesicular monoamine transporter type 2 inhibitory properties, as a repositioned treatment to reduce chorea in Huntington's disease (HD). METHODS: A randomized, placebo-controlled proof-of-concept study was performed in 32 HD patients allocated to 2 arms of 4 sequential 6-week periods each. Patients received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. The primary endpoint was improvement by at least 2 points in the total maximal chorea score in any active drug period compared with the placebo period. RESULTS: The primary endpoint was met in 57.1% of the patients. Improvements ≥3, ≥4, ≥5 and ≥6 points vs. placebo treatment were observed in 28.6, 25.0, 17.9 and 10.7% of the patients, respectively. A mixed-model analysis found a significant improvement in the total maximal chorea score of -1.14 (95% confidence interval, -2.11 to -0.16; P = .0224) with 200 mg twice daily SOM3355 treatment compared with placebo treatment. These results were paralleled by Clinical and Patient Global Impression of Change ratings (secondary endpoints). An elevation in plasma prolactin levels by 1.7-1.9-fold was recorded (P < .005), probably reflecting the effect on the dopamine pathway, consistent with vesicular monoamine transporter type 2 inhibition. The most frequent adverse events during SOM3355 administration were mild to moderate. CONCLUSION: Within the limits of this study, the results suggest that SOM3355 reduces chorea in patients with HD and is well-tolerated. Larger studies are necessary to confirm its therapeutic utility as an antichoreic drug. EudraCT number: 2018-000203-16 and ClinicalTrials.gov Identifier: NCT03575676.
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Corea , Enfermedad de Huntington , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Corea/tratamiento farmacológico , Corea/inducido químicamente , Corea/complicaciones , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Tetrabenazina/efectos adversos , Resultado del Tratamiento , Método Doble CiegoRESUMEN
INTRODUCTION/AIMS: Data on safety and tolerability of the vaccines against severe acute respiratory virus coronavirus-2 (SARS-CoV-2, or coronavirus disease-2019 [COVID-19]) in patients with myasthenia gravis (MG) are currently limited. In this study we investigated the safety of mRNA-based two-dose vaccination in a cohort of patients with MG. METHODS: This investigation was a prospective observational study of messenger RNA (mRNA)-based vaccines administered to patients with MG with stable disease. Local and systemic reactogenicity after injection was monitored for each dose administered. The patients were categorized and clinically assessed following the recommendations of the Myasthenia Gravis Foundation of America. RESULTS: Thirty-six males and 55 females (mean age at first vaccine dose, 58.8 years; standard deviation, = 17.1 years) received vaccines. Seventy-two patients (79.1%) were taking one or more immunosuppressant(s). The most frequent adverse effects were injection-site pain, fatigue, myalgia, chills, fever, and headache. Local and systemic reactions were transient; 58.2% of the patients developed one or more reaction(s). There were no anaphylactic reactions. None of the patients had a myasthenic crisis, and two developed a mild deterioration compared with their Quantitative Myasthenia Gravis baseline score. The clinical outcome scores showed no exacerbation of MG symptoms. Patients over 65 years of age developed fewer adverse effects. COVID-19 vaccination did not induce clinical exacerbation in stable patients with MG, regardless of their age, sex, history of myasthenic crisis, or whether they were taking immunosuppressants. DISCUSSION: Our data are consistent with the mRNA COVID-19 vaccine being well tolerated in patients with well-controlled MG. The findings may contribute to decisions in vaccination campaigns in the future.
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Vacunas contra la COVID-19 , COVID-19 , Miastenia Gravis , Vacunas , Femenino , Humanos , Masculino , Persona de Mediana Edad , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Inmunosupresores/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , ARN Mensajero , SARS-CoV-2 , Vacunas/uso terapéuticoRESUMEN
OBJECTIVE: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. METHODS: This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. RESULTS: The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. INTERPRETATION: We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806.
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Distrofia Muscular de Duchenne , ARN Largo no Codificante , Humanos , Distrofina/genética , Distrofina/metabolismo , Estudios de Cohortes , Estudios Transversales , Exones/genética , Distrofia Muscular de Duchenne/metabolismo , Fenotipo , Actinina/genéticaRESUMEN
BACKGROUND: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. METHODS: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. RESULTS: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. CONCLUSION: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.
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Neuropatías Amiloides Familiares , Oligonucleótidos , Humanos , Neuropatías Amiloides Familiares/tratamiento farmacológico , Polineuropatías/tratamiento farmacológico , Prealbúmina/genética , Calidad de Vida , Oligonucleótidos/efectos adversosRESUMEN
BACKGROUND: Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort. METHODS: We designed a clinical case-control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)-based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status. RESULTS: We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.
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Predisposición Genética a la Enfermedad , Miastenia Gravis , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Miastenia Gravis/epidemiología , Miastenia Gravis/genética , Factores de RiesgoRESUMEN
INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
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Infecciones por Citomegalovirus , Distrofia Muscular Facioescapulohumeral , Adolescente , Adulto , Infecciones por Citomegalovirus/patología , Humanos , Imagen por Resonancia Magnética , Contracción Muscular , Músculo EsqueléticoRESUMEN
BACKGROUND: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. METHODS: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. RESULTS: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. CONCLUSIONS: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).
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OBJECTIVE: Sports-related activity has been proposed as a risk factor for ALS, particularly among professionals playing American football and soccer, with a reported prevalence between two and forty times higher than the general population. Early onset (by two decades) was described among Italian soccer players as early as 2005. This study aims to characterise the phenotype of seven Spanish retired professional and semi-professional soccer players. METHODS: The cases were identified using the following sources: (i) personal archives from a leading ALS Unit, (ii) PubMed and specialised websites, and (iii) self-reports of patients in the media. Age and site of onset, survival time, history of trauma, playing position and time between retirement and first symptoms were investigated for soccer players in the Spanish league diagnosed between 2000 and 2020. RESULTS: Seven ALS cases were identified. The mean age at onset was 41.5 years (SD 9.2, median 45.5, range 31.5-51.2). Onset was bulbar in one individual, while six experienced spinal onset. Three patients had the flail arm syndrome variant. Two cases were goalkeepers, two defenders and three midfielders. Four had a history of trauma (two serious). Survival time for the two deceased patients was 71.8 months. Mean time between retirement and first symptoms was 9.4 years (SD 8.0, median 15.2, range 0.1-17.5). CONCLUSIONS: Our study has the largest sample size of non-Italian league soccer professionals and semi-professionals, and our results corroborate early onset (by 23.7 years). Unlike the Italian cohorts, bulbar onset is rare, and upper limb onset is most common.
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Esclerosis Amiotrófica Lateral , Fútbol , Adulto , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Italia/epidemiología , Factores de Riesgo , EspañaRESUMEN
Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer's disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.
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Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Neuropatología/métodos , Estudios RetrospectivosRESUMEN
Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Riluzol/uso terapéutico , Tiazoles/uso terapéutico , Adolescente , Adulto , Anciano , Benzamidas , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas , Piridinas , Resultado del Tratamiento , Adulto JovenRESUMEN
Despite the genetic heterogeneity reported in familial amyotrophic lateral sclerosis (ALS) (fALS), Cu/Zn superoxide-dismutase (SOD1) gene mutations are the second most common cause of the disease, accounting for around 20% of all families (ALS1) and isolated sporadic cases (sALS). At least 186 different mutations in the SOD1 gene have been reported to date. The possibility of a single founder and separate founders have been investigated for D90A (p.D91A) and A4V (p.A5V), the most common mutations worldwide. High-throughput single nucleotide polymorphism genotyping studies have suggested two founders for A4V (one for the Amerindian population and another for the European population) although the possibility that the two populations are descended from a single ancient founder cannot be ruled out. We used 15 genetic variants spanning the human chromosome 21 from the SOD1 gene to the SCAF4 gene, comparing them with the population reference panels, to demonstrate that the first A4V Spanish pedigree shared the genetic background reported in the European population.
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PURPOSE OF REVIEW: Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist. RECENT FINDINGS: The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients. SUMMARY: The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.
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BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
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ADN Mitocondrial/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Paraplejía/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Trastornos Parkinsonianos/genética , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Myasthenic crisis (MC) is a potentially life-threatening complication of myasthenia gravis. Its precipitating factors include surgical procedures, particularly thymectomy. The role of preoperative intravenous immunoglobulin (IVIg) in preventing MC in patients scheduled for thymectomy and other surgery with general anaesthesia is unknown. Our objective was to test the hypothesis that preoperative IVIg is effective in preventing myasthenic crisis in patients with myasthenia gravis scheduled for surgery under general anaesthesia, including thymectomy. METHODS: A prospective, randomized, double-blind, single-centre study was conducted over a 4-year period. The treatment group received IVIg, 0.4 g/kg/day preoperatively for 5 consecutive days, and the placebo group received saline solution under the same conditions. The two groups were age-matched, with similar functional status, and Myasthenia Gravis Foundation of America class. All patients had well-controlled myasthenia gravis with minimal manifestations before surgery. The primary outcome measured was MC. Intubation times, time in the recovery room, number of postoperative complications, and days of hospitalization were the secondary outcomes measured. RESULTS: A total of 47 patients were randomized, 25 to the IVIg group and 22 to placebo. There were 19 men and 28 women, with a mean age of 58.6 years, mean body mass index of 27.8 kg/m2, and mean acetylcholine receptor antibodies of 12.9 nmol/l. The mean forced vital capacity was 84.4%. The mean quantitative myasthenia gravis sum score was 6.3. Ten patients (five in each arm) had a history of MC. Thymectomy was performed in 16 patients. Only one patient in the placebo group presented with MC requiring non-invasive ventilation (but no reintubation) for 6 days. Neither differences between groups in the univariate analysis nor risk factors for MC in the multivariate analysis were found. CONCLUSIONS: Preoperative IVIg to prevent MC does not appear to be justified in well-controlled myasthenia gravis patients. This study provides class I evidence that preparation with IVIg to prevent MC is not necessary in well-controlled myasthenia gravis patients scheduled for surgery with general anaesthesia.