Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial.

Under compassionate use, chimeric antigen receptor (CAR) T cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIMs). Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T cell therapy (CABA-201) in the RESET-Myositis phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was observed. Creatine kinase levels decreased, and muscular strength improved post-infusion. Peripheral B cells were depleted rapidly following infusion, and the subject achieved peripheral B cell aplasia by day 15 post-infusion. Peripheral B cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline, whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4+ effector memory T cells and exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.

The Dermatomyositis Disease Symptom Questionnaire (DM-DSQ): A Measure to Assess the Patient Experience of Dermatomyositis Symptoms.

OBJECTIVE: Dermatomyositis (DM) symptoms negatively affect the quality of life of individuals living with the disease. Disease-specific, patient-reported outcome (PRO) instruments are needed to assess symptoms important to individuals with DM. This study aimed to conceptualize patient DM experience and disease activity definition to refine the development of the Dermatomyositis Disease Symptom Questionnaire (DM-DSQ), a novel PRO instrument capturing patient-reported symptoms. METHODS: An observational, qualitative study was conducted with 30 individuals with DM (aged ≥ 18 yrs) in the US. A 1-hour semistructured interview, including concept elicitation and cognitive debriefing, was conducted with each participant. Inductive coding was used to identify concepts; a saturation analysis was conducted to confirm sample size. Concepts from transcripts were used to refine the preliminary conceptual model and DM-DSQ items. RESULTS: Concept elicitation analysis findings included disease symptoms (eg, muscle weakness) and functional impacts (eg, walking). The analysis achieved conceptual saturation; the first 5 interviews uncovered most of the concepts. During cognitive debriefing of the DM-DSQ, participants found the items relevant, comprehensive, and easily understood (except for "skin sensitivity in sunlight"). The revised DM-DSQ content appears preliminarily valid in the patient population surveyed, pending further additions and debriefing based on refinement of the preliminary conceptual disease model and items. CONCLUSION: The DM-DSQ is being used in a phase II clinical trial and could become a valuable tool for studies evaluating PROs in patients with DM. Preliminary results indicate its content validity; extensive psychometric analysis using clinical trial data will determine its ability to capture symptoms for patients with DM.

Efficacy and safety of maintenance intravenous immunoglobulin in generalized myasthenia gravis patients with acetylcholine receptor antibodies: A multicenter, double-blind, placebo-controlled trial.

INTRODUCTION/AIMS: Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. METHODS: Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). RESULTS: The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. DISCUSSION: Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study.

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

Effects of enzyme replacement therapy on bone density in late onset Pompe disease.

Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.

Safety and outcomes with efgartigimod use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Multiple novel therapies have been approved for patients with myasthenia gravis. Our aim is to describe the early experience of efgartigimod use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). METHODS: This multicenter retrospective study included AChR+ve gMG patients from five major neuromuscular centers who were treated with efgartigimod and had both pre- and post-efgartigimod myasthenia gravis activities of daily living (MG-ADL) scores. Information regarding MG history, concomitant treatment(s), MG-ADL and other MG-specific measures, laboratory data, and adverse events were recorded. RESULTS: A total of 37 patients (M:23, F:14) with a mean age of 65.56 (±14.74) y were included in this cohort. A total of 36/37 patients completed at least one cycle and 28 patients completed at least two cycles of efgartigimod. A total of 72% (26/36) of patients had a clinically meaningful reduction (≥2 point change) in MG-ADL after the completion of the first cycle of efgartigimod (mean pre-efgartigimod 8.02) (±3.09) versus post-efgartigimod 4.33 (±3.62). Twenty-five percent (9/36) achieved minimal symptom expression status after one cycle and 25% (7/28) after the second cycle. Treatment benefit was sustained after cycle 2. Three out of four patients with thymoma in this cohort had clinically significant reductions in MG-ADL scores. Immunoglobulin G (IgG) levels decreased by about 60% (n = 10). One patient had a relapse of Clostridium difficile infection resulting in the discontinuation of therapy. Four patients had mild side effects. DISCUSSION: Efgartigimod led to clinically meaningful improvement in MG-ADL in diverse AChR+ve gMG patients but treatment frequency to achieve optimal symptom control needs to be explored.

Imaging beyond muscle magnetic resonance imaging in inclusion body myositis.

Diagnosis of inclusion body myositis (IBM), the most common acquired muscle disorder in adults above the age of 40, remains dependent on demonstration of the classic clinical phenotype and confirmed by muscle histopathological examination. The European Neuromuscular Centre (ENMC) 2011 diagnostic criteria for the diagnosis of IBM includes the demonstration of one or more of the muscle pathological findings - inflammation, vacuolation or protein aggregation. Muscle biopsy is an invasive procedure and patients often require more than one biopsy to establish a definitive diagnosis of IBM. Over the past few years, there has been considerable gain in knowledge regarding various imaging modalities that may complement the diagnosis of IBM, and in some cases have the potential to obviate the need for more invasive procedures, such as muscle biopsy. Positron emission tomography (PET) using different ligands may serve as a surrogate biomarker of therapeutic target engagement in IBM. This review concentrates on a critical evaluation of the literature looking at the utility of muscle ultrasound, dual energy x-ray absorptiometry (DEXA), and positron emission tomography and their role in IBM.

Inclusion body myositis: evolving concepts.

PURPOSE OF REVIEW: To discuss recent developments in our understanding of epidemiology, diagnostics, biomarkers, pathology, pathogenesis, outcome measures, and therapeutics in inclusion body myositis (IBM). RECENT FINDINGS: Recent epidemiology data confirms a relatively higher prevalence in the population aged above 50 years and the reduced life expectancy. Association with cancer and other systemic disorders is better defined. The role of magnetic resonance imaging (MRI) and ultrasound in diagnosis as well as in following disease progression has been elucidated. There are new blood and imaging biomarkers that show tremendous promise for diagnosis and as outcome measures in therapeutic trials. Improved understanding of the pathogenesis of the disease will lead to better therapeutic interventions, but also highlights the importance to have sensitive and responsive outcome measures that accurately quantitate change. SUMMARY: There are exciting new developments in our understanding of IBM which should lead to improved management and therapeutic options.

COVID-19 infection in patients with late-onset Pompe disease.

INTRODUCTION/AIMS: Severe acute respiratory syndrome coronavirus-2 2019 (SARS-CoV2/COVID-19) is frequently more severe in individuals with pre-existing respiratory and cardiovascular conditions. The impact on patients with neuromuscular disorders is of concern, but remains largely unknown. Late-onset Pompe disease (LOPD) is a lysosomal-storage disorder characterized by progressive skeletal and respiratory muscle degeneration. Mortality is typically caused by respiratory failure. We examined the impact of COVID-19 on these patients. METHODS: This is a case series of four patients with LOPD who contracted COVID-19. RESULTS: All patients had a mild/moderate illness from COVID-19 and did not require hospitalization. Neurological worsening occurred in one, with no change in physical ability in the other three, and respiratory symptoms remained stable in all four. DISCUSSION: COVID-19 infection can result in a benign course in some patients with LOPD. However, individuals with LOPD remain at high risk and should receive COVID-19 vaccinations and exercise precautions to avoid exposure to COVID-19 infection.

Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS: Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS: Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION: The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Utility of video-fundoscopy and prospects of portable stereo-photography of the ocular fundus in neurological patients.

BACKGROUND: Proper evaluation of ocular fundi is an integral part of neurological examination. Unfortunately, neurology residents are increasingly uncomfortable performing fundoscopy and interpreting findings because of diminishing skills and lack of experience. This became more prominent during the COVID-19 pandemic as fundoscopy requires proximity to the patient. With the recent dramatic improvement of smartphone cameras, fundus photography using the PanOptic Ophthalmoscope (Welch Allyn, Skaneateles Falls, NY) with a smartphone adapter offered an alternative to direct fundoscopic examination. We present the first experience with our own design of a universal smartphone adapter. METHODS: This is a single-center case series, consecutive for a single user and certain presenting neurological symptoms, which is aimed to evaluate the feasibility and practicality of a new, universal PanOptic smartphone adapter. Presenting symptoms included headache, ocular symptoms, seizure, or encephalopathy. We used 3D modeling and printing techniques to create the adapter. We also developed a methodology of capturing stereoscopic images of the optic disc using a single smartphone camera, but the method was not systematically evaluated in this paper. RESULTS: Here we present our initial experience of fundus video/photography in patients, who presented with encephalopathy, headache, seizure, vision loss, and other ocular symptoms. Fundoscopic abnormalities were discovered in 11 out of 100 patients. Some were incidental findings and were unrelated to the presentation. In one case, fundoscopy played a critical role in establishing the correct diagnosis. CONCLUSIONS: Our custom-designed smartphone adapter allowed obtaining high-quality video and photo recordings using PanOptic Ophthalmoscope. The acquisition of high-quality photos enables a high-yield diagnostic tool and allows revisiting the image in the patient's chart. Improvement of smartphone cameras opens vast horizons for stereo-fundoscopy and 3D reconstruction of the ocular fundus without using sophisticated and costly equipment. Microscopic eye movements allow taking snapshots of two side-by-side photos for 3D reconstruction and stereoscopic image viewing, which is the next level of optic disc assessment.

Multisystem proteinopathy: Where myopathy and motor neuron disease converge.

Multisystem proteinopathy (MSP) is a pleiotropic group of inherited disorders that cause neurodegeneration, myopathy, and bone disease, and share common pathophysiology. Originally referred to as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), attributed to mutations in the gene encoding valosin-containing protein (VCP), it has more recently been discovered that there are several other genes responsible for similar clinical and pathological phenotypes with muscle, brain, nerve, and bone involvement, in various combinations. These include heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1, hnRNPA1), sequestosome 1 (SQSTM1), matrin 3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN), all of which share disruption of RNA stress granule function and autophagic degradation. This review will discuss each of the genes implicated in MSP, exploring the molecular pathogenesis, clinical features, current standards of care, and future directions for this diverse yet mechanistically linked spectrum of disorders.

Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study.

INTRODUCTION/AIMS: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+ ) gMG previously treated with rituximab. METHODS: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. RESULTS: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean -4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean -4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval -1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. DISCUSSION: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously.

Update on immune-mediated therapies for myasthenia gravis.

With the exception of thymectomy, immune modulatory treatment strategies and clinical trials in myasthenia gravis over the past 50 y were mainly borrowed from experience in other nonneurologic autoimmune disorders. The current experimental therapy paradigm has significantly changed such that treatments directed against the pathological mechanisms specific to myasthenia gravis are being tested, in some cases as the initial disease indication. Key advances have been made in three areas: (i) the expanded role and long-term benefits of thymectomy, (ii) complement inhibition to prevent antibody-mediated postsynaptic membrane damage, and (iii) neonatal Fc receptor (FcRn) inhibition as in vivo apheresis, removing pathogenic antibodies. Herein, we discuss these advances and the potential for these newer therapies to significantly influence the current treatment paradigms. While these therapies provide exciting new options with rapid efficacy, there are anticipated challenges to their use, especially in terms of a dramatic increase in cost of care for some patients with myasthenia gravis.

Examination of the human motor endplate after brachial plexus injury with two-photon microscopy.

INTRODUCTION: After traumatic nerve injury, neuromuscular junction remodeling plays a key role in determining functional outcomes. Immunohistochemical analyses of denervated muscle biopsies may provide valuable prognostic data regarding clinical outcomes to supplement electrodiagnostic studies. METHODS: We performed biopsies on nonfunctioning deltoid muscles in two patients after gunshot wounds and visualized the neuromuscular junctions using two-photon microscopy with immunohistochemistry. RESULTS: Although the nerves in both patients showed evidence of acute Wallerian degeneration, some of the motor endplates were intact but exhibited significantly decreased surface area and volume. Both patients exhibited substantial recovery of motor function over several weeks postinjury. DISCUSSION: Two-photon microscopic assessment of neuromuscular junction integrity and motor endplate morphometry in muscle biopsies provided evidence of partial sparing of muscle innervation. This finding supported the clinical judgment that eventual recovery would occur. With further study, this technique may help to guide operative decisionmaking after traumatic nerve injuries.

SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.

BACKGROUND: Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype-phenotype relationships. METHODS: Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1. RESULTS: DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1. CONCLUSIONS: The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).