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To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Introduction : Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody‐positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open‐label extension of REGAIN, evaluating eculizumab's long‐term safety and efficacy. Methods : Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results : The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN ( P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open‐label eculizumab ( P < 0.0001). Discussion : These findings provide evidence for the long‐term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019

Objective: To study the concurrent and construct validity and test-retest reliability in the practice setting of an outcome measure for myasthenia gravis (MG). Methods:Eleven centers participated in the validation study of the Myasthenia Gravis Composite (MGC) scale. Patients with MG were evaluated at 2 consecutive visits. Concurrent and construct validities of the MGC were assessed by evaluating MGC scores in the context of other MGspecific outcome measures. We used numerous potential indicators of clinical improvement to assess the sensitivity and specificity of the MGC for detecting clinical improvement. Test-retest reliability was performed on patients at the University of Virginia.Results: A total of 175 patients with MG were enrolled at 11 sites from July 1, 2008, to January 31, 2009. A total of 151 patients were seen in follow-up. Total MGC scores showed excellent concurrent validity with other MG-specific scales. Analyses of sensitivities and specificities of the MGC revealed that a 3-point improvement in total MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC also appears to represent a meaningful improvement to most patients, as indicated by improved 15-item myasthenia gravis quality of life scale (MG-QOL15) scores. The psychometric properties were no better for an individualized subscore made up of the 2 functional domains that the patient identified as most important to treat. The test-retest reliability coefficient of the MGC was 98%, with a lower 95% confidence interval of 97%, indicating excellent test-retest reliability. Conclusions:The Myasthenia Gravis Composite is a reliable and valid instrument for measuring clinical status of patients with myasthenia gravis in the practice setting and in clinical trials. Outcome measures for myasthenia gravis (MG) differ in ease of use, time to completion, what is being measured, how it is being measured, and who reports symptoms and impairments (i.e., patient-reported vs physician-reported). 1-15 Most of these scales are unweighted but a few have weighted test item response options. 3,7,9 The Myasthenia Gravis Composite (MGC) scale consists of test items that measure symptoms and signs of MG, with weighted response options (table 1). 3 The individual test items of the MGC were selected from existing MG-specific scales based on their performance during 2 randomized, controlled clinical trials of mycophenolate mofetil for MG. 3,16,17 The test items were selected so as to be meaningful to both the physician and the patient, frequently abnormal in patients with active disease, and responsive to clinical change. 3 We present the results of validity and test-retest reliability analyses of the MGC in the patient care setting.METHODS Validity testing of the MGC was conducted at 11 neuromuscular centers (9 in the United States and 2 in Europe) during the routine care of subjects with MG, following approval by each center's ethical standards committee on human experimen-