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Background: Individuals with lung cancer (LC) face a variety of symptoms that significantly impact their lives. We use extensive patient input to determine the relative importance and prevalence of these symptoms and identify which demographic features are associated with a higher level of disease burden., Methods: We performed semi-structured qualitative interviews with participants with LC to identify potentially important symptoms. We then conducted a cross-sectional study, in which participants rated the relative importance of 162 individual symptoms covering 14 symptomatic themes. Participant responses were analyzed by age, sex, disability status, disease duration, LC stage, type of treatment received, and smoking history, among other categories., Results: Our cross-sectional study had 139 participants with LC. The most prevalent symptomatic themes reported by this population were fatigue (85.5%), impaired sleep and daytime sleepiness (73.5%), and emotional issues (73.0%). The symptomatic themes that had the greatest average impact (on a scale of 0 to 4, with 4 being the most impactful) were social role dissatisfaction (1.67), inability to do activities (1.64), and fatigue (1.60). Disability status had the strongest association with symptomatic theme prevalence. LC stage (stage IV), receipt of therapy, and smoking experience were also associated with higher frequency of symptomatic themes., Conclusions: Individuals with LC face diverse and disease-specific symptoms that affect their daily lives. Patient insight on the prevalence and relative importance of these symptoms is invaluable to advance meaningful therapeutic interventions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-831/coif). CH is the recipient of the grant award from URVentures that funded this research. He receives royalties for the use of multiple disease specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation. He receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Neurocrine Biosciences, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich’s Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. He is the director of the University of Rochester’s Center for Health + Technology. JCK has provided consultation/participated on advisory boards for Amgen, Boehringer Ingelheim, Bristol Myers Squibb, and EQRX. She has received support from Amgen, Bristol Myers Squibb, Foundation Medicine, Genentech, Lung Ambition Alliance, Mirati, Novartis, and Takeda, paid to GO2 Foundation for Lung Cancer. She is the PI on a research project unrelated to this work, funded by Bristol Myers Squibb and Genentech and paid to GO2 Foundation for Lung Cancer. Jacinta Wiens is now an employee of Merck but was employed at GO2 Foundation for Lung Cancer during her participation on this study. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Background: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA., Methods: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete., Findings: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose., Interpretation: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed., Funding: Ionis Pharmaceuticals, Biogen., Competing Interests: Declaration of interests CFB, LM, DAN, and SX are employees of Ionis Pharmaceuticals, which funded the trial, and own stock options in Ionis Pharmaceuticals. CAT received support from Ionis Pharmaceuticals for consultation and sponsored research and carried out collaborative research with CFB under National Institutes of Health (NIH) grant U01NS072323; provides consulting to Biogen, Vertex, Entrada, and Avidity Biosciences; received honoraria from Sanofi; served on scientific advisory boards for Dyne and Pepgen; and serves on the Myotonic Dystrophy Foundation Board. KE received consulting fees from Ionis Pharmaceuticals, Avidity, and Dyne Therapeutics; and received honoraria from the Myotonic Dystrophy Foundation and the Muscular Dystrophy Association. CH receives royalties for the use of multiple disease specific instruments; provided consultation to Biogen, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation; and receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Neurocrine Biosciences, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. WDA received a consulting fee and grant funding from Avidity Biosciences and a consulting fee from Dyne Therapeutics. TA received a grant or contract from the Myotonic Dystrophy Foundation and was on the Myotonic Dystrophy Foundation scientific advisory board. JWD received consulting fees from Affinia Therapeutics and Shift Therapeutics; honoraria from Biogen and Roche Pharmaceuticals; participated in advisory boards for AMO Pharmaceuticals, Avidity Biosciences, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, and Vertex Pharmaceuticals; has leadership roles for Muscular Dystrophy Association, Myotonic Dystrophy Foundation, and Cure Congenital Muscular Dystrophy. GD is an employee of Biogen and owns stock options in Biogen. TD received consulting fees from Dyne, Roche/Genentech Pharmaceuticals, Biogen, Trinds, and ATOM; speaking honoraria for Genentech, Biogen, Roche, and Sarepta; has served on Advisory boards for Novartis, Pfizer, Actigraph, Scholar Rock, Sarepta, Sanofi Genzyme, and Cytokinetics; has unpaid leadership roles for myotonic dystrophy exercise recommendations and physical therapy guidance and the CureSMA Medical Advisory Council. NEJ received royalties or licenses from University of Rochester; received consulting fees from AMO Pharma Fulcrum Therapeutics, Avidity Biosciences, Dyne, Vertex, Arthex, and Entrada; participated in a Data Safety Monitoring Board for Biogen; and owns stock or stock options in ML Bio Solutions. DJL received funding from the DuchenneXchange Advisory Council, Cure Duchenne. JMS received consulting fees from Dyne Therapeutics, Roche, Avidity, ML Bio, Fulcrum Therapeutics, MT Pharma, Sarepta, and Amylyx; payment or honorarium from MDA; and stock or stock options from Dyne Therapeutics. SHS received consulting fees from Reata Pharmaceuticals, Avidity Biosciences, and Dyne therapeutics. KMB was an employee of Ionis Pharmaceuticals at the time the trial was conducted; is a current employee of and owns stock options in Acadia Pharmaceuticals; is an advisor to non-profit organisations Myotonic Dystrophy Foundation and SMA Foundation; and is a Board Member of DTx Pharma. CFB is a Board member of Flamingo Therapeutics and Hereditary Disease Foundation. RM is the chair of three clinical trials in Duchenne muscular dystrophy funded by TRiNDS. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: To determine the prevalence and relative importance of symptoms experienced by children and adults with Friedreich ataxia (FA) and to identify factors associated with a higher burden of disease., Methods: We conducted qualitative interviews with individuals with FA and caregivers of pediatric individuals with FA to identify potential symptoms of importance to those living with FA. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in FA and to determine which factors are associated with a higher burden of disease., Results: Thirty-nine participants provided 2,527 quotes regarding the symptomatic burden of FA. Two hundred two individuals (153 individuals with FA and 49 caregivers) participated in a subsequent cross-sectional study. Individuals with FA and caregivers identified impaired coordination, limitations with mobility and walking, inability to do activities, fatigue, and lower extremity weakness as the most prevalent and life-altering symptomatic themes in FA. Muscle stiffness and functional staging for ataxia were associated with the prevalence of symptomatic themes in FA. In addition, the length of smaller GAA expansion and the mean length of both GAA expansions were strongly associated with the onset of symptoms in FA., Discussion: There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions., (© 2022 American Academy of Neurology.)

Background: To facilitate advances in spinal muscular atrophy therapeutic research, it is important to determine the impact and prevalence of symptoms experienced by children with spinal muscular atrophy. Methods: We conducted qualitative interviews with caregivers of children with spinal muscular atrophy. From these interviews, we generated a survey inquiring about 260 symptoms of importance grouped into 17 symptomatic themes. Results: Sixteen caregivers of children with spinal muscular atrophy aged from 4 months to 12 years participated in initial interviews, and 77 caregivers completed the survey. Higher symptom prevalence was associated with spinal muscular atrophy type, SMN2 copy number, and functional status. Hip, thigh, or knee weakness had the greatest reported impact on the lives of children with spinal muscular atrophy. Conclusions: This research provides one of the largest data sets regarding disease burden in children with spinal muscular atrophy. The most prevalent symptoms are not identical to those with the greatest impact. This unique insight into the most impactful symptoms will help focus therapeutic development in spinal muscular atrophy.

Background: As novel therapeutic interventions are being developed and tested in the amyotrophic lateral sclerosis (ALS) population, there is a need to better understand the symptoms and issues that have the greatest impact on the lives of individuals with ALS. We aimed to determine the frequency and relative importance of symptoms experienced by adults in a national ALS sample and to identify factors that are associated with the greatest disease burden in this population., Methods: We conducted 15 qualitative interviews of individuals with varied ALS phenotypes and analyzed 732 quotes regarding the symptomatic disease burden of ALS between August 2018 and March 2019. We subsequently conducted a national, cross-sectional study of 497 participants with ALS and ALS variants through the Centers for Disease Control and Prevention's (CDC) National ALS Registry between July 2019 and December 2019. Participants reported on the prevalence and relative importance of 189 symptomatic questions representing 17 symptomatic themes that were previously identified through qualitative interviews. Analysis was performed to determine how age, sex, education, employment, time since onset of symptoms, location of symptom onset, feeding tube status, breathing status and speech status relate to symptom and symptomatic theme prevalence., Findings: Symptomatic themes with the highest prevalence in our sample were an inability to do activities (93.8%), fatigue (92.6%), problems with hands or fingers (87.7%), limitations with mobility or walking (86.7%), and a decreased performance in social situations (85.7%). Participants identified inability to do activities and limitations with mobility or walking as having the greatest overall effect on their lives., Interpretation: Individuals with ALS experience a variety of symptoms that affect their lives. The prevalence and importance of these symptoms differ among the ALS population. The most prevalent and important symptoms offer potential targets for improvements in future therapeutic interventions., Funding: Research funding was provided by ALS Association., Competing Interests: CZ has previously provided consultation to Recursion Pharmaceuticals and reports no other disclosures. RB receives grants or contracts from the 10.13039/100000971ALS Association, Medicinova, Healey Center, and Orion with payments through 10.13039/100006510Duke University for various ALS projects and ALS trials. He receives book royalities through Demos Publishing. He provides consultation to ALS Association, Alexion, Amylyx, Apellis, Black Swan, Corcept, Cytokinetics, GenieUS, Guidepoint, ITF Pharma, New Biotic, Shinkei, and Woolsey Pharma. He has received payments for speaking on ALS from Amylyx. He has received payments for developing education materials on ALS from Projects in Knowledge and Medscape. He has participated on Data Safety Monitoring Boards for AB Science, Biogen, Brainstorm, Neurosense, and PTC. He has served on the scientific advisory board at GenieUS. VG is an employee of Biohaven Pharmaceuticals (his contribution to this work was done as part of his role at the University of Miami). He has received consultation/advisory board fees from Amylyx Pharmacuticals. JS has received grants or contracts from 10.13039/100000065NINDS (U01 ReSolve U01NS101944), NINDS (R21 CAPN3 R21TR003184), FSHD Canada (MOVE + FSHD), FSHD Society (MOVE FSHD), 10.13039/100004952MDA (MD CRNG), 10.13039/100012644Friends of FSH Research (MOVE FSHD). He has provided consultation and served on SAB with Avidity, Dyne, Fulcrum, Arrowhead, ML Bio, and Sarepta. He has provided consultation to MT Pharma, He has provided consultation and served on the advisory board for Amylyx. He has served on the steering committee at Roche. MB reports grants from 10.13039/100000971ALS Association (16-TACL-242 and 17-LGCA-331), 10.13039/100000002NIH (U54-NS092091, R01-NS105479 and U01- NS107027), and 10.13039/100005202Muscular Dystrophy Association (645863). He has received consulting fees from Alector, Biogen, Novartis, Sanofi, UCB, UniQure. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study (UMIP142-A.) In addition, he has a provisional patent pending entitled ‘Determining Onset of Amyotrophic Lateral Sclerosis.’ He serves on the Board of Trustees for the ALS Association (unpaid). CH receives royalty payments through the University of Rochester for copyrighted patient reported outcome measures including one for ALS. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, Neurocrine Biosciences, and the Marigold Foundation. He is scheduled to have travel reimbursement to present at the upcoming Muscle Study Group Meeting. JS, SR, DA, EW, JSW, AV, ND, JH, JW, JC, and PM report no disclosures., (© 2022 The Authors.)

Introduction: Patients with Crohn's disease (CD) experience a variety of symptoms that significantly affect their lives. In this study, we (i) ascertain the most prevalent and impactful symptoms in CD and (ii) identify modifying factors that are associated with a higher disease burden in CD., Methods: We conducted semistructured interviews with adult participants with CD to determine what issues have the greatest impact on their lives. Next, we conducted a large cross-sectional study of individuals with CD to determine the prevalence and relative importance of those symptoms and themes and to identify the demographic features that are associated with a higher disease burden., Results: Sixteen individuals with CD provided 792 direct quotes regarding their symptomatic burden. Four hundred three people with CD participated in our cross-sectional study. The symptomatic themes with the highest prevalence in CD were gastrointestinal issues (93.0%), fatigue (86.4%), dietary restrictions (77.9%), and impaired sleep or daytime sleepiness (75.6%). The symptomatic themes that had the greatest impact on patients' lives (0-4 scale) related to fatigue (1.82), impaired sleep or daytime sleepiness (1.71), gastrointestinal issues (1.66), and dietary restrictions (1.61). Symptomatic theme prevalence was strongly associated with a higher number of soft stools per day, greater number of bowel movements per day, missed work, employment and disability status, and having perianal disease., Discussion: Patients with CD experience numerous symptoms that affect their daily life. These symptoms, some underrecognized, vary based on disease and demographic characteristics and represent potential targets for future therapeutic interventions., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Introduction/aims: Spinal muscular atrophy (SMA) treatment may increase survival and improve physical function among adolescents and young adults. Validated patient-reported outcome measures are needed to understand which treatment benefits are clinically meaningful and to develop targeted resources for this population. To date, use of the SMA Health Index (SMA-HI) in pediatric and young adult populations has been limited. Here, we report results from a survey of adolescents and young adults with SMA to quantifiably understand individuals' perceptions of disease burden., Methods: Participants aged 12-25 y with a self-reported diagnosis of SMA completed an online survey containing demographic questions and the SMA-HI, a patient-reported outcome measure that assesses individuals' perceptions of disease burden in 15 symptomatic areas., Results: Eighty-eight participants completed the survey. Total SMA-HI scores and SMA-HI subscale scores including shoulder and arm function; back, chest, and abdominal function; activity participation; hand and finger strength; swallowing function; gastrointestinal function; respiratory function; mobility and ambulation, and total disease burden were significantly higher (greater disease burden) in patients with poorer motor function and severe SMA. SMA-HI total and subscale scores were generally lower in adolescents (12-17 y old) versus adults (18-25 y old), suggesting a possible progression of symptomatic disease burden over time., Discussion: This study demonstrates the utility of the SMA-HI for measuring clinically relevant disease burden in adolescents and young adults with SMA. This study demonstrates how disease burden varies by age, SMA type, and other demographics., (© 2022 Wiley Periodicals LLC.)

This study determined the frequency and impact of symptoms on quality of life in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: In preparation for upcoming clinical trials involving patients with Crohn's disease (CD), we examine the validity, reliability and usability of the Crohn's Disease-Health Index (CD-HI). The CD-HI is a multifaceted, disease-specific patient reported outcome measure (PROM) designed to measure CD symptomatic disease burden during clinical trials. As promising therapeutic interventions are being tested among CD patients, there is a clear need for researchers to have access to a valid, sensitive, and reliable patient reported outcome tool to track disease burden. This research describes the development and validation of the CD-HI as an efficient mechanism to quantify how CD patients both feel and function., Methods: We conducted semi-structured, qualitative interviews with CD patients to identify potential symptoms of importance in CD. We then conducted a large, cross-sectional survey study with CD patients to identify the prevalence and importance of symptoms identified during the prior interviews. Symptom questions in the first version of the CD-HI were selected based on overall frequency and impact in a large population of CD patients, generalizability, and potential to respond to therapeutic intervention. Questions which measured a similar concept were grouped into subscales using factor analysis. The first version of the CD-HI was beta tested to explore the usability and relevance of the instrument to patients. We then performed test-retest reliability of each question and subscale. Lastly, we determined the internal consistency for each subscale and the overall instrument. The CD-HI is now finalized and available for use in upcoming clinical trials., Results: Sixteen adults with CD participated in semi-structured qualitative interviews, providing 792 quotes regarding the symptomatic burden of CD. Four hundred and three adults with CD completed an online survey to determine the prevalence and relative importance of 148 patient identified symptoms. Questions were selected for the CD-HI based on their prevalence and relative importance to CD patients. Sixteen adults with CD participated in beta interview testing to address the usability and relevance of the instrument. Patients found the CD-HI to be clear, highly relevant, and easy to use. Test-retest reliability was conducted with twenty-three adults with CD, where participants completed the CD-HI at baseline and fourteen days later. One question was removed to optimize the overall reliability of the instrument. The final version of the CD-HI contains subscales that measure the following granular areas of CD health: 1) fatigue; 2) dietary restrictions; 3) gastrointestinal health; 4) sleep and daytime sleepiness; 5) bowel and bladder function; 6) emotional health; 7) joint health; 8) pain; 9) neck and back health; 10) activity participation; 11) social health; and 12) skin health. Total CD disease burden is measured using a weighted composite of these subscale scores., Conclusion: This research successfully demonstrates the ability of the CD-HI to report valid, reliable, and patient-relevant data as a disease-specific PROM. The CD-HI provides researchers and clinicians with an optimal mechanism to record relevant changes in CD health using the patient's perspective., (Copyright © 2021 by The American College of Gastroenterology.)

Patient report outcome measures in Spinal Muscular Atrophy (SMA) represent a potential complement to observer rated scales which can be used to better understand treatment response. We developed, translated and validated an Italian version of the Spinal Muscular Atrophy Health Index (SMAHI), a disease-specific, patient reported outcome measure questionnaire, designed to estimate the patients' perception of disease burden. Test-retest reliability was assessed in 37 patients (16 children aged 12-17 and 21 adults) and was excellent in both cohorts. Internal consistency in an additional 98 patients (24 children, 74 adults) was also excellent (Cronbach's alpha = 0.93 and 0.91 respectively). In children the highest level of disease burden was generated from lower limb dysfunction and fatigue as well as their perception of decreased performance in social situations. Most patients in the adult cohort were sitters and complained of problems with upper limb functions as well as of fatigue. The SMAHI-IT was also able to differentiate between SMA types according to diseases severity. The results of our study demonstrate that the SMAHI can be considered a marker of disease-specific burden in patients with SMA with a high test-retest reliability and internal validity in Italian patients aged 12 and older., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The personal relationships listed below have not in any way influenced the work reported in this paper. Valeria A Sansone provides intellectual and teaching activities for Biogen, Avexis, Roche, Santhera, Sarepta, PTC, Dyne. Alice Pirola has nothing to declare. Andrea Lizio has nothing to declare. Lucia C Greco has nothing to declare. Giorgia Coratti reports consultancy activity for Biogen, Avexis, Roche, Genesis Pharma, Biologix. Jacopo Casiraghi has nothing to declare. Marika Pane provides intellectual, advisory board and teaching activities for Biogen, Avexis, Roche. Maria Carmela Pera reports consultancy activity for Roche. Italiano Cristina has nothing to declare. Sonia Messina has nothing to declare. Susanna Pozzi has nothing to declare. Maria Sframeli has nothing to declare. Adele D'Amico has nothing to declare. Enrico Bertini has nothing to declare. Claudio Bruno provides consultation in scientific Advisory Boards for Avexis, Bioegn, Roche, Sarepta, PTC. Luca Mauro has nothing to declare. Francesca Salmin has nothing to declare. Claudia Stancanelli has nothing to declare. Marina Pedemonte has nothing to declare. Emilio Albamonte has nothing to declare. Christine Izzi has provided consulting to Recursion Pharmaceuticals. Chad Heatwole receives royalties for the use of multiple disease specific instruments. He has provided consultation to Biogen Idec, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Inc., Scholar Rock, and the Marigold Foundation. He receives grant support from Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. Eugenio Mercuri provides intellectual, advisory board and teaching activities for Biogen, Avexis, Roche., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1)., Methods: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months., Results: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants., Conclusions: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period., Classification of Evidence: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months., (© 2020 American Academy of Neurology.)

The Charcot-Marie-Tooth Health Index (CMT-HI) is a disease-specific patient-reported outcome measure measuring overall disease burden in Charcot-Marie-Tooth (CMT) patients, designed for natural history studies and clinical trials in English-speaking affected individuals. We developed and validated its Italian Charcot-Marie-Tooth Health Index (I-CMT-HI) version. The questionnaire was translated and culturally adapted from source into Italian by two neurologists experienced in CMT and neuromuscular disorders (NMDs). The two translations were reviewed by a panel of seven experts in CMT and NMD. The provisional version was back-translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the panel and a patient representative from ACMT-Rete. A series of clinically and genetically characterized CMT patients completed the final questionnaire; 11 participated in a test-retest reliability assessment of the instrument. The I-CMT-HI was administered to 30 CMT patients (13 CMT1A, eight CMTX1, two CMT1B, two CMT1E, two CMT2I, one CMT2A, one CMT2N, one distal Hereditary Motor Neuropathy), with test-rest in 11:14 females and 16 males, aged (mean ± SD) 48.0 ± 16.4 years (range 18-81), with CMT Examination Score (CMTES) = 10.0 ± 4.4 (range 2-18). The I-CMT-HI mean total score was 29.4 ± 21.2 (range 0.1-60.3). The I-CMT-HI showed a high test-retest reliability: intraclass correlation coefficient = 0.95 (95% confidence interval, 0.84-0.99). No patient had difficulty in completing the questionnaire and none reported any problem with the questions' formulation. The total CMT-HI score was positively correlated with age and CMTES, with higher disease burden with increasing age and disease severity according to the CMTES. The I-CMT-HI is now ready for use in clinical studies in the Italian population., (© 2020 Peripheral Nerve Society.)

Objective : Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. Methods : A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments. Specific physical symptoms assessed consisted of fatigue, pain, weakness, shortness of breath, difficulty sleeping, speech problems, depression and other mood changes, and cognitive changes. PALS, caregivers of living patients with ALS (C-LPALS), and caregivers of deceased patients with ALS (C-DPALS) were contacted by email to participate in a 30-minute online survey. Results : 887 PALS, 444 C-LPALS, and 193 C-DPALS responded to the survey. In comparison to PALS, C-LPALS perceived that PALS had significantly higher rates of all surveyed symptoms except for pain and weakness. Caregivers self-reported higher stress levels than PALS ( p  < 0.001). 35% (135/383) of caregivers reported experiencing a devastating or near devastating financial impact of ALS and 64% (247/383) of caregivers felt their own health had worsened. Caregivers were significantly less likely to perceive a positive response to treatment in comparison to PALS ( p  < 0.001). Conclusions : PALS and caregivers report a number of symptoms beyond weakness that affect daily life which may be targets of future interventions. There are opportunities to improve services and care for caregivers to reduce the burden of illness.

Introduction: There is currently little evidence regarding oculopharyngeal muscular dystrophy (OPMD) disease burden reported by patients. In this study we aim to elicit direct patient input regarding OPMD disease burden., Methods: We conducted semistructured interviews with 25 participants with genetically confirmed OPMD and a wide range of disease duration (15 ± 8 years). Using the Framework Technique, themes and categories were then extracted., Results: Analyses revealed 7 themes (physical impact, mental impact, social impact, perception of progression, treatment perceptions, coping strategies, and access to disease information), encompassing 27 categories of OPMD disease burden. The most frequent categories were related to dysphagia, coping strategies for dysphagia, and impaired mobility., Discussion: This study demonstrates the importance of considering, when providing clinical care, the broad range of coping strategies patients use to deal with OPMD symptoms, especially dysphagia, to properly assess limitations and monitor real disease progression., (© 2019 Wiley Periodicals, Inc.)

Introduction: Limb-girdle muscular dystrophy (LGMD) consists of over 30 genetic conditions with varying clinical phenotypes primarily affecting pelvic girdle, shoulder girdle, and other proximal limb muscles. Studies focusing on the physical, mental, and social effects of this disease from the patient's perspective are limited., Methods: Adults with LGMD were interviewed and asked to identify issues that have the greatest impact on their quality of life. Each interview was recorded, transcribed, coded, and analyzed., Results: Participants provided 1385 direct quotes. One hundred sixty-five potential symptoms of importance were identified and grouped into 15 larger themes. The most frequently reported themes included limitations with mobility, difficulty performing activities, social role limitations, and emotional distress., Discussion: There are multiple symptoms that alter the lives of adults with LGMD. These affect their physical, emotional, and social health, and may be amenable to medical intervention., (© 2019 Wiley Periodicals, Inc.)

Introduction: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood., Methods: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis., Results: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes., Discussion: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes., (© 2019 Wiley Periodicals, Inc.)

Objective: To determine the frequency and relative importance of the most meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to identify the demographic and clinical features that are associated with the greatest disease burden in this population., Methods: We performed a cross-sectional study involving 328 participants with FSHD. Collectively, participants reported the prevalence and relative importance of 274 symptoms and 15 symptomatic themes. We assessed the association between symptomatic theme prevalence and participants' age, sex, disease duration, pain level, employment status, and education., Results: Participants answered >48,000 questions regarding their disease burden. The symptomatic themes with the highest prevalence in our sample were problems with shoulders or arms (96.9%), limitations with activities (94.7%), core weakness (93.8%), fatigue (93.8%), limitations with mobility and walking (93.6%), changed body image due to the disease (91.6%), and pain (87.7%). Problems with shoulders and arms and limitations with mobility and walking had the greatest effect on participants' lives. Employment status and the report of pain had the most extensive association with the prevalence of symptoms, with employment being associated with 8 of 15 of the symptomatic themes and pain being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD experienced a similar prevalence of all symptomatic themes., Conclusions: Adults with FSHD experience a variety of symptoms that play an important role in their disease burden. These symptoms have a variable prevalence and importance in the FSHD population and are associated with disease duration, employment status, and pain level., (© 2019 American Academy of Neurology.)

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., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, patient-reported outcome measure. The objective of this study was to translate, evaluate, and validate a Japanese version of the MDHI (MDHI-J)., Methods: We utilized forward and backward translations and qualitative interviews with 11 myotonic dystrophy type 1 (DM1) participants. We subsequently tested the internal consistency, test-retest reliability, concurrent validity against muscle strength, and 3 quality-of-life measures, and the known-groups validity of the MDHI-J with 60 adult patients., Results: The MDHI-J was found to be culturally appropriate, comprehensive, and clinically relevant. The MDHI-J and its subscales had high internal consistency (mean Cronbach's α = 0.91), test-retest reliability (intraclass coefficient 0.678-0.915), and concurrent validity (Spearman's ρ - 0.869 to 0.904). MDHI-J scores were strongly associated with employment, duration of symptoms, and modified Rankin Scale., Discussion: The MDHI-J is suitable and valid to measure patient-reported disease burden in adult Japanese patients with DM1. Muscle Nerve 59:577-577, 2019., (© 2019 Wiley Periodicals, Inc.)

Purpose of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit., Recent Findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations., Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.

Objective: To determine the frequency and relative importance of symptoms experienced by adults with spinal muscular atrophy (SMA) and to identify factors that are associated with a higher burden of disease in this population., Methods: We conducted a cross-sectional study of 359 adults with SMA using the International SMA Patient Registry. Participants provided input regarding 20 symptomatic themes and 207 symptoms that potentially affect adults with SMA. Participants were asked about the relative importance of each symptom, and analysis was conducted to determine how age, sex, SMA type, education, mobility, and employment status relate to symptom prevalence., Results: Limitations with mobility or walking (98.6%) and the inability to do activities (98.6%) were the 2 themes with the highest prevalence in the study sample. Limitation with mobility or walking was the theme that was identified as having the greatest effect on the lives of adults with SMA. Employment status was associated with the prevalence of 4 of 20 themes and a reliance on an assistive device was associated with 7 of 20 themes. The prevalence of breathing difficulties, choking or swallowing difficulties, and communication difficulties differed among those with different SMA types., Conclusions: There are many symptomatic themes that affect the lives of adults with SMA. These themes vary in prevalence and relative importance in the adult SMA population., (© 2018 American Academy of Neurology.)

Introduction: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD)., Methods: Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year., Results: There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning., Discussion: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018., (© 2018 Wiley Periodicals, Inc.)

Objective: The development of a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease is an important step in the preparation for therapeutic trials. This study describes the development of the Charcot-Marie-Tooth Health Index (CMTHI)., Methods: Inherited Neuropathy Consortium Contact Registry participants were queried on the symptoms that most impacted their lives. The CMTHI was developed based on these responses. Factor analysis, assessment of test-retest reliability, known group validity, and patient interviews were utilized to refine the instrument., Results: The final CMTHI contains 18 themes that capture Charcot-Marie-Tooth disease (CMT) burden. The CMTHI has a high internal consistency and test-retest reliability. The CMTHI was able to discriminate between patient groups expected to have different disease burden. The CMTHI was able to discriminate levels of disability as measured by the CMT examination score and the mobility-Disability Severity Index., Interpretation: The CMTHI represents a valid and reliable outcome to assess patient-reported disease burden in CMT. Ann Neurol 2018;84:225-233., (© 2018 American Neurological Association.)

Introduction: Validation studies of disease-specific instruments for myotonic dystrophy type-1 (DM1) are required prior to their global use in clinical trials involving different cultures and countries. Here we translate and culturally adapt the Myotonic Dystrophy Health Index (MDHI), a disease-specific patient-reported outcome (PRO) measure, for a French DM1 population., Methods: Using the International Society for Pharmacoeconomics and Outcomes Research Task Force method for translation and adaptation of PRO questionnaires, we created a French translation of the MDHI. We subsequently tested this instrument in a cohort of French-speaking patients with DM1., Results: The MDHI was forward and back translated and modified by consensus to create the most compatible translation. Cognitive interviews were conducted with 5 patients with DM1 to ensure the usability and understanding of the translation., Discussion: The French version of the MDHI is an optimal translation of the original instrument that is acceptable to native patients and ready for clinical trial use. Muscle Nerve 57: 686-689, 2018., (© 2017 Wiley Periodicals, Inc.)

Introduction: We developed an evaluator-administered functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD-COM) comprising patient-identified areas of functional burden for future clinical trials., Methods: We performed a prospective observational study of 41 patients with FSHD at 2 sites. The FSHD-COM includes functional assessment of the legs, shoulders and arms, trunk, hands, and balance/mobility. We determined the test-retest reliability and convergent validity compared to established FSHD disease metrics., Results: The FSHD-COM demonstrated excellent test-retest reliability (intraclass correlation coefficient [ICC] 0.96; subscale ICC range, 0.90-0.94). Cross-sectional associations between the FSHD-COM and disease duration, clinical severity, and strength were moderate to strong (Pearson correlation coefficient range |0.51-0.92|)., Discussion: The FSHD-COM is a disease-relevant, functional composite outcome measure suitable for future FSHD clinical trials that shows excellent test-retest reliability and cross-sectional associations to disease measures. Future directions include determining multisite reliability, sensitivity to change, and the minimal clinically important change in the FSHD-COM. Muscle Nerve, 2018., (© 2018 Wiley Periodicals, Inc.)

Introduction: When preparing for clinical trials in myotonic dystrophy type-1 (DM1), it is important that researchers develop and identify patient-reported outcome measures with good measurement properties., Methods: Fifty-two DM1 patients enrolled in 2 clinical studies completed the Myotonic Dystrophy Health Index (MDHI), 36-Item Short Form Health Survey (version 2; SF-36v2), Individualized Neuromuscular Quality of Life questionnaire (INQoL), and a questionnaire comparing the relevance, usability, overall preference, and perceived responsiveness of each measure. The associations between instrument scores and physical function, genetic test results, and employment status were examined., Results: The MDHI was preferred over the INQoL in 13 of 13 areas and was preferred over the SF-36v2 in 9 of 13 areas. The MDHI was the only score that was associated with participant employment status, CTG repeat length, and the 3 measurements of clinical function., Discussion: The MDHI correlates well with physical function and is viewed favorably by participants in DM1 clinical studies. Muscle Nerve, 2018., (© 2018 Wiley Periodicals, Inc.)

Congenital muscular dystrophies (CMD) cause progressive muscle weakness resulting in severe motor disabilities. Previous studies focused on the effects of motor disability. Here, we explore other factors affecting health related quality-of-life (HRQOL) in CMD. Qualitative interviews were conducted with participant-parent dyads to identify symptoms having the greatest impact on HRQOL. Symptoms were classified into themes and domains representing physical, mental, social health, and disease specific issues. Social role limitations and specific activity impairment were frequently mentioned. A greater understanding of symptoms impacting HRQOL will provide a framework for improved clinical care and patient centered outcomes as new therapies are developed.

The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, self-reported outcome measure that assesses total disease burden and 17 areas of Myotonic Dystrophy type 1 (DM1) specific health. This study translated the MDHI into Italian and validated the instrument using a cohort of Italian DM1 patients. Italian DM1 patients were interviewed regarding the form and content of the instrument. Thirty-eight DM1 patients were subsequently recruited to test the reliability and concurrent validity of the instrument by serially completing the MDHI and a battery of clinical tests. Lastly, we determined the internal consistency of the Italian MDHI and each of its subscales. The internal consistency was excellent in the total Italian MDHI score and acceptable in all of its subscales; the test-retest reliability was high (intraclass correlation coefficient = 0.95); Italian MDHI total scores and subscales were associated with neuromuscular function, cognitive and social health, respiratory function, and quality of life. Overall, the Italian MDHI is valid and well suited to measure the multi-dimensional aspects of disease burden in Myotonic Dystrophy clinical trials., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Myotonic dystrophy (DM) is an autosomal dominant, repeat expansion, progressive disorder with no drug therapies. Consequently, to better define a regulatory pathway in anticipation of new treatment strategies under investigation, the Myotonic Dystrophy Foundation convened a workshop entitled "Patient-Centered Therapy Development for Myotonic Dystrophy" in September 2015. Participants included representatives from academia, industry, the patient community, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Presenters described the symptom burden of the disease, and existing data on DM biomarkers, endpoints, natural history, and benefit-risk considerations. FDA participants helped clarify the regulatory requirements for new drug treatment approvals and DM-specific issues such as variability, slow progression, and low prevalence. Workshop attendees gained a better understanding of DM and the current status of existing data and tools to support therapeutic drug research and development.

Introduction: In preparation for future clinical trials, we determined the reliability, relationship to measures of disease severity, and consistency across sites of the 6 Minute Walk Test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD)., Methods: Genetically defined and clinically affected FSHD participants at 2 sites performed the 6MWT, the Timed Up and Go, and the 30 foot Go/Timed 10 meter test as measures of mobility using standard procedures., Results: Eight-six participants representing the full range of severity performed the 6MWT. The mean 6MWT distance was 404.3 meters (SD 123.9), with no difference between sites. The 6MWT was reliable (n = 25; intraclass correlation coefficient = 0.99) and demonstrated moderate to strong correlations with lower extremity strength, functional outcomes, and FSHD Clinical Score., Conclusions: The 6MWT is reliable and is associated with other measures of FSHD disease severity. Future directions include assessing its sensitivity to disease progression. Muscle Nerve 55: 333-337, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: Inclusion body myositis (IBM) is the most common form of idiopathic inflammatory myopathy in adults older than 50 years. Few studies have focused on the functional, physical, and social limitations of this disease. This study identifies pertinent symptoms that impact the health and daily function of patients with IBM., Methods: We used semistructured interviews with 10 biopsy-confirmed adults with IBM to identify the psychological, physical, and functional limitations that have the greatest impact on the lives of patients with IBM., Results: Participants with IBM provided 644 direct quotes identifying issues that have the greatest effect on their lives. Two hundred nine individual symptoms and 17 symptomatic themes were identified by patients as having a significant impact on their lives. The symptomatic themes mentioned most frequently involved mobility and ambulation, emotional distress, and activity impairment., Conclusions: Identifying critical issues to patients with IBM is potentially useful for clinicians whose aim is to provide optimal care to patients with IBM.

Introduction: In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD)., Methods: We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared with measures of strength, FSHD disease severity, and functional outcomes., Results: Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics., Conclusions: EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54: 696-701, 2016., (© 2016 Wiley Periodicals, Inc.)

There are multiple symptoms that affect adults with spinal muscular atrophy (SMA). The extent of these symptoms and their impact on individuals' lives is not fully known. We interviewed 15 adults with genetically confirmed SMA. Participants were asked to identify issues that have significant impact on their lives. Interviews were recorded, transcribed, coded, and analyzed. Participants provided 1045 direct quotes. 177 potential symptoms of importance were identified. Symptoms were grouped by like topics into fourteen symptomatic themes. The symptoms and issues identified by SMA patients alter their physical, mental, and social health and may be amendable to therapeutic intervention.

Objective: Herein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood., Methods: Children with CDM and age-matched controls aged 0 to 13 years were enrolled. Participants were divided into cohorts based on the following age groups: 0-2, 3-6, and 7-13 years. Each cohort received age-appropriate evaluations including functional testing, oral facial strength testing, neuropsychological testing, quality-of-life measurements, and ECG. Independent-samples t test or Wilcoxon 2-sample test was used to compare the differences between children with CDM and controls. Probability values less than 0.05 are reported as significant., Results: Forty-one participants with CDM and 29 healthy controls were enrolled. The 6-minute walk was significantly different between CDM (258.3 m [SD 176.0]) and control participants (568.2 m [SD 73.2]). The mean lip force strength was significantly different in CDM (2.1 N [SD 2.8)] compared to control participants (17.8 N [SD 7.6]). In participants with CDM, the mean IQ (65.8; SD 18.4) was 3 SDs below the mean compared to standardized norms. Measurements of grip strength, sleep quality, and quality of life were also significantly different. Strength measures (oral facial strength, grip strength, and 6-minute walk) correlated with each other but not with participant IQ., Conclusions: This work identifies important phenotypes associated with CDM during childhood. Several measures of strength and function were significantly different between participants with CDM and controls and may be useful during future therapeutic trials., (© 2016 American Academy of Neurology.)

Introduction: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1)., Methods: We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures., Results: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures., Conclusions: Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients., (© 2015 Wiley Periodicals, Inc.)

Objective: To determine the frequency and relative importance of the most life-affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms., Methods: We conducted a cross-sectional study of adult patients with DM2 from a National Registry of DM2 Patients to assess the prevalence and relative importance of 310 symptoms and 21 symptomatic themes. Participant responses were compared by age categories, sex, educational attainment, employment status, and duration of symptoms., Results: The symptomatic themes with the highest prevalence in DM2 were the inability to do activities (94.4%), limitations with mobility or walking (89.2%), hip, thigh, or knee weakness (89.2%), fatigue (89.2%), and myotonia (82.6%). Participants identified the inability to do activities and fatigue as the symptomatic themes that have the greatest overall effect on their lives. Unemployment, a longer duration of symptoms, and less education were associated with a higher average prevalence of all symptomatic themes (p < 0.01). Unemployment, a longer duration of symptoms, sex, and increased age were associated with a higher average effect of all symptomatic themes among patients with DM2 (p < 0.01)., Conclusions: The lives of patients with DM2 are affected by a variety of symptoms. These symptoms have different levels of significance and prevalence in this population and vary across DM2 subgroups in different demographic categories., (© 2015 American Academy of Neurology.)

Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence., Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors., Results and Recommendations: Available genetic testing for FSHD type 1 is highly sensitive and specific. Although respiratory insufficiency occurs rarely in FSHD, patients with severe FSHD should have routine pulmonary function testing. Routine cardiac screening is not necessary in patients with FSHD without cardiac symptoms. Symptomatic retinal vascular disease is very rare in FSHD. Exudative retinopathy, however, is potentially preventable, and patients with large deletions should be screened through dilated indirect ophthalmoscopy. The prevalence of clinically relevant hearing loss is not clear. In clinical practice, patients with childhood-onset FSHD may have significant hearing loss. Because undetected hearing loss may impair language development, screening through audiometry is recommended for such patients. Musculoskeletal pain is common in FSHD and treating physicians should routinely inquire about pain. There is at present no effective pharmacologic intervention in FSHD. Available studies suggest that scapular fixation is safe and effective. Surgical scapular fixation might be cautiously offered to selected patients. Aerobic exercise in FSHD appears to be safe and potentially beneficial. On the basis of the evidence, patients with FSHD might be encouraged to engage in low-intensity aerobic exercises., (© 2015 American Academy of Neurology.)

Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI)., Methods: Initially we partnered with 278 myotonic dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test-retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants., Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test-retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities., Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI., (Copyright © 2013 Wiley Periodicals, Inc.)

Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To compare the short-term financial costs of treating a patient in myasthenia gravis crisis with intravenous immunoglobulin (IVIG) versus plasma exchange., Methods: An itemized comparative cost-minimization analysis of IVIG versus plasma exchange for myasthenia gravis crisis was performed. Calculations were based on each therapy's implementation cost, associated hospitalization times, and predicted cost to treat known complications. A cost superiority determination was proposed based on the total cost profile of each therapy., Results: The difference in total cost favored IVIG over plasma exchange with an average savings of $22,326 per patient. Sensitivity analysis demonstrated that overall costs are highly dependent on IVIG dosing, hospital lengths of stay, and the number of plasma exchange days required., Conclusions: The use of IVIG for myasthenia gravis crisis may be a short-term cost minimizing therapy compared with plasma exchange. Additional prospective studies are required to evaluate the extended cost profile and efficacy of these therapies.

Background: Myotonic dystrophy type 2 (DM2) is a recently discovered adult muscular dystrophy. Similar to DM1, this disease causes progressive debilitating weakness, clinical myotonia, and early cataracts and is thought to cause widespread physiologic dysfunction of multiple organ systems., Objective: To analyze and compile the laboratory abnormalities of patients with DM2., Design: Baseline DM2 laboratory data were compiled representing 68 different types of laboratory tests and 1442 total studies., Setting: University medical center., Patients: Eighty-three adults with genetically confirmed or clinically probable DM2 were identified. Of these patients, 49 had documented baseline laboratory screening., Main Outcome Measures: The individual frequencies of abnormal laboratory values in the population with DM2 studied., Results: Of the 1442 studies, results for 359 (24.9%) were outside of their standard reference ranges. Of the 68 types of laboratory tests studied, 43 had values from 15 or more different patients with DM2. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including the levels of creatine kinase, total cholesterol, lactate dehydrogenase, and alanine aminotransferase. In addition, serum levels of IgG were low in 75% of all patients with DM2 tested, and absolute lymphocyte counts were low in 54% of all patients with DM2 tested., Conclusions: There is a high frequency of laboratory abnormalities in patients with DM2. These abnormalities provide insight into the widespread pathologic manifestations of DM2 and may form a basis for clinical monitoring and disease screening.

Mycophenolate mofetil (MMF) has been used to treat myasthenia gravis (MG) for over 10 years. MMF's use in the MG population stems from its theoretical mechanism of action and the medical literature that supports its benefit in MG patients. Recently, two large, double-blinded, placebo-controlled, randomized clinical trials were initiated to study the effectiveness of MMF for MG. One of these studies found no benefit in taking MMF with 20 mg of prednisone as compared to taking prednisone alone, while the other study demonstrated no advantage in taking MMF against placebo during a 36-week prednisone taper. This article critically reviews the medical literature on MMF's use in MG and suggests further research avenues on this topic.