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It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1). First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10-20 ulnar nerve stimuli at 10-50 HZ were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90% and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1 RT was longer for train lengths of 20 stimuli (mean: 9 s in DM1; 0.20 in normals) than for 10 stimuli (mean: 3 s in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups PF increased greatly as stimulus frequency rose from 10-50 HZ but only slightly as train length rose from 10-20 stimuli. Voluntary handgrip RT (mean: 1.9 s) was less than evoked FDI RT (mean: 9 s). In DM1, evoked RT can be "dialed up" by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30-50 HZ may be useful in antimyotonic drug trials, particularly when grip RT is normal or equivocal. [ABSTRACT FROM AUTHOR]

Patients with FSHD can develop scapular winging and loss of ability to raise arm. Reachable workspace (RWS) is able to describe upper extremity (UE) reaching ability. We analyzed data from 175 clinically affected and genetically confirmed adults with FSHD enrolled in the Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study. Our objective was to 1) investigate the relationship between UE reaching ability and muscle strength (using quantitative muscle testing, QMT); and (2) describe how different reaching abilities correspond to patient-reported function at home. There were strong correlations between total relative surface area (i.e., upper extremity reachability in the frontal plane) and UE strength measured by QMT. For each successive 25 % decrease in total relative surface area, there was a corresponding mean 18 % decrease in predicted UE strength and a mean 9-point decrease in the Upper Extremity Functional Index. Individuals that could not reach the right upper medial quadrant reported more difficulty performing various upper extremity activities of daily living and had decreases in the physical function as reported by the PROMIS-57 questionnaire. RWS provides a meaningful measurement of upper extremity strength and function in patients with FSHD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LHW reports consultancy/advisory board for Fulcrum Therapeutics, Avidity, Argenx, and data safety monitoring board for Syneos/Scholar Rock. MNH reports consultancy/advisory board for Fulcrum Therapeutics, Avidity, and Bioniks. MPM reports funding from the National Institutes of Health, US Food and Drug Administration, CureSMA; consultant for Fulcrum Therapeutics, Inc., has served on Data and Safety Monitoring Boards for Eli Lilly and Company, Neurocrine Biosciences Inc., ReveraGen BioPharma, Inc., NS Pharma, Inc., Prilenia, Seelos Therapeutics, Neurocrine Biosciences, Inc. KE has served on advisory boards or has received consulting fees from Biogen, Acceleron, PTC, Ionis Pharmaceuticals, Fulcrum Therapeutics, Dyne Therapeutics, Avidity Biosciences and Roche. RNT reports consultancy with Fulcrum Therapeutics, Arrowhead, Dyne Therapeutics, Acceleron, MT Pharma, miRecule, and Roche Pharma. KRW was an employee of F. Hoffmann-La Roche Ltd. SS reports honoraria from Lupin and Fulcrum Therapeutics, support for travel from UCB, Sanofi, and Fulcrum Therapeutics; participation on Data and Safety Monitoring Boards for UCB, Sanofi, Amicus. KM reports consultancy for Avidity Biosciences. PS has served as consultant for Sarepta, Genentech, Biogen, Alexion, Argenx, UCB, Sanofi, Prizer; served on speakers’ bureaus for CSL Behring, Grifols, Alexion, Biogen, Genentech, Argenx, Catalyst, UCB, Novartis; served on Data and Safety Monitoring Boards for Taysha, Exicison, Encoded. BE received research funding from Biogen, Genentech, Alexion, Pharnext, Avidity, NMD Pharma, and Viela Bio and served as a consultant for Biogen, Genentech, and Argenx. RJB reports consultancy/advisory board for Aavanti Bio, Scholar Rock, Avexis, Pfizer, Reata, and Sarepta Therapeutics. NEJ receives royalties from the CCMDHI and the CMTHI; receives research funds from Dyne, AveXis, Takeda, Sanofi Genzyme, Pepgen, Vertex Pharmaceuticals, Fulcrum Therapeutics, Sarepta, and AskBio; has provided consultation for Takeda, Pepgen, Arthex, AveXis, AMO Pharma, Fulcrum Therapeutics, Dyne, Avidity, and Vertex Pharmaceuticals. VAS reports consulting fees from Avidity biosciences and Dyne Therapeutics. JJH reports consultancy/advisory board for Fulcrum Therapeutics, Avidity Biosciences, Sanofi, and Bioniks. JS has served as consultant for Arrowhead, ML Bio, MT Pharma, Epic Bio, Armatus; served on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics, Avidity, Fulcrum Therapeutics, Roche., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The severity of spinal muscular atrophy (SMA) is inversely correlated with the number of survival of motor neuron 2 (SMN2) copies an individual has. This observational, retrospective analysis of natural history data included untreated individuals with a genetic diagnosis of types 1-3 SMA and stratified disease-related characteristics by SMN2 copy number. The outcomes investigated were time to: death, permanent ventilation, respiratory support, feeding support, scoliosis surgery, and achievement and loss of motor milestones. Of 134 individuals; 33 had two SMN2 copies and 101 had 3 or more copies. Survival was linked to increasing SMN2 copy number: mean age at death for individuals with two SMN2 copies was 8 months (standard deviation [SD]: 4 months) and 10 years (SD: 5 months) for individuals with three copies, and no deaths were reported in individuals with ≥4 SMN2 copies. Increasing SMN2 copy number was linked to a longer time to permanent ventilation, respiratory support, feeding support, and scoliosis, as well as loss of motor milestones. SMA disease-related endpoints showed distinct patterns between groups with differing SMN2 copy numbers. Prediction and assessment of disease progression may be stratified by SMN2 copy number, which will be important for evaluating the impact of treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CSS, SS, AS, CK, RSS, KG, and TMK are employees of F. Hoffmann-La Roche Ltd and hold stock options in F. Hoffmann-La Roche Ltd. VAR was an employee of F. Hoffmann-La Roche Ltd during study conduct. CJG is an employee of Genentech Inc. (a member of the Roche Group) and holds stock in F. Hoffmann-La Roche Ltd. DCD and WBM have no interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Clinical trials in Duchenne muscular dystrophy (DMD) require 3-6 months of stable glucocorticoids, and the primary outcome is explored at 48-52 weeks. The factors that influence the clinical outcome assessment (COA) trajectories soon after glucocorticoid initiation are relevant for the design and analysis of clinical trials of novel drugs. We describe early COA trajectories, associated factors, and the time from glucocorticoid initiation to COA peak., Methods: This was a prospective 18-month analysis of the Finding the Optimum Corticosteroid Regimen for Duchenne Muscular Dystrophy study. Four COAs were investigated: rise from supine velocity (RFV), 10-meter walk/run velocity (10MWRV), North Star Ambulatory Assessment (NSAA) total score, and 6-minute walk test distance (6MWT). The relationships of baseline age (4-5 vs 6-7 years), COA baseline performance, genotype, and glucocorticoid regimen (daily vs intermittent) with the COA trajectories were evaluated using linear mixed-effects models., Results: One hundred ninety-six glucocorticoid-naïve boys with DMD aged 4-7 years were enrolled. The mean age at baseline was 5.9 ± 1.0 years, 66% (n = 130) were on daily regimens, 55% (n = 107) showed a 6MWT distance >330 metres; 41% (n = 78) showed RFV >0.2 rise/s; 76% (n = 149) showed 10MWRV >0.142 10m/s, and 41.0% (n = 79) showed NSAA total score >22 points. Mean COA trajectories differed by age at glucocorticoid initiation ( p < 0.01 for RFV, 10MWRV, and NSAA; p < 0.05 for 6MWT) and regimen ( p < 0.01 for RFV, 10MWRV, and NSAA). Boys younger than 6 years reached their peak performance 12-18 months after glucocorticoid initiation. Boys aged 6 years or older on a daily regimen peaked between months 9 and 12 and those on an intermittent regimen by 9 months. The baseline COA performance was associated with the NSAA ( p < 0.01) and the 6MWT trajectory in boys younger than 6 years on a daily regimen ( p < 0.01). Differences in the mean trajectories by genotype were not significant., Discussion: Glucocorticoid regimen, age, duration of glucocorticoid exposure, and baseline COA performance need to be considered in the design and analysis of clinical trials in young boys with DMD.

Aim: To investigate functional motor performance in a large cohort of young steroid-naïve males with Duchenne muscular dystrophy (DMD) and typically developing males, and to develop specific reference curves for both groups. Also, to describe associations between anthropometric values and functional motor outcomes., Method: Cross-sectional data of 196 steroid-naïve males with DMD aged 4 to 8 years and 497 typically developing males aged 2 years 6 months to 8 years were included. Both groups were evaluated with the time to rise from the floor test, 10-metre walk/run test, 6-minute walk test, and North Star Ambulatory Assessment. Reference curves with centiles 5%, 10%, 25%, 50%, 75%, 90%, and 95% were estimated using quantile regression., Results: Males with DMD scored significantly worse on all functional motor outcomes than age-matched typically developing males (p < 0.001): 89% to 95% of the males with DMD scored below the 5th centile of the typically developing males. No or weak correlations exist between anthropometric values and functional motor outcomes., Interpretation: The estimated reference curves can support consultation with families of young males with DMD and can support the evaluation of treatment for reaching motor skills and functional motor outcomes compared with typically developing males., (© 2023 Mac Keith Press.)

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD., Competing Interests: Declaration of Competing Interest LHW reports consultancy/advisory board for Fulcrum Therapeutics, Argenx, Avidity, Ultragenyx, PepGen, data safety monitoring board for Scholar Rock. KE has served on advisory boards or has received consulting fees from Biogen, Acceleron, PTC, Ionis Pharmaceuticals, Fulcrum Therapeutics, Dyne Therapeutics, Avidity Biosciences and Roche. RNT reports consultancy with Fulcrum Therapeutics, Arrowhead, Dyne Therapeutics, Acceleron, MT Pharma, miRecule, and Roche Pharma. JS has served as consultant for Arrowhead, ML Bio, MT Pharma, Epic Bio, Armatus; served on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics, Avidity, Fulcrum Therapeutics, Roche. PS has served as consultant for Sarepta, Genentech, Biogen, Alexion, Argenx, UCB; served on speakers’ bureaus for CSL Behring, Grifols, Alexion, Biogen, Genentech, Argenx, Catalyst. KRW is an employee of F. Hoffmann-La Roche Ltd. BE received research funding from Biogen, Genentech, Alexion, Pharnext, and Viela Bio and served as a consultant for Biogen, Genentech, and Argenx. NJ has received grant funding from NINDS (R01NS104010), NCATS (21TR003184), CDC (U01DD001242–02) and the FDA (7R01FD006071–02). He receives royalties from the CCMDHI and the CMTHI; receives research funds from Dyne, AveXis, Takeda, Sanofi Genzyme, Pepgen, Vertex Pharmaceuticals, Fulcrum Therapeutics, Sarepta, and AskBio; has provided consultation for Takeda, Pepgen, Arthex, AveXis, AMO Pharma, Fulcrum Therapeutics, Dyne, Avidity, and Vertex Pharmaceuticals. KM reports consultancy for Avidity Biosciences. RJB reports consultancy/advisory board for Aavanti Bio, Scholar Rock, Avexis, Pfizer, Reata, and Sarepta Therapeutics. SLO, MRP, MD have no disclosures., (Copyright © 2023. Published by Elsevier B.V.)

Introduction/aims: Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex., Methods: We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death., Results: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01)., Discussion: Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2., (© 2022 Wiley Periodicals LLC.)

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage., Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy., Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019)., Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66)., Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017., Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%])., Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy., Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Background and Objectives: Duchenne muscular dystrophy (DMD) is a pediatric neuromuscular disorder caused by mutations in the dystrophin gene. Genotype-phenotype associations have been examined in glucocorticoid-treated boys, but there are few data on the young glucocorticoid-naive DMD population. A sample of young glucocorticoid-naive DMD boys is described, and genotype-phenotype associations are investigated., Methods: Screening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD) study, an international, multicenter, randomized, double-blind, clinical trial comparing 3 glucocorticoid regimens in glucocorticoid-naive, genetically confirmed boys with DMD between 4 and <8 years of age., Results: One hundred ninety-six boys were recruited. The mean ± SD age at randomization was 5.8 ± 1.0 years. The predominant mutation type was out-of-frame deletions (67.4%, 130 of 193), of which 68.5% (89 of 130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping (13.0%, 25 of 193). Stop codon mutations accounted for 10.4% (20 of 193). The mean age at first parental concerns was 29.8 ± 18.7 months; the mean age at genetic diagnosis was 53.9 ± 21.9 months; and the mean diagnostic delay was 25.9 ± 18.2 months. The mean diagnostic delay for boys diagnosed after an incidental finding of isolated hyperCKemia (n = 19) was 6.4 ± 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 ± 4.2 and 29.0 ± 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with exon 8 skippable deletions, who had better performance on time to walk/run 10 m ( p = 0.02) compared to boys with deletions not amenable to skipping., Discussion: This study describes clinical and genetic characteristics of a sample of young glucocorticoid-naive boys with DMD. A low threshold for creatine kinase testing can lead to an earlier diagnosis. Motor and speech delays were common presenting symptoms. The effects of low pretreatment height on growth and adult height require further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials . TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01603407., (© 2021 American Academy of Neurology.)

Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors., 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA., Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models., Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events., Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA., Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: The purpose of this study was to examine the psychometric properties of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) in children and youth with Spinal Muscular Atrophy (SMA)., Methods: In this prospective cross-sectional study, caregivers of children and youth with SMA completed the PEDI-CAT Daily Activities and Mobility domains. A subset of caregivers completed a questionnaire about the measure., Results: Mean ranks of scaled scores for Daily Activities (n = 96) and Mobility (n = 95) domains were significantly different across the three SMA types and across the three motor classifications. Normative scores indicated that 85 participants (89.5%) had limitations in Mobility and 51 in Daily Activities (53.1%). Floor effects were observed in≤10.4% of the sample for Daily Activities and Mobility. On average, caregivers completed the Mobility domain in 5.4 minutes and the Daily Activities domain in 3.3 minutes. Most caregivers reported that they provided meaningful information (92.1%), were willing to use the PEDI-CAT format again (79%), and suggested adding content including power wheelchair mobility items., Conclusion: Convergent validity was demonstrated for the Daily Activities and Mobility domains. Normative scores detected limitations in Mobility and Daily Activity performance for most participants with SMA. The PEDI-CATwas feasible to administer and caregivers expressed willingness to complete the PEDI-CAT in the future.

Introduction: Loss of ambulation in Duchenne muscular dystrophy presages scoliosis, respiratory failure, and death. Strategies to maintain ankle range of motion are employed, but little evidence exists to support these approaches and limited information is available concerning current practice., Methods: In this study we assessed baseline bracing data from 187 boys participating in a multicenter, international clinical trial., Results: Ankle-foot orthoses (AFOs) were recommended for 54% of the boys, with nighttime static AFOs and nighttime dynamic AFOs utilized in 94% and 6% of these boys, respectively. Daytime static AFOs were recommended for 3 boys. Compliance with bracing recommendations was 54% for nighttime static braces and 67% for nighttime dynamic braces., Discussion: The basis for the variation in recommended AFO use is unknown and requires further study. Long-term follow-up of boys may permit assessment of the effects of AFO use., (© 2019 Wiley Periodicals, Inc.)

Introduction: Recent evidence demonstrates that women with myotonic dystrophy type 1 are at increased risk of reproductive organ tumors. However, studies of reproductive cancer risk factors in those patients are lacking. Methods: Using questionnaires, we collected and analyzed personal history information related to cancer risk factors from women enrolled in a UK and US registry for myotonic dystrophy ( dystrophia myotonica ; DM) patients. Results: The survey was completed by 242 DM type 1 (DM1) and 44 DM type 2 (DM2) women enrolled in the UK Registry ( N = 124) and the US National Registry ( N = 162). The mean age at DM1 diagnosis was 33.8 years (standard deviation, SD = 13.2) and for DM2 was 49.2 ( SD = 13.0). Mean age at survey was 48.7 ( SD = 12.8) and 59.1 years ( SD = 12.8) for DM1 and DM2, respectively. There were no statistically significant differences between DM1 and DM2 regarding menstrual history or fertility-related factors. Yet, women with DM2 were more likely to have used menopausal hormone therapy (HT) than women with DM1 (52.3 vs. 22.1%, p < 0.0001), and more women with DM2 had a hysterectomy (53.5 vs. 29.5%, p < 0.01). These differences were not statistically significant after age adjustment ( OR = 2.00, p = 0.08, and OR = 1.40, p = 0.38, respectively). The frequency of self-reported reproductive organ tumors was not significantly different comparing DM1 to DM2 ( p = 0.28). However, the data suggested that women with DM2 appear to have a lower risk of malignant tumors compared to those with DM1 ( OR = 0.72, p = 0.69). Discussion: Our study is the first to characterize a wide range of reproductive risk factors in women with DM. We observed no significant differences between DM1 and DM2 in the factors that were evaluated, which suggests that the known excesses of ovarian and endometrial cancer previously reported in women with DM1 cannot be attributed to greater prevalence of standard cancer-related reproductive risk factors. Larger studies evaluating the possible link between reproductive cancer risk factors and risk of tumors in women with DM are needed., (Copyright © 2019 Higgs, Hilbert, Wood, Martens, Marini-Bettolo, Nikolenko, Alsaggaf, Lochmüller, Moxley, Greene, Wang and Gadalla.)

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.)

Background and Purpose: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1., Method: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering., Results: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk., Conclusion: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance., (© 2018 EAN. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

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.)

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013., Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies., Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients., Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

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.)

Objective: To analyze gastrointestinal (GI) manifestations, their progression over time, and medications being used to treat GI symptoms in a large cohort of patients with myotonic dystrophy types 1 (DM1) and 2 (DM2)., Methods: We analyzed patient-reported data and medical records in a national registry cohort at baseline and 5 years., Results: At baseline, the majority of patients reported trouble swallowing in DM1 (55%; n = 499 of 913) and constipation in DM2 (53%; n = 96 of 180). Cholecystectomy occurred in 16.5% of patients with DM1 and 12.8% of patients with DM2, on average before 45 years of age. The use of medications indicated for gastroesophageal reflux disease was reported by 22.5% of DM1 and 18.9% of patients with DM2. Greater risk of a GI manifestation was associated with higher body mass index and longer disease duration in DM1 and female sex in DM2. At the 5-year follow-up, the most common new manifestations were trouble swallowing in patients with DM1 and constipation in patients with DM2., Conclusions: GI manifestations were common in both DM1 and DM2, with a relatively high frequency of gallbladder removal in DM1 and DM2 occurring at a younger age compared to normative data in the literature. Studies are needed to determine the pathomechanism of how sex, weight gain, and duration of disease contribute to GI manifestations and how these manifestations affect quality of life and clinical care for patients with DM1 and DM2., (© 2017 American Academy of Neurology.)

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments., (Copyright © 2017. Published by Elsevier Inc.)

Background and Purpose: Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined., Method: Information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure were collected from 266 DM patients who were enrolled in the US National Institutes of Health National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members., Results: Seventy-seven subjects reported having skin tumors that were either benign (n = 31), malignant (n = 32) or both (n = 14). Female gender [odds ratio (OR) = 2.27, 95% confidence interval (CI) 1.02-5.05, P = 0.04], older age (OR = 1.10, 95% CI 1.05-1.16, P < 0.001) and DM1 subtype (OR = 3.42, 95% CI 1.27-9.26, P = 0.02) were associated with a malignant skin tumor. The associations between malignant skin tumors and known risk factors [light eye color (OR = 1.62, 95% CI 0.78-3.39, P = 0.20), light skin complexion (OR = 1.31, 95% CI 0.63-2.73, P = 0.48) and moderate/extensive face freckles (OR = 1.47, 95% CI 0.50-4.34, P = 0.49)] were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR = 4.28, 95% CI 0.91-19.95, P = 0.06, and OR = 2.19, 95% CI 0.67-7.09, P = 0.19, for sunburn with and without blistering, respectively)., Conclusions: Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. It is recommended that DM patients adhere to sun exposure protective behavior., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Introduction: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA)., Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types., Results: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types., Conclusions: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016., (© 2016 Wiley Periodicals, Inc.)

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.)

Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA)., Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores., Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component., Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients., (© 2015 Wiley Periodicals, Inc.)

Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I)., Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered., Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02)., Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design., (© 2014 American Academy of Neurology.)

The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.

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.)

Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS)., Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores., Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures., Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

Introduction: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials., Methods: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods., Results: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning., Conclusion: QMA is an automated, non-invasive technique for evaluating myotonia in NDM., (Copyright © 2012 Wiley Periodicals, Inc.)

Patients with myotonic dystrophy (DM) have recently been reported to be at increased risk of tumor development, but clinical associations related to this observation are unknown. We calculated the odds ratios (ORs) and 95 % confidence intervals (CI) of self-reported tumor development by patients' demographic and clinical characteristics to evaluate factors associated with tumor development in DM patients, using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members. Of the 911 participants, 47.5 % were male and 85.7 % had DM type 1 (DM1). Compared to DM1, patients with DM type 2 (DM2) were older at registry enrollment (median age 55 vs. 44 years, p < 0.0001) and at DM diagnosis (median age 48 vs. 30 years, p < 0.0001); and more likely to be females (p = 0.001). At enrollment, 95 (10.4 %) DM patients reported a history of benign or malignant tumor. Tumors were associated with female gender (OR 1.9, 95 % CI 1.2-3.1, p = 0.007) and DM1 (OR 2.1, 95 % CI 1.1-4.1, p = 0.03). In a subgroup analysis of patients with blood-based DNA testing results (397 DM1, 54 DM2), repeat expansion size was not associated with tumor risk in DM1 (p = 0.26) or DM2 (p = 0.34). In conclusion, female gender and DM1 subtype, but not DNA repeat expansion size, were associated with increased risk of tumors in DM. Follow-up studies are warranted to determine if oncogenes associated with dystrophia myotonica-protein kinase are altered in DM, and to determine if repeat expansion size, as in our study, is not associated with tumor development.

Introduction: Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally., Methods: The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies., Results: To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease., Conclusions: Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The relationships between the Expanded Hammersmith Functional Motor Scale (HFMSE) and genotype and motor and respiratory outcomes were examined in patients with spinal muscular atrophy types II and III (n = 70). The correlation between the HFMSE and Gross Motor Function Measure was r = 0.98. Correlations between HFMSE and forced vital capacity (percentage of predicted normal) (n = 56) and a functional rating (n = 57) were r = 0.87 and r = 0.92, respectively. Correlations with strength were as follows: knee extension, r = 0.74 (n = 60); elbow flexion, r = 0.77 (n = 61); and knee flexion, r = 0.74 (n = 58). The HFMSE differentiated patients by SMN2 copy number (P = .0007); bi-level positive airway pressure use, <8 versus ≥8 hours/day (P < .0001); ambulatory status (P < .0001); and spinal muscular atrophy type (P < .0001). The HFMSE demonstrates significant associations with established measures of function, strength, and genotype, and discriminates patients based on function, diagnostic category, and bi-level positive airway pressure need. Time of administration averaged 12 minutes. The HFMSE is a valid, time-efficient outcome measure for clinical trials in spinal muscular atrophy types II and III.

Objective: To evaluate the safety and tolerability of recombinant human insulin-like growth factor 1 (rhIGF-1) complexed with IGF binding protein 3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1)., Design: Open-label dose-escalation clinical trial., Setting: University medical center., Participants: Fifteen moderately affected ambulatory participants with genetically proven myotonic dystrophy type 1., Intervention: Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 for 24 weeks followed by a 16-week washout period., Main Outcome Measures: Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks receiving rhIGF-1/ rhIGFBP-3 treatment., Results: All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual-energy x-ray absorptiometry increased by 1.95 kg (P < .001) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (P = .002), a mean increase in HDL levels of 5.0 mg/dL (P = .03), a mean reduction in hemoglobin A(1c) levels of 0.15% (P = .03), and a mean increase in testosterone level (in men) of 203 ng/dL (P = .002) while taking rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (9 participants), as did mild transient hypoglycemia (3), lightheadedness (2), and transient papilledema (1)., Conclusions: Treatment with rhIGF-1/rhIGFBP-3 was generally well tolerated in patients with myotonic dystrophy type 1. Treatment with rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvement in metabolism but not increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease., Trial Registration: clinicaltrials.gov Identifier: NCT00233519.

Purpose: To develop and evaluate an expanded version of the Hammersmith Functional Motor Scale allowing for evaluation of ambulatory SMA patients., Procedures: Thirty-eight patients with SMA type II or III were evaluated using the Gross Motor Function Measure and the Hammersmith Functional Motor Scale. Based on statistical and clinical criteria, we selected 13 Gross Motor Function Measure items to develop an expanded HFMS. The expanded Hammersmith Functional Motor Scale was validated by comparison with the Gross Motor Function Measure minus the 13 items (GMFM-75) and an assessment of clinical function. The reliability of the expanded Hammersmith Functional Motor Scale in 36 patients was established., Findings: The expanded Hammersmith Functional Motor Scale was highly correlated with the GMFM-75 and the clinical function assessment (p=0.97, and p=0.90). The expanded Hammersmith Functional Motor Scale showed excellent test-retest reliability (International Coordinating Committee = 0.99)., Conclusions: The expanded Hammersmith Functional Motor Scale allows assessment of high functioning SMA type II and III patients. Ease of administration and correlation with established motor function measures justify use in future SMA clinical trials.

The aim of this study was to develop a reliable, sensitive, quantitative measure of grip myotonia and strength and to determine whether CTG repeat length is correlated with grip myotonia and with muscle strength in myotonic dystrophy type 1 (DM1). Three maximum voluntary isometric contractions (MVICs) of the finger flexors (i.e., handgrip) were recorded on 2 successive days using a computerized handgrip myometer in 29 genetically confirmed DM1 patients and 17 normals. An automated computer program calculated MVIC peak force (PF) and relaxation times (RTs) along the declining (relaxation) phase of the force recordings at 90%, 75%, 50%, 10%, and 5% of PF. Patients also underwent quantitative strength testing (QST) manual muscle testing (MMT). The patients had longer grip RTs and lower PFs than normals. RT (90% to 5%) was above the normal mean +2.5 SD in 25 (86%) patients. In DM1, prolongation of RT was mainly in the terminal (50% to 5%), rather than the initial (90% to 50%) phase of relaxation. PFs and RTs for each patient were reproducible on consecutive days. RTs were positively correlated with leukocyte CTG repeat length, whereas measures of muscle strength, such as PF, QST, and MMT, were negatively correlated with repeat length. We conclude that computerized handgrip myometry provides a sensitive, reliable measure of myotonia and strength in DM1 and offers a method to assess natural history and response to treatment.

To quantitate improvement in hand-grip myotonia and muscle strength (i.e., the "warm-up" phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand-grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm-up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm-up = 0). In DM1, 70% of warm-up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm-up was highly correlated with the severity of myotonia, and with day 2 warm-up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm-up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm-up in force output.

Objective: To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1)., Methods: First dorsal interosseous twitch and tetanic contractions evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points., Results: Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length., Conclusions: In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.

This article describes the development of a computerized health maintenance tracking system for primary care practice and its features. Research has shown existing computerized health maintenance tracking systems are unsatisfactory for the average practitioner for these reasons: (1) Data entry is slow or requires duplication of entries for billing purposes; (2) the system is linked to a totally computerized medical record that is expensive and complex to maintain; (3) health maintenance status options are limited to "YES/NO" and do not inform the practitioner of the full range of possible situations; (4) physician reminders are created only for patients with an appointment; (5) patient reminders are not generated on a regular basis regardless of appointment status; (6) it is difficult to change individual and global health maintenance schedules. The system described here downloads demographic and health maintenance data from the practice's billing system. Six health maintenance status options are available: D = done and normal, X = done but abnormal, N = not indicated, R = patient refused, E = done elsewhere, I = abnormal but inactive. A health maintenance status report is created for both the patient and provider once a year, in the month of the patient's birth unless an alternate month has been designated, regardless of the patient's appointment status. Patients are encouraged to make an appointment for overdue health maintenance procedures, unless already scheduled.