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Hereditary inclusion body myopathy (HIBM) or GNE myopathy is caused by a defect in the biosynthetic pathway for sialic acid. Muscle weakness begins in adulthood in the distal legs and progresses over decades, although the quadriceps remain relatively strong. The objective of this study was to characterize the pattern and extent of weakness, evaluate functional limitations and establish the relationship between strength and function in adults with HIBM. Ambulatory subjects enrolled in a Phase 2 study of extended release sialic acid were evaluated prior to randomization. Assessments included hand-held dynamometry (HHD), manual muscle testing, a six-minute walk test (6MWT), gait speed, sit-to-stand, stair climb and weighted arm lift tests. 47 subjects, 29 females and 18 males, with a mean age of 40years (18–64) were evaluated. Most subjects utilized orthoses (62%) or an assistive device (51%) for walking. Intraclass correlation coefficients for repeat HHD and functional tests ranged from 0.814 to 0.987. Mean individual hip flexor, hip adductor and knee flexor force was ⩽20% of predicted normal and 81% of subjects lacked full anti-gravity dorsiflexion power bilaterally. Knee extensors were the strongest muscle group at 58% of predicted bilaterally. The mean 6MWT distance was 278m, 39% of normal. Knee extensor strength was not a strong predictor of 6MWT distance (r =0.60). A composite measure of lower extremity (LE) strength without knee extensors showed a strong positive relationship to 6MWT distance (r =0.92) and sit-to-stand test repetitions (r =0.82). Composite LE strength of <10kg force was associated with slower 25ft walking speeds and longer stair climb times. All upper extremity (UE) muscle groups were <50% (42–49) of predicted. UE strength by HHD was related to weighted arm lift repetitions (r =0.75). Ambulatory patients with HIBM show profound weakness in a number of muscle groups. HHD results correlated well with volitional measures of physical function. [Copyright &y& Elsevier]

GNE myopathy or hereditary inclusion body myopathy (HIBM) is an autosomal recessive myopathy presenting with distal leg weakness in early adulthood. Progressive weakness results in greater dependence and disability over time. A disease-specific measurement of functional activity is needed to better understand the burden of illness, inform the design of clinical studies and optimize care. After clinical interview of patients, a 25-item questionnaire was developed to assess ability and independence in three domains: mobility, upper extremity (UE) use and self-care. Each item was rated from 0 to 4 with higher scores representing better function. Total scores range from 0 to 100; subscale scores range from 0 to 40 for Mobility, 0–32 for UE and 0–28 for Self-Care. The GNE Myopathy Functional Activity Scale (GNEM-FAS) was administered to 47 ambulatory subjects enrolled in a Phase 2 study of extended release sialic acid. Physical therapists completed the GNEM-FAS based on clinical observation and subject interview. Scores were compared to performance on volitional measures of strength and function, as well as scores on the Inclusion Body Myositis Functional Rating Scale (IBMFRS), a validated instrument for myositis. The mean GNEM-FAS total score was 69 out of 100 (23–94). Mobility subscores averaged 50%, UE, 81% and Self-Care, 82% of the maximum possible. Higher Mobility scores were associated with greater lower extremity strength (r =0.83) and longer 6MWT distances (r =0.83). A moderate association was seen between the UE domain scores and UE strength (r =0.66). Self-care domain scores and the stair climb time were negatively related (r =−0.68). There was a strong correlation between GNEM-FAS total scores and IBMFRS scores (r =0.94). Mobility was limited more than UE or self-care function in this cohort of ambulatory subjects with GNE myopathy. Repeat administration in treated and untreated patients with varying degrees of severity is underway to further validate the instrument. [Copyright &y& Elsevier]

Dysferlin-deficient limb girdle muscular dystrophy (LGMD R2), also referred to as dysferlinopathy, can be associated with respiratory muscle weakness as the disease progresses. Clinical practice guidelines recommend biennial lung function assessments in patients with dysferlinopathy to screen for respiratory impairment. However, lack of universal access to spirometry equipment and trained specialists makes regular monitoring challenging. This study investigated the use of the Performance of Upper Limb (PUL) clinical scale entry item as a low-cost screening tool to identify patients with dysferlinopathy at risk of respiratory impairment. Using data from 193 patients from the Jain Foundation's International Clinical Outcomes Study, modelling identified a significant positive relationship between the PUL entry item and forced vital capacity (FVC). Eighty-eight percent of patients with the lowest PUL entry item score of 1 presented with FVC % predicted values of <60 %, suggestive of respiratory impairment. By contrast, only 10 % of the remainder of the cohort (PUL entry item of 2 or more) had an FVC of <60 %. This relationship also held true when accounting for ambulatory status, age, and sex as possible confounding factors. In summary, our results suggest that the PUL entry item could be implemented in clinical practice to screen for respiratory impairment where spirometry is not readily available., Competing Interests: Declaration of competing interest Apart from the grant from the Jain Foundation that financed the study, there are no relevant conflicts of interest that impact on the paper referenced above., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy., Competing Interests: MJ receives fee support for PhD studies from the Jain Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub.)

Background: Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function., Methods: This is a retrospective analysis of prospectively collected data through the CINRG Duchenne Natural history study (DNHS). The objectives of this analysis are to understand the progression of ankle contractures for individuals with DMD and to investigate the relationship between progressive lower limb contractures, knee strength, and Timed Function Tests.A collection of TFTs including supine to stand (STS), 10 meter walk test (10MWT), and timed stair climbing (4SC) have been used to monitor disease progression and are predictive of loss of ambulation in these patients [4]. Multiple factors contribute to loss of ambulation, including progressive loss of strength and contracture development that leads to changing biomechanical demands for ambulation. A better understanding of the changes in strength and range of motion (ROM) that contribute to loss of function is important in a more individualized rehabilitation management plan. In this longitudinal study, we measured strength using quantitative muscle testing (QMT) with the CINRG Quantitative Measurement System (CQMS)), ROM was measuresed with a goniometer and TFTs were measured using a standard stopwatch and methodology., Results: We enrolled 440 participants; mean baseline age was 8.9 (2.1, 28.0) years with 1321 observations used for analysis. GC use was stratified based on duration on drug with 18.7%at < 6 months or naïve; 4.3%<1 year; 58.0%1 < 10 years; and 19.3%between 10-25 years of GC use. Ankle ROM was better for those on GC compared to GC naive but did not significantly influence long-term progression rates. QMT, ROM, age and GCs contribute to speed of TFTs. Knee extension (KE) strength and Dorsiflexion (DF) ROM are significant predictors of speed for all TFTs (p < 0.001). Of the variables used in this analysis, KE strength is the primary predictor of walking speed, estimating that every pound increase in KE results in a 0.042 m/s improvement in 10MWT, and a smaller similar increase of 0.009 m/s with every degree of ankle DF ROM., Conclusion: GC use provides an improvement in strength and ROM but does not affect rate of change. Knee strength has a greater influence on speed of TFTs than DF ROM, although both are statistically significant predictors of speed. Results show that retaining knee strength [1, 2], along with joint flexibility, may be important factors in the ability to perform walking, climbing and supine to stand activities.

Objective: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., Methods: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., Results: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., Interpretation: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000-10000 [1, 2]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually causes loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change., Objective: The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in standardized time function tests (TFT) used to monitor disease progression in DMD., Method: This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run (10MWT), and 4 stair climb (4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status., Results: All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT (-0.138, -0.212), Supine to Stand (-0.026, -0.023) and 4 stair climb (-0.034, -0.035) with an effect size greater or close to 0.2., Conclusion: The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD.

Objective: To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD)., Methods: An open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity., Results: Oral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy., Conclusions: Daily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study., Classification of Evidence: This study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year., Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis., Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint., Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials., Clinicaltrialsgov Identifier: NCT01676077., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Improved outcome measures are essential to efficiently screen the growing number of potential amyotrophic lateral sclerosis (ALS) therapies., Methods: This longitudinal study of 100 (70 male) participants with ALS compared Accurate Test of Limb Isometric Strength (ATLIS), using a fixed, wireless load cell, with ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC)., Results: Participants enrolled at 5 U.S. sites. Data were analyzed from 66 participants with complete ATLIS, ALSFRS-R, and VC data over at least 3 visits. Change in ATLIS was less variable both within- and among-person than change in ALSFRS-R or VC. Additionally, participants who had normal ALSFRS-R arm and leg function averaged 12 to 32% below expected strength values measured by ATLIS., Conclusions: ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710-715, 2017., (© 2017 Wiley Periodicals, Inc.)

Introduction: The Accurate Test of Limb Isometric Strength (ATLIS) device can reliably measure the strength of 12 muscle groups using a fixed load cell. The purpose of this study was to analyze ATLIS data from healthy adults to calculate an individual's predicted strength scores., Methods: ATLIS data were collected from 432 healthy adults. Linear regression models were developed to predict each muscle group's strength. The R-squared statistic assessed variability accounted for by the models., Results: Simple main effects models stratified by gender were used to establish regression equations for each muscle using factors of age, weight, and height., Conclusions: Normalizing raw strength scores controls for biometric factors, thus enabling meaningful comparisons between subjects and allowing each muscle to contribute equally to a summary score. Normalized scores are easily interpreted for broad clinical uses, and derived summary scores establish individuals' disease progression rates using a common scale, allowing for more efficient clinical trials., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: Acid maltase deficiency (AMD, or Pompe disease) is an inherited myopathic disorder of glycogen degradation. Diagnosis is often delayed. Muscle ultrasound could improve diagnosis., Methods: We compared skeletal muscle ultrasound images from adults with AMD (n = 10) to other myopathies (n = 81) and, in AMD, compared qualitative (Heckmatt) and quantitative (backscatter) ultrasound measurements with strength and function., Results: Qualitative ultrasound was abnormal in at least one muscle in all AMD subjects. Ultrasound patterns specific for AMD were: normal triceps brachii despite abnormalities in elbow flexors (89% vs. 17%, P < 0.0001); focal abnormalities affecting deep more than superficial biceps brachii (40% vs. 4%, P = 0.002); and more severe involvement of vastus intermedius than rectus femoris (40 vs. 11%, P = 0.03). In AMD, both qualitative (Heckmatt) and quantitative (backscatter) ultrasound measures increased with decreasing strength and function., Conclusions: Muscle ultrasound identifies the presence and specific patterns of AMD pathology, measures disease severity, and can help in the diagnosis of AMD., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Obesity exacerbates the age-related decline in physical function and causes frailty in older persons. However, appropriate treatment for obese older persons is unknown. We evaluated the effects of weight loss and exercise therapy on physical function and body composition in obese older persons., Methods: We screened 40 obese older volunteers and eventually randomized 27 frail obese older volunteers to treatment or control groups. Treatment consisted of 6 months of weekly behavioral therapy for weight loss in conjunction with exercise training 3 times per week. Physical function was evaluated with measurements of frailty (Physical Performance Test, peak oxygen consumption, and Functional Status Questionnaire); strength, gait, and balance tests; body composition with dual-energy x-ray absorptiometry; and quality of life using the Medical Outcomes Survey 36-Item Short-Form Health Survey. Results are reported as mean +/- SD., Results: Two subjects in the treatment group did not comply with the intervention, and 1 subject in the control group withdrew. Analyses included all 27 subjects originally randomized to the treatment and control groups. The treatment group lost 8.4% +/- 5.6% of body weight, whereas weight did not change in the control group (+0.5% +/- 2.8%; P<.001). Compared with the control group, fat mass decreased (-6.6 +/- 3.4 vs +1.7 +/- 4.1 kg; P<.001), without a change in fat-free mass (-1.2 +/- 2.1 vs -1.0 +/- 3.5 kg; P = .75) in the treatment group. The Physical Performance Test score (2.6 +/- 2.5 vs 0.1 +/- 1.0; P = .001), peak oxygen consumption (1.7 +/- 1.6 vs 0.3 +/- 1.1 mL/min per kilogram; P = .02), and Functional Status Questionnaire score (2.9 +/- 3.7 vs -0.2 +/- 3.9; P = .02) improved in treated subjects compared with control subjects. Treatment also improved strength, walking speed, obstacle course, 1-leg limb stance time, and health survey physical subscale scores (all P<.05)., Conclusion: These findings suggest that weight loss and exercise can ameliorate frailty in obese older adults. Trial Registration clinicaltrials.gov Identifier: NCT00146133.

Objective: To evaluate the prevalence of frailty and interrelationships among body composition, physical function, and quality of life in community-dwelling obese elderly (OE) persons., Research Methods and Procedures: Fifty-two OE, 52 nonobese frail, and 52 nonobese nonfrail subjects, matched for age and sex, were studied. Subjective and objective measures of functional status were evaluated by using the physical performance test, exercise stress test, lower extremity (LE) strength, gait speed, static and dynamic balance, functional status questionnaires, and health-related quality-of-life questionnaire (Medical Outcomes Short Form). Body composition was evaluated by using DXA, and muscle quality was evaluated by determining the ratio of LE strength to LE lean mass., Results: Among OE subjects, 96% met our standard criteria for mild to moderate frailty. Compared with the nonobese nonfrail group, the OE and nonobese frail groups had lower and similar scores in physical performance test, peak aerobic power, and functional status questionnaire, and exhibited similar impairments in strength, walking speed, balance, and health-related quality of life. Although absolute fat-free mass (FFM) was greater, the percentage body weight as FFM and muscle quality was lower in the OE group than in the other two groups., Discussion: Physical frailty, which predisposes to loss of independence, is common in community-living OE men and women. Physical frailty in OE subjects was associated with low percentage FFM, poor muscle quality, and decreased quality of life. These findings suggest that weight loss therapy may be particularly important in OE persons to improve physical function, in addition to improving the medical complications associated with obesity.