Eduard Gappmaier

Ataluren treatment of patients with nonsense mutation dystrophinopathy

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double‐blind, placebo‐controlled study; males ≥5 years with nm‐dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N = 57); ataluren 20, 20, 40 mg/kg (N = 60); or placebo (N = 57) for 48 weeks. The primary endpoint was change in 6‐Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ = 31.3 meters, post hoc P = 0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm‐dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Muscle Nerve 50: 477–487, 2014

Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort

Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X‐linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with “private” mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55. Hum Mutat 30:1657–1666, 2009.

THE 6-minute walk test and other endpoints in Duchenne muscular dystrophy: Longitudinal natural history observations over 48 weeks from a multicenter study

Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double‐blind, placebo‐controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6‐minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6‐minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand‐held myometry. Results: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. Conclusion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. Muscle Nerve 48: 343–356, 2013

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6‐minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6‐minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013

LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor‐β binding protein 4, was previously discovered in a genome‐wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort.

Clinical and genetic characterization of manifesting carriers of DMD mutations

Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.

Influence of spasticity on mobility and balance in persons with multiple sclerosis.

Background and Purpose: Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes that presumably affects mobility and balance. This investigation examined the hypothesis that persons with multiple sclerosis (MS) who have spasticity of the lower legs would have more impairment of mobility and balance compared to those without spasticity. Methods: Participants were 34 ambulatory persons with a definite diagnosis of MS. The expanded disability status scale (EDSS) was used to characterize disability in the study sample. All participants underwent measurements of spasticity in the gastroc-soleus muscles of both legs (modified Ashworth scale), walking speed (timed 25-foot walk), mobility (Timed Up and Go), walking endurance (6-minute walk test), self-reported impact of MS on walking ability (Multiple Sclerosis Walking Scale-12), and balance (Berg Balance Test and Activities-specific Balance Confidence Scale). Results: Fifteen participants had spasticity of the gastroc-soleus muscles based on modified Ashworth scale scores. The spasticity group had lower median EDSS scores indicating greater disability (P=0.03). Mobility and balance were significantly more impaired in the group with spasticity compared to the group without spasticity: timed 25-foot walk (P = 0.02, d = −0.74), Timed Up and Go (P = 0.01, d = −0.84), 6-minute walk test (P < 0.01, d = 1.03), Multiple Sclerosis Walking Scale-12 (P = 0.04, d = −0.76), Berg Balance Test (P = 0.02, d = −0.84) and Activities-specific Balance Confidence Scale (P = 0.04, d = −0.59). Discussion and Conclusion: Spasticity in the gastroc-soleus muscles appears to have negative effect on mobility and balance in persons with MS. The relationship between spasticity and disability in persons with MS requires further exploration.

Ambulatory Activity in Individuals With Multiple Sclerosis

Background and Purpose: Specific characteristics of physical activity limitations associated with multiple sclerosis (MS) remain unclear. Our purpose was to examine the impact of MS disability on physical activity behaviors involving ambulation. We also explored relationships among ambulatory activity parameters and clinical measures of gait, balance, and fatigue. Methods: Twenty-one adults with MS participated: 11 without ambulatory limitation (Expanded Disability Status Scale [EDSS] score ⩽ 4.5) and 10 with ambulatory limitation (EDSS score > 4.5). Participants wore a step activity monitor for up to 7 days. Daily values were calculated for parameters indicative of (1) overall activity, (2) upper limits of activity output, and (3) activity work-rest cycles. Clinical measures included Multiple Sclerosis Walking Scale, Timed 25-Foot Walk, Timed Up and Go test, 6-Minute Walk, Dynamic Gait Index, Berg Balance Scale, Activities-specific Balance Confidence Scale, and Modified Fatigue Impact Scale. Statistical analyses were conducted using nonparametric tests. Results: Participants without limitation were more active, demonstrated higher upper limits of activity output, and had longer activity bouts than participants with limitation (P < 0.05). Only 1 participant averaged more than 100 steps per minute over a 30-minute period. Of the ambulatory activity parameters, daily step count was most strongly related to gait and balance measures. Of the clinical measures, EDSS and Multiple Sclerosis Walking Scale scores were most strongly related to daily step count. Conclusion: Individuals with MS are not necessarily sedentary, but few may achieve recommended daily physical activity levels. Ambulatory activity characteristics revealed new insights into physical activity limitations in MS. The study findings suggest that disability status should direct physical activity interventions.

Effects of high-intensity resistance training on strength, mobility, balance, and fatigue in individuals with multiple sclerosis: a randomized controlled trial.

Background and Purpose: Resistance exercise via negative, eccentrically induced work (RENEW) has been shown to be associated with improvements in strength, mobility, and balance in multiple clinical populations. However, RENEW has not been reported for individuals with multiple sclerosis (MS). Methods: Nineteen individuals with MS (8 men, 11 women; age mean = 49 ± 11 years; Expanded Disability Status Scale [EDSS] mean = 5.2 ± 0.9) were randomized into either standard exercise (STAND) or standard exercise and RENEW training (RENEW) for 3×/week for 12 weeks. Outcome measures were lower extremity strength (hip/knee flexion and extension, ankle plantar and dorsiflexion, and the sum of these individual values [sum strength]); Timed Up and Go (TUG), 10-m walk, self-selected pace (TMWSS) and maximal-pace (TMWMP), stair ascent (S-A) and descent (S-D) and 6-Minute Walk Test (6MWT), Berg Balance Scale (BBS), Fatigue Severity Scale (FSS). Results: No significant time effects or interactions were observed for strength, TUG, TMWSS, TMWMP, or 6MWT. However, the mean difference in sum strength in the RENEW group was 38.60 (representing a 15% increase) compared to the sum strength observed in the STAND group with a mean difference of 5.58 (a 2% increase). A significant interaction was observed for S-A, S-D, and BBS as the STAND group improved whereas the RENEW group did not improve in these measures. Discussion and Conclusions: Contrary to results in other populations, the addition of eccentric training to standard exercises did not result in significantly greater lower extremity strength gains in this group of individuals with MS. Further this training was not as effective as standard exercise alone in improving balance or the ability to ascend and descend stairs. Following data collection, reassessment of required sample size indicates we were likely underpowered to detect strength differences between groups.

Top 10 research questions related to physical activity and multiple sclerosis

An estimated 2.5 million people worldwide are living with multiple sclerosis (MS), and this disease may be increasing in prevalence. MS is a disease of the central nervous system that is associated with heterogeneous symptoms and functional consequences, and the current first-line disease-modifying therapies often become ineffective later in the disease. There is increasing evidence for the benefits of physical activity (PA) in people with MS, but this population is generally physically inactive and sedentary. We proposed 10 research questions to guide future research on PA and MS: (1) Is PA an MS disease-modifying behavior? (2) What are the benefits of PA among people with MS? (3) What is the optimal PA prescription for people with MS? (4) What are the safety issues with PA in people with MS? (5) What characteristics of people with MS modify the benefits of PA? (6) What variables explain participation in PA among people with MS? (7) What are effective behavioral interventions for PA change in people with MS? (8) How do we translate PA research into clinical MS practice? (9) What is the role of sedentary behavior in people with MS? And (10) what is the optimal measurement of PA in people with MS? These questions are critical for informing our understanding of the short- and long-term consequences of PA in MS as well as for identifying approaches for promoting and sustaining PA in MS. Addressing these questions may greatly improve the lives of people with this chronic disease.