- Email: [email protected]
Early scoliosis surgery may prevent deterioration of respiratory function in Ullrich congenital muscular dystrophy
S264
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
controlled, multi-center, 48-week study will evaluate the effects of the two PMOs on ambulation, endurance and muscle function measured by the 6-Minute Walk Test (6MWT). Secondary endpoints will evaluate restoration of dystrophin in muscle tissue and respiratory muscle function as measured by pulmonary function tests (PFT). Patients (n = 99) will be randomized by genotype 2:1 to active-treatment (SRP-4045 or SRP-4053) or placebo. All patients will undergo a muscle biopsy at baseline and at either Week 24 or 48. Safety assessments will include adverse event monitoring, ECG, ECHO, and safety laboratory tests. The primary analysis of clinical outcomes will be based on the combined population receiving either drug compared to the placebo population. The study design highlights a novel approach in combining two exon-skipping drug candidates (SRP-4045 and SRP-4053) within a single trial. This is important for future exon skipping therapies in DMD as they will target increasingly smaller patientpopulations, making it difficult to conduct separate, well-powered clinical trials for each compound. http://dx.doi.org/10.1016/j.nmd.2015.06.283
G.P.260 Are effects of Translarna (Ataluren) on muscle strength more discernible in younger patients with Duchenne muscular dystrophy (DMD)? C. McDonald 1, A. Reha 2, G. Elfring 2, P. Trifilis *,2, S. Park 2, T. Ong 2, S. Peltz 2, R. Spiegel 2, Ataluren DMD Study Group 2 1 University of California, School of Medicine, Davis, CA, USA; 2 PTC Therapeutics, South Plainfield, NJ, USA Emergent DMD natural history data indicate that younger patients (<7 years old) experience substantial decreases in muscle strength but little change in muscle function over a 1-year period. Patients ≥7 years old, however, show substantial decreases in muscle function but little change in muscle strength. These observations suggest that assessing muscle strength may be more useful as an outcome measure in younger patients. As a part of a phase 2b, randomized double-blind, placebo-controlled study of Ataluren, change in muscle strength was assessed by hand-held dynamometry over 48 weeks in ambulatory males ≥5 years old with nonsense mutation DMD. Data were analyzed by age <7 or ≥7 years. Muscle groups evaluated were knee extension, knee flexion, elbow extension, elbow flexion, and shoulder abduction. Bilateral values were averaged. Screening and baseline values taken 6 weeks apart were used to determine test–retest reliability. Patients <7 years old included 14 patients randomized to placebo and 9 randomized to Ataluren 40 mg/kg/day. Mean changes were −1.05 lbs for placebo vs 0.42 lbs for Ataluren in knee extension, 0.12 vs 0.10 lbs in knee flexion, −0.90 lbs vs 0.31 lbs in elbow extension, −0.39 lbs vs 1.07 lbs in elbow flexion, and 0.00 lbs vs 0.50 lbs in shoulder abduction. Test–retest reliability was highest for knee extension (r = .84). With emergent natural history data elucidating the course of the disease, selection of endpoints appropriate for the age range of the study population is critical in DMD. Muscle strength is lost predominantly during the early stages of DMD. In younger patients, therefore, it is possible to demonstrate a treatment effect of preservation of muscle strength. In the most reliable myometry parameter in younger patients, knee extension, a difference of 1.47 lbs favoring Ataluren vs placebo was observed. In older patients, floor effects preclude detection of a treatment effect of muscle strength stabilization. http://dx.doi.org/10.1016/j.nmd.2015.06.284
CONGENITAL MUSCULAR DYSTROPHIES G.P.261 The application of antisense oligonucleotide therapy in collagen 6-related congenital muscular dystrophy H. Zhou *, E. Marrosu, F. Muntoni University College London, Dubowitz Neuromuscular Centre, London, UK
The severe collagen VI-related congenital muscular dystrophy (CMD) variant, known as Ullrich CMD (UCMD), is caused by either recessive or dominant mutations in one of the three collagen 6 genes (COL6A1, COL6A2 and COL6A3). The fact that 50% of mutations are de-novo dominant, and that haploinsufficiency is not associated with clinical phenotypes in collagen 6 genes, provides the theoretical basis for using antisense oligonucleotide (AON) to selectively silence the mutant allele as a therapeutic strategy. In this study, we have been focusing on developing allele-specific silencing therapeutic approach by using the RNase H cleavage strategy. Three skin fibroblast cell lines from UCMD patients carrying dominant mutations in Collagen 6A1, A2 and A3 genes are used as cellular model in this study. AONs are synthesized in various chemical modifications and in different length. Over 20 candidate AONs have been analysed with different design approaches and chemical modifications, including morpholino, 2′-O-Methyl, locked nucleic acid and 2-deoxy-2′-fluoro-b-D-arabinonucleic acid and phosphorothiate DNA chimeras. The efficacy is assessed by allele-specific reverse transcript PCR. So far two antisense sequences targeting COL6A1 and A3 have been identified in efficiently suppressing the mutant alleles. Functional analysis using immunohistochemistry shows that the characteristic intracellular collagen VI accumulation in some UCMD fibroblast cell lines can be dramatically reduced after efficacious AON treatment and is accompanied with increased extracellular matrix collagen VI expression. Quantitative analysis of collagen VI extracellular matrix expression is currently being further evaluated by flow cytometry study. Our study shows the therapeutic potential of AON in UCMD by selectively targeting and silencing the mutant COL6 allele. Further improvement on the design of AON to target common SNPs is still required for the wider application of this strategy in the therapy of UCMD. http://dx.doi.org/10.1016/j.nmd.2015.06.285
G.P.262 Early scoliosis surgery may prevent deterioration of respiratory function in Ullrich congenital muscular dystrophy K. Kohashi *,1, A. Ishiyama 1, E. Takeshita 1, Y. Shimizu-Motohashi 1, T. Saito 1, E. Nakagawa 1, H. Komaki 1, K. Sugai 1, I. Nishino 2, W. Saito 3, M. Takaso 3, M. Sasaki 1 1 National Center of Neurology and Psychiatry, Department of Child Neurology, Tokyo, Japan; 2 National Center of Neurology and Psychiatry, Department of Neuromuscular Research, Tokyo, Japan; 3 Kitasato University School of Medicine, Department of Orthopedic Surgery, Kanagawa, Japan Patients with Ullrich congenital muscular dystrophy (UCMD) typically present with rapidly progressive scoliosis and respiratory insufficiency before 10 years of age. Progressive scoliosis aggravates respiratory function; however, currently, the benefits of scoliosis surgery in UCMD remain inconclusive. We investigated whether early scoliosis surgery prevents the deterioration of respiratory function in UCMD by reviewing the medical records of 22 patients diagnosed with sarcolemma-specific collagen VI deficiency using immunohistochemistry in muscle specimens. All patients had undergone a spirogram every 6 to 12 months after the diagnosis. Three patients underwent scoliosis surgery: one at 6 years and two at 8 years of age. Follow-up spirograms were performed after each surgery. Noninvasive positive pressure ventilation (NPPV) was introduced to all of surgically treated patients and 12 non-treated patients. For each group, percent vital capacity (%VC) was converted to its logarithmic form and analyzed by linear approximation. The resulting slope of the surgically treated patients was −0.007 (95% confidence interval [CI], −0.023 to −0.009), whereas that of non-treated patients with NPPV was −0.048 (95% CI, −0.058 to −0.038). There was a significant improvement of %VC aggravation in the operated group with a p-value of 0.005 in F test. A recent report on scoliosis surgery in UCMD showed no favorable effect on respiratory function; however, the patients in that study had undergone surgery after 10 years of age. In our analysis, scoliosis surgery before 10 years of age significantly changed the progression of respiratory function in treated patients compared with that in non-treated patients. This result indicates that scoliosis
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 10
S265
surgery performed at a younger age may decrease the progression of respiratory failure in UCMD.
Lyon, Bron, France; USA
http://dx.doi.org/10.1016/j.nmd.2015.06.286
Electrical Impedance Myography is a non-invasive method of measuring muscle health. Resistance is a measured value related to the extracellular and intracellular elements of the muscle such as fibrosis. Reactance is a measured value of the capacitance of the muscle fiber membrane. The phase angle is a calculated value to signify change in voltage output compared to current input and suggestive of the health of the muscle. EIM has been proposed as a meaningful biomarker in the ALS population and is currently being investigated in other neuromuscular diseases (Duchenne Muscular Dystrophy, Spinal Muscular Atrophy). Collagen VI related dystrophy (COL6-RD) is a progressive neuromuscular disease in which individuals present with weakness, contractures, distal joint laxity, respiratory difficulties, with many unable to attain or maintain ambulatory status. The goal of this study was to compare, in individuals with COL6-RD, EIM phase angle measurements with the Motor Function Measure (MFM) 32, North Star Ambulatory Assessment (NSAA) and myometry measurements. Twenty-one individuals with COL6-RD (ages 7–19 years; 12 males; 11 ambulant) participated in this study as part of a natural history study. EIM measurements were assessed unilaterally: deltoids, triceps, biceps, wrist flexors, quadriceps, hamstrings, tibialis anterior and gastrocnemius. MFM32 and NSAA were administered; muscle strength of bilateral elbow flexors/extensors and knee flexors/extensors were measured. EIM scores were totaled as a composite score and compared to total MFM32 and NSAA scores (Spearman’s rho correlation) and compared to myometry sum (Pearson’s correlations). EIM correlated with MFM32 (0.742, p = 0.01), NSAA (0.791, p = 0.01), and myometry (0.622, p = 0.01). Preliminary findings of this study suggest the use of EIM as biomarker in individuals with COL6RD. Future studies should compare EIM measures to ultrasound imaging, muscle biopsy findings, and its sensitivity to change over time.
G.P.263 Comparison of upper extremity measures in individuals with COL6 and LAMA2-muscular dystrophies M. Jain *,1, K. Meilleur 2, C. Nichols 1, M. Waite 1, R. Parks 1, B. Hodsdon 1, R. Bendixen 3, N. Hsia 4, A. Glanzman 4, L. Nelson 5, K. Keller 6, T. Duong 7, M. McGuire 8, J. Dastgir 9, S. Donkervoort 9, M. Leach 9, J. Collins 8, C. Vuillerot 10, A. Rutkowski 11, C. Bönnemann 9 1 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 2 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 3 University of Pittsburgh, Pittsburgh, USA; 4 Children’s Hospital of Philadelphia, Philadelphia, USA; 5 University of Texas Southwestern Medical Center, Dallas, USA; 6 Rady Children’s Hospital, San Diego, USA; 7 Children’s National Medical Center, Washington, DC, USA; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; 9 National Institutes of Health, NINDS, Bethesda, USA; 10 Hospices Civils de Lyon, Bron, France; 11 Kaiser Permanente SCPMG, Cure CMD, Los Angeles, USA Congenital muscular dystrophies (CMD) are a heterogeneous group of early onset degenerative diseases of the muscle leading to progressive weakness, affecting mobility and respiratory function; Collagen VI-related dystrophies (COL6-RD) and Laminin alpha2-related muscular dystrophy (LAMA2-RD) are 2 of the most common subtypes. Therapeutic interventions targeting both populations are currently under development. In preparation for clinical trials, it is important to select outcome measures to evaluate the efficacy of therapeutic interventions. The goal of this study was to examine the relationships between various upper extremity (UE) measures to determine if they are feasible and reliable in ambulatory and non-ambulatory individuals with COL6-RD and LAMA2-RD. Our cohort included 37 individuals diagnosed with COL6-RD (n = 18) and LAMA2-RD (n = 19) as part of a larger natural history study. Of the 37 individuals, 11 were ambulant; with an equitable gender distribution; males = 18, females = 19. We administered UE measures, including the Jebsen Hand Function Test (Jebsen), myometry (elbow flexors/extensors), grip/hand strength as measured by the Myogrip and Myopinch, and distal hand function as measured by the Moviplate, Motor Function Measure 32 (D3-distal function) and the Brooke Upper Extremity Scale. While all tests were administered bilaterally, maximal scores for each side were totaled and analyzed as a sum of the scores. Spearman’s rho correlations were calculated, resulting in high correlations between D3 measurements and myometry (r = .831), Myogrip (r = .848), Myopinch (r = .837), the Moviplate (r = .721) and there was a large inverse correlation between D3 and the Jebsen (r = −823) and the Brooke (r = −.755, all p < 0.01). These data support the use of these assessments to measure upper extremity/hand function in non-ambulant and ambulant individuals with COL6-RD and LAMA2-RD. http://dx.doi.org/10.1016/j.nmd.2015.06.287
G.P.264 Electrical impedance myography as a potential biomarker in individuals with COL6-related dystrophy C. Nichols 1, T. Lehky 2, M. Waite 1, T. Duong 3, L. Nelson 4, K. Keller 5, D. Lott 6, K. Meilleur 7, J. Collins 8, J. Dastgir 2, C. Vuillerot 9, A. Rutkowski 10, S. Donkervoort 2, M. Leach 2, M. Jain *,1, C. Bönnemann 2 1 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 2 National Institutes of Health, NINDS, Bethesda, USA; 3 Children’s National Medical Center, Washington, DC, USA; 4 University of Texas Southwestern Medical Center, Dallas, USA; 5 Rady Children’s Hospital, San Diego, USA; 6 University of Florida, Gainesville, USA; 7 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; 9 Hospices Civils de
Kaiser Permanente SCPMG, Cure CMD, Los Angeles,
http://dx.doi.org/10.1016/j.nmd.2015.06.288
G.P.265 Validation of actiGraph GT3X accelerometers in collagen 6-related muscular dystrophy and LAMA2-related muscular dystrophy K. Meilleur 1, J. Elliott 1, M. Linton 1, C. Vuillerot 2, R. Bendixen 3, I. Arveson 1, F. Tounkara 1, M. Waite 4, C. Nichols 4, K. Yang 5, S. Donkervoort 5, J. Dastgir 6, M. Leach 5, C. Bönnemann 5, M. Jain *,4 1 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 2 Hospices Civils de Lyon, Bron, France; 3 University of Pittsburgh, Pittsburgh, USA; 4 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 5 National Institutes of Health, NINDS, Bethesda, USA; 6 Columbia University, Department of Neurology, New York, USA This study aimed to determine whether ActiGraph GT3X accelerometers (AG) reliably measure energy expenditure for individuals with Collagen VI-Related Muscular Dystrophy (COL6-RD) or LAMA2-Related Muscular Dystrophy (LAMA2-RD). This objective was twofold: 1) to assess the validity of the step-counting function of AG in congenital muscular dystrophy, and 2) to assess criterion validity of AG against clinical measures of motor function. Patients often perform at top motor capacity in clinic. Measuring activity at home may better reflect typical motor performance. AG provides a means of capturing normal activity outside of the clinical setting. AG has not been validated in COL6-RD or LAMA2-RD. In clinic, AG step-count data were validated against a manual step-counter in 11 ambulatory subjects. Motor measures were administered, including the North Star Ambulatory Assessment (NSAA), Motor Function Measure 32 (MFM32), Six-Minute Walk Test (6MWT), and a self-reported measure of limitations of activity (ACTIVLIM). Participants then wore AG at home for seven days. Measurements captured by AG, including vector magnitude counts per minute (VM CPM), steps per minute (SPM), and % moderate-vigorous physical activity (% MVPA), were compared with the motor measures. Data were analyzed by Spearman correlation. The correlation between AG-counted steps and hand-counted steps
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
controlled, multi-center, 48-week study will evaluate the effects of the two PMOs on ambulation, endurance and muscle function measured by the 6-Minute Walk Test (6MWT). Secondary endpoints will evaluate restoration of dystrophin in muscle tissue and respiratory muscle function as measured by pulmonary function tests (PFT). Patients (n = 99) will be randomized by genotype 2:1 to active-treatment (SRP-4045 or SRP-4053) or placebo. All patients will undergo a muscle biopsy at baseline and at either Week 24 or 48. Safety assessments will include adverse event monitoring, ECG, ECHO, and safety laboratory tests. The primary analysis of clinical outcomes will be based on the combined population receiving either drug compared to the placebo population. The study design highlights a novel approach in combining two exon-skipping drug candidates (SRP-4045 and SRP-4053) within a single trial. This is important for future exon skipping therapies in DMD as they will target increasingly smaller patientpopulations, making it difficult to conduct separate, well-powered clinical trials for each compound. http://dx.doi.org/10.1016/j.nmd.2015.06.283
G.P.260 Are effects of Translarna (Ataluren) on muscle strength more discernible in younger patients with Duchenne muscular dystrophy (DMD)? C. McDonald 1, A. Reha 2, G. Elfring 2, P. Trifilis *,2, S. Park 2, T. Ong 2, S. Peltz 2, R. Spiegel 2, Ataluren DMD Study Group 2 1 University of California, School of Medicine, Davis, CA, USA; 2 PTC Therapeutics, South Plainfield, NJ, USA Emergent DMD natural history data indicate that younger patients (<7 years old) experience substantial decreases in muscle strength but little change in muscle function over a 1-year period. Patients ≥7 years old, however, show substantial decreases in muscle function but little change in muscle strength. These observations suggest that assessing muscle strength may be more useful as an outcome measure in younger patients. As a part of a phase 2b, randomized double-blind, placebo-controlled study of Ataluren, change in muscle strength was assessed by hand-held dynamometry over 48 weeks in ambulatory males ≥5 years old with nonsense mutation DMD. Data were analyzed by age <7 or ≥7 years. Muscle groups evaluated were knee extension, knee flexion, elbow extension, elbow flexion, and shoulder abduction. Bilateral values were averaged. Screening and baseline values taken 6 weeks apart were used to determine test–retest reliability. Patients <7 years old included 14 patients randomized to placebo and 9 randomized to Ataluren 40 mg/kg/day. Mean changes were −1.05 lbs for placebo vs 0.42 lbs for Ataluren in knee extension, 0.12 vs 0.10 lbs in knee flexion, −0.90 lbs vs 0.31 lbs in elbow extension, −0.39 lbs vs 1.07 lbs in elbow flexion, and 0.00 lbs vs 0.50 lbs in shoulder abduction. Test–retest reliability was highest for knee extension (r = .84). With emergent natural history data elucidating the course of the disease, selection of endpoints appropriate for the age range of the study population is critical in DMD. Muscle strength is lost predominantly during the early stages of DMD. In younger patients, therefore, it is possible to demonstrate a treatment effect of preservation of muscle strength. In the most reliable myometry parameter in younger patients, knee extension, a difference of 1.47 lbs favoring Ataluren vs placebo was observed. In older patients, floor effects preclude detection of a treatment effect of muscle strength stabilization. http://dx.doi.org/10.1016/j.nmd.2015.06.284
CONGENITAL MUSCULAR DYSTROPHIES G.P.261 The application of antisense oligonucleotide therapy in collagen 6-related congenital muscular dystrophy H. Zhou *, E. Marrosu, F. Muntoni University College London, Dubowitz Neuromuscular Centre, London, UK
The severe collagen VI-related congenital muscular dystrophy (CMD) variant, known as Ullrich CMD (UCMD), is caused by either recessive or dominant mutations in one of the three collagen 6 genes (COL6A1, COL6A2 and COL6A3). The fact that 50% of mutations are de-novo dominant, and that haploinsufficiency is not associated with clinical phenotypes in collagen 6 genes, provides the theoretical basis for using antisense oligonucleotide (AON) to selectively silence the mutant allele as a therapeutic strategy. In this study, we have been focusing on developing allele-specific silencing therapeutic approach by using the RNase H cleavage strategy. Three skin fibroblast cell lines from UCMD patients carrying dominant mutations in Collagen 6A1, A2 and A3 genes are used as cellular model in this study. AONs are synthesized in various chemical modifications and in different length. Over 20 candidate AONs have been analysed with different design approaches and chemical modifications, including morpholino, 2′-O-Methyl, locked nucleic acid and 2-deoxy-2′-fluoro-b-D-arabinonucleic acid and phosphorothiate DNA chimeras. The efficacy is assessed by allele-specific reverse transcript PCR. So far two antisense sequences targeting COL6A1 and A3 have been identified in efficiently suppressing the mutant alleles. Functional analysis using immunohistochemistry shows that the characteristic intracellular collagen VI accumulation in some UCMD fibroblast cell lines can be dramatically reduced after efficacious AON treatment and is accompanied with increased extracellular matrix collagen VI expression. Quantitative analysis of collagen VI extracellular matrix expression is currently being further evaluated by flow cytometry study. Our study shows the therapeutic potential of AON in UCMD by selectively targeting and silencing the mutant COL6 allele. Further improvement on the design of AON to target common SNPs is still required for the wider application of this strategy in the therapy of UCMD. http://dx.doi.org/10.1016/j.nmd.2015.06.285
G.P.262 Early scoliosis surgery may prevent deterioration of respiratory function in Ullrich congenital muscular dystrophy K. Kohashi *,1, A. Ishiyama 1, E. Takeshita 1, Y. Shimizu-Motohashi 1, T. Saito 1, E. Nakagawa 1, H. Komaki 1, K. Sugai 1, I. Nishino 2, W. Saito 3, M. Takaso 3, M. Sasaki 1 1 National Center of Neurology and Psychiatry, Department of Child Neurology, Tokyo, Japan; 2 National Center of Neurology and Psychiatry, Department of Neuromuscular Research, Tokyo, Japan; 3 Kitasato University School of Medicine, Department of Orthopedic Surgery, Kanagawa, Japan Patients with Ullrich congenital muscular dystrophy (UCMD) typically present with rapidly progressive scoliosis and respiratory insufficiency before 10 years of age. Progressive scoliosis aggravates respiratory function; however, currently, the benefits of scoliosis surgery in UCMD remain inconclusive. We investigated whether early scoliosis surgery prevents the deterioration of respiratory function in UCMD by reviewing the medical records of 22 patients diagnosed with sarcolemma-specific collagen VI deficiency using immunohistochemistry in muscle specimens. All patients had undergone a spirogram every 6 to 12 months after the diagnosis. Three patients underwent scoliosis surgery: one at 6 years and two at 8 years of age. Follow-up spirograms were performed after each surgery. Noninvasive positive pressure ventilation (NPPV) was introduced to all of surgically treated patients and 12 non-treated patients. For each group, percent vital capacity (%VC) was converted to its logarithmic form and analyzed by linear approximation. The resulting slope of the surgically treated patients was −0.007 (95% confidence interval [CI], −0.023 to −0.009), whereas that of non-treated patients with NPPV was −0.048 (95% CI, −0.058 to −0.038). There was a significant improvement of %VC aggravation in the operated group with a p-value of 0.005 in F test. A recent report on scoliosis surgery in UCMD showed no favorable effect on respiratory function; however, the patients in that study had undergone surgery after 10 years of age. In our analysis, scoliosis surgery before 10 years of age significantly changed the progression of respiratory function in treated patients compared with that in non-treated patients. This result indicates that scoliosis
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 10
S265
surgery performed at a younger age may decrease the progression of respiratory failure in UCMD.
Lyon, Bron, France; USA
http://dx.doi.org/10.1016/j.nmd.2015.06.286
Electrical Impedance Myography is a non-invasive method of measuring muscle health. Resistance is a measured value related to the extracellular and intracellular elements of the muscle such as fibrosis. Reactance is a measured value of the capacitance of the muscle fiber membrane. The phase angle is a calculated value to signify change in voltage output compared to current input and suggestive of the health of the muscle. EIM has been proposed as a meaningful biomarker in the ALS population and is currently being investigated in other neuromuscular diseases (Duchenne Muscular Dystrophy, Spinal Muscular Atrophy). Collagen VI related dystrophy (COL6-RD) is a progressive neuromuscular disease in which individuals present with weakness, contractures, distal joint laxity, respiratory difficulties, with many unable to attain or maintain ambulatory status. The goal of this study was to compare, in individuals with COL6-RD, EIM phase angle measurements with the Motor Function Measure (MFM) 32, North Star Ambulatory Assessment (NSAA) and myometry measurements. Twenty-one individuals with COL6-RD (ages 7–19 years; 12 males; 11 ambulant) participated in this study as part of a natural history study. EIM measurements were assessed unilaterally: deltoids, triceps, biceps, wrist flexors, quadriceps, hamstrings, tibialis anterior and gastrocnemius. MFM32 and NSAA were administered; muscle strength of bilateral elbow flexors/extensors and knee flexors/extensors were measured. EIM scores were totaled as a composite score and compared to total MFM32 and NSAA scores (Spearman’s rho correlation) and compared to myometry sum (Pearson’s correlations). EIM correlated with MFM32 (0.742, p = 0.01), NSAA (0.791, p = 0.01), and myometry (0.622, p = 0.01). Preliminary findings of this study suggest the use of EIM as biomarker in individuals with COL6RD. Future studies should compare EIM measures to ultrasound imaging, muscle biopsy findings, and its sensitivity to change over time.
G.P.263 Comparison of upper extremity measures in individuals with COL6 and LAMA2-muscular dystrophies M. Jain *,1, K. Meilleur 2, C. Nichols 1, M. Waite 1, R. Parks 1, B. Hodsdon 1, R. Bendixen 3, N. Hsia 4, A. Glanzman 4, L. Nelson 5, K. Keller 6, T. Duong 7, M. McGuire 8, J. Dastgir 9, S. Donkervoort 9, M. Leach 9, J. Collins 8, C. Vuillerot 10, A. Rutkowski 11, C. Bönnemann 9 1 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 2 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 3 University of Pittsburgh, Pittsburgh, USA; 4 Children’s Hospital of Philadelphia, Philadelphia, USA; 5 University of Texas Southwestern Medical Center, Dallas, USA; 6 Rady Children’s Hospital, San Diego, USA; 7 Children’s National Medical Center, Washington, DC, USA; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; 9 National Institutes of Health, NINDS, Bethesda, USA; 10 Hospices Civils de Lyon, Bron, France; 11 Kaiser Permanente SCPMG, Cure CMD, Los Angeles, USA Congenital muscular dystrophies (CMD) are a heterogeneous group of early onset degenerative diseases of the muscle leading to progressive weakness, affecting mobility and respiratory function; Collagen VI-related dystrophies (COL6-RD) and Laminin alpha2-related muscular dystrophy (LAMA2-RD) are 2 of the most common subtypes. Therapeutic interventions targeting both populations are currently under development. In preparation for clinical trials, it is important to select outcome measures to evaluate the efficacy of therapeutic interventions. The goal of this study was to examine the relationships between various upper extremity (UE) measures to determine if they are feasible and reliable in ambulatory and non-ambulatory individuals with COL6-RD and LAMA2-RD. Our cohort included 37 individuals diagnosed with COL6-RD (n = 18) and LAMA2-RD (n = 19) as part of a larger natural history study. Of the 37 individuals, 11 were ambulant; with an equitable gender distribution; males = 18, females = 19. We administered UE measures, including the Jebsen Hand Function Test (Jebsen), myometry (elbow flexors/extensors), grip/hand strength as measured by the Myogrip and Myopinch, and distal hand function as measured by the Moviplate, Motor Function Measure 32 (D3-distal function) and the Brooke Upper Extremity Scale. While all tests were administered bilaterally, maximal scores for each side were totaled and analyzed as a sum of the scores. Spearman’s rho correlations were calculated, resulting in high correlations between D3 measurements and myometry (r = .831), Myogrip (r = .848), Myopinch (r = .837), the Moviplate (r = .721) and there was a large inverse correlation between D3 and the Jebsen (r = −823) and the Brooke (r = −.755, all p < 0.01). These data support the use of these assessments to measure upper extremity/hand function in non-ambulant and ambulant individuals with COL6-RD and LAMA2-RD. http://dx.doi.org/10.1016/j.nmd.2015.06.287
G.P.264 Electrical impedance myography as a potential biomarker in individuals with COL6-related dystrophy C. Nichols 1, T. Lehky 2, M. Waite 1, T. Duong 3, L. Nelson 4, K. Keller 5, D. Lott 6, K. Meilleur 7, J. Collins 8, J. Dastgir 2, C. Vuillerot 9, A. Rutkowski 10, S. Donkervoort 2, M. Leach 2, M. Jain *,1, C. Bönnemann 2 1 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 2 National Institutes of Health, NINDS, Bethesda, USA; 3 Children’s National Medical Center, Washington, DC, USA; 4 University of Texas Southwestern Medical Center, Dallas, USA; 5 Rady Children’s Hospital, San Diego, USA; 6 University of Florida, Gainesville, USA; 7 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 8 Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; 9 Hospices Civils de
Kaiser Permanente SCPMG, Cure CMD, Los Angeles,
http://dx.doi.org/10.1016/j.nmd.2015.06.288
G.P.265 Validation of actiGraph GT3X accelerometers in collagen 6-related muscular dystrophy and LAMA2-related muscular dystrophy K. Meilleur 1, J. Elliott 1, M. Linton 1, C. Vuillerot 2, R. Bendixen 3, I. Arveson 1, F. Tounkara 1, M. Waite 4, C. Nichols 4, K. Yang 5, S. Donkervoort 5, J. Dastgir 6, M. Leach 5, C. Bönnemann 5, M. Jain *,4 1 National Institutes of Health, National Institute of Nursing Research, Bethesda, USA; 2 Hospices Civils de Lyon, Bron, France; 3 University of Pittsburgh, Pittsburgh, USA; 4 National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 5 National Institutes of Health, NINDS, Bethesda, USA; 6 Columbia University, Department of Neurology, New York, USA This study aimed to determine whether ActiGraph GT3X accelerometers (AG) reliably measure energy expenditure for individuals with Collagen VI-Related Muscular Dystrophy (COL6-RD) or LAMA2-Related Muscular Dystrophy (LAMA2-RD). This objective was twofold: 1) to assess the validity of the step-counting function of AG in congenital muscular dystrophy, and 2) to assess criterion validity of AG against clinical measures of motor function. Patients often perform at top motor capacity in clinic. Measuring activity at home may better reflect typical motor performance. AG provides a means of capturing normal activity outside of the clinical setting. AG has not been validated in COL6-RD or LAMA2-RD. In clinic, AG step-count data were validated against a manual step-counter in 11 ambulatory subjects. Motor measures were administered, including the North Star Ambulatory Assessment (NSAA), Motor Function Measure 32 (MFM32), Six-Minute Walk Test (6MWT), and a self-reported measure of limitations of activity (ACTIVLIM). Participants then wore AG at home for seven days. Measurements captured by AG, including vector magnitude counts per minute (VM CPM), steps per minute (SPM), and % moderate-vigorous physical activity (% MVPA), were compared with the motor measures. Data were analyzed by Spearman correlation. The correlation between AG-counted steps and hand-counted steps