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Clinical, pathologic, genetic features of collagen 6-related myopathy in Korea
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Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
was statistically significant. Initially, there were low correlations between AG data and the motor measures. However, we separately analyzed data from only the five subjects whose lifestyles were most similar, with markedly different results: SPM had statistically significant correlations with NSAA, MFM32, 6MWT, and ACTIVLIM; and % MVPA had statistically significant correlations with NSAA, MFM32, and 6MWT. Measuring activity outside the clinic may be accomplished with AG. However, further work is needed to confirm these findings in a greater number of subjects, particularly with LAMA2-RD. http://dx.doi.org/10.1016/j.nmd.2015.06.289
G.P.266 Gait in children with collagen 6 disorders – A prospective study K. Carroll *, R. Kennedy, K. de Valle, M. Ryan, A. Kornberg The Royal Children’s Hospital, Neurology Department, Melbourne, Australia Bethlem myopathy and Ullrich congenital muscular dystrophy are caused by mutations in genes encoding collagen type 6. These conditions are characterized by progressive muscle weakness, scoliosis and contractures. Gait abnormalities in this population have not previously been formally assessed. A cohort of eight children aged 7–13 years with genetically confirmed collagen 6-related myopathies were enrolled in this prospective study. Functional measures included a 10 m timed test of running, reported fall frequency and mobility. Gait was tested at typical and fast walking speeds, in shoes, using an electronic walkway. Data were compared to that from an age-matched local cohort of typically developing (TD) children. Results from the initial assessments are reported (mean (95% confidence interval)). The children had a mean 10 m run time of 5.82 s (4.41–7.23). Four children were frequent fallers (at least once per week) and five children reported impaired mobility particularly affecting medium to long distances as indicated by their Functional Mobility Scale score. The children with collagen 6 disorders walked more slowly (23.4% (14.8–31.9)) with shorter step length (18.4% (10.7–26.1)) and an increased double support phase (73.3% (55.1–91.5)) compared with their TD peers at self-selected typical walking speed. Similar differences were detected at fast walking speeds. There was increased asymmetry in step length compared to the TD children at both speeds. These results suggest that children with collagen 6 disorders walk differently and have functional limitations compared with TD children. Serial studies will evaluate the longitudinal evolution of these gait and functional changes. http://dx.doi.org/10.1016/j.nmd.2015.06.290
G.P.267 Clinical, pathologic, genetic features of collagen 6-related myopathy in Korea J. Lee *,1, H. Park 2, Y. Park 3, S. Kim 4, Y. Choi 1 1 Yonsei University College of Medicine, Department of Neurology, Seoul, South Korea; 2 Ewha Womans University School of Medicine, Department of Neurology, Seoul, South Korea; 3 Pusan National University School of Medicine, Department of Neurology, Pusan, South Korea; 4 Yonsei University College of Medicine, Department of Pathology, Seoul, South Korea Mutations in the collagen 6 genes (COL6A1, COL6A2, COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which were believed previously as separate disease entities but now known as collagen VI-related myopathy, having a broad clinical spectrum. We aimed to analyze the clinical, pathological and genetic characteristics of patients with collagen VI-related myopathy in Korea. We studied 10 patients, who underwent clinical examination, electromyography, muscle biopsy, and genetic tests for collagen VI. Of a total of 10 patients, mean age at the first symptoms and diagnosis was 4.7 years old and 12.9 years old. Joint contractures are found in mostly ankle joint. At the diagnosis, 9 of 10 patients were able to walk alone without aid. Muscle biopsy showed increased muscle fiber size variation, degenerating fibers with endomysial fibrosis in eight muscle specimen, and two
muscle specimens showed sarcolemma specific collagen VI α deficiency in immunohistochemistry. In genetic study, we detected four sporadic patients carrying mutations of triple helix domain, three autosomal dominant and one sporadic patients harboring splicing mutations, resulting in exon 14 skipping, and one novel mutation (c.428 + 1G > T) in COL6A1 gene. We found one autosomal dominant patient with mutation of COL6A2 gene (c.856-1G > C, AD). In our report, a patient with COL6A2 gene mutation was reported for the first time in Korea, and that mutation was novel splicing mutation. We found that in Korea, COL6A1 gene mutations are more frequent (9/10) than previous reports, and early onset patients (<2 years old, 5 patients) had more frequent prevalence (4/5) of missense mutations of triple helix domain in COL6A1 gene rather than late onset patients (≥2 years old, 5 patients). Our findings would be helpful for understanding and finding collagen VI-related myopathy. http://dx.doi.org/10.1016/j.nmd.2015.06.291
G.P.268 Col6A2 null mice are a new mouse model of collagen-VI related dystrophies and relevant to the human disease P. Mohassel *, J. Rooney, Y. Zou, C. Bönnemann NIH/NINDS, Bethesda, MD, USA Mutations in collagen VI cause a spectrum of muscle disease ranging from severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy. The three protein components of collagen VI encoded by Col6A1, Col6A2, and Col6A3, undergo extensive assembly after translation before being excreted and incorporated into the extracellular matrix (ECM). Collagen VI is an integral component of the ECM, making collagen VI related dystrophies prototypical disorders of the muscle ECM. However, how the mutations result in muscle weakness, atrophy, degeneration and fibrosis remains unknown. In this study, we introduce a new mouse model of collagen VI related dystrophies, characterized by homozygous inactivation of the Col6A2 alleles (Col6A2 −/−) and characterize the histologic and functional changes associated with this genotype in skeletal muscle fibers. Col6A2 −/− mice show histologic abnormalities including myofiber atrophy, degenerating and regenerating myofibers, increased internalized nuclei, and increased fibrosis consistent with a dystrophic myopathy. These findings correlate with decreased performance on functional assessments of muscle strength and activity compared to wild-type controls. Preliminary data suggest that Col6A2 −/− mice show decreased grip strength normalized to body weight, run shorter distances on a treadmill before exhaustion, and show decreased overall mobility and activity. Col6A2 knockout mice serve as a novel animal model for collagen VI-related dystrophies. Similar to patients, they exhibit typical, albeit milder, histologic and functional changes and can be used to study pathogenic mechanisms of the disease and test efficacy of potential therapeutic interventions. http://dx.doi.org/10.1016/j.nmd.2015.06.292
G.P.269 Correlation between crural muscle fatty change and maximum motor function in Fukuyama congenital muscular dystrophy patients K. Ishigruo *,1, K. Ishigaki 1, T. Sato 1, T. Murakami 1, M. Shichiji 1, K. Saito 2, M. Osawa 1, S. Nagata 1 1 Tokyo Women’s Medical University, School of Medicine, Department of Pediatrics, Tokyo, Japan; 2 Tokyo Women’s Medical University, School of Medicine, Institute of Medical Genetics, Tokyo, Japan Recently, T1-weighted skeletal muscle magnetic resonance imaging (MRI), which can precisely detect fatty replacement as bright signals, has been recognized as a useful technique for differential diagnosis or assessing the progression of neuromuscular disorders. Several skeletal muscle MRI studies of the lower limbs in genetically distinct neuromuscular disorders have been performed with the aim of identifying the specific patterns of each disease. Fukuyama congenital muscular dystrophy (FCMD), the most common
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
was statistically significant. Initially, there were low correlations between AG data and the motor measures. However, we separately analyzed data from only the five subjects whose lifestyles were most similar, with markedly different results: SPM had statistically significant correlations with NSAA, MFM32, 6MWT, and ACTIVLIM; and % MVPA had statistically significant correlations with NSAA, MFM32, and 6MWT. Measuring activity outside the clinic may be accomplished with AG. However, further work is needed to confirm these findings in a greater number of subjects, particularly with LAMA2-RD. http://dx.doi.org/10.1016/j.nmd.2015.06.289
G.P.266 Gait in children with collagen 6 disorders – A prospective study K. Carroll *, R. Kennedy, K. de Valle, M. Ryan, A. Kornberg The Royal Children’s Hospital, Neurology Department, Melbourne, Australia Bethlem myopathy and Ullrich congenital muscular dystrophy are caused by mutations in genes encoding collagen type 6. These conditions are characterized by progressive muscle weakness, scoliosis and contractures. Gait abnormalities in this population have not previously been formally assessed. A cohort of eight children aged 7–13 years with genetically confirmed collagen 6-related myopathies were enrolled in this prospective study. Functional measures included a 10 m timed test of running, reported fall frequency and mobility. Gait was tested at typical and fast walking speeds, in shoes, using an electronic walkway. Data were compared to that from an age-matched local cohort of typically developing (TD) children. Results from the initial assessments are reported (mean (95% confidence interval)). The children had a mean 10 m run time of 5.82 s (4.41–7.23). Four children were frequent fallers (at least once per week) and five children reported impaired mobility particularly affecting medium to long distances as indicated by their Functional Mobility Scale score. The children with collagen 6 disorders walked more slowly (23.4% (14.8–31.9)) with shorter step length (18.4% (10.7–26.1)) and an increased double support phase (73.3% (55.1–91.5)) compared with their TD peers at self-selected typical walking speed. Similar differences were detected at fast walking speeds. There was increased asymmetry in step length compared to the TD children at both speeds. These results suggest that children with collagen 6 disorders walk differently and have functional limitations compared with TD children. Serial studies will evaluate the longitudinal evolution of these gait and functional changes. http://dx.doi.org/10.1016/j.nmd.2015.06.290
G.P.267 Clinical, pathologic, genetic features of collagen 6-related myopathy in Korea J. Lee *,1, H. Park 2, Y. Park 3, S. Kim 4, Y. Choi 1 1 Yonsei University College of Medicine, Department of Neurology, Seoul, South Korea; 2 Ewha Womans University School of Medicine, Department of Neurology, Seoul, South Korea; 3 Pusan National University School of Medicine, Department of Neurology, Pusan, South Korea; 4 Yonsei University College of Medicine, Department of Pathology, Seoul, South Korea Mutations in the collagen 6 genes (COL6A1, COL6A2, COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which were believed previously as separate disease entities but now known as collagen VI-related myopathy, having a broad clinical spectrum. We aimed to analyze the clinical, pathological and genetic characteristics of patients with collagen VI-related myopathy in Korea. We studied 10 patients, who underwent clinical examination, electromyography, muscle biopsy, and genetic tests for collagen VI. Of a total of 10 patients, mean age at the first symptoms and diagnosis was 4.7 years old and 12.9 years old. Joint contractures are found in mostly ankle joint. At the diagnosis, 9 of 10 patients were able to walk alone without aid. Muscle biopsy showed increased muscle fiber size variation, degenerating fibers with endomysial fibrosis in eight muscle specimen, and two
muscle specimens showed sarcolemma specific collagen VI α deficiency in immunohistochemistry. In genetic study, we detected four sporadic patients carrying mutations of triple helix domain, three autosomal dominant and one sporadic patients harboring splicing mutations, resulting in exon 14 skipping, and one novel mutation (c.428 + 1G > T) in COL6A1 gene. We found one autosomal dominant patient with mutation of COL6A2 gene (c.856-1G > C, AD). In our report, a patient with COL6A2 gene mutation was reported for the first time in Korea, and that mutation was novel splicing mutation. We found that in Korea, COL6A1 gene mutations are more frequent (9/10) than previous reports, and early onset patients (<2 years old, 5 patients) had more frequent prevalence (4/5) of missense mutations of triple helix domain in COL6A1 gene rather than late onset patients (≥2 years old, 5 patients). Our findings would be helpful for understanding and finding collagen VI-related myopathy. http://dx.doi.org/10.1016/j.nmd.2015.06.291
G.P.268 Col6A2 null mice are a new mouse model of collagen-VI related dystrophies and relevant to the human disease P. Mohassel *, J. Rooney, Y. Zou, C. Bönnemann NIH/NINDS, Bethesda, MD, USA Mutations in collagen VI cause a spectrum of muscle disease ranging from severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy. The three protein components of collagen VI encoded by Col6A1, Col6A2, and Col6A3, undergo extensive assembly after translation before being excreted and incorporated into the extracellular matrix (ECM). Collagen VI is an integral component of the ECM, making collagen VI related dystrophies prototypical disorders of the muscle ECM. However, how the mutations result in muscle weakness, atrophy, degeneration and fibrosis remains unknown. In this study, we introduce a new mouse model of collagen VI related dystrophies, characterized by homozygous inactivation of the Col6A2 alleles (Col6A2 −/−) and characterize the histologic and functional changes associated with this genotype in skeletal muscle fibers. Col6A2 −/− mice show histologic abnormalities including myofiber atrophy, degenerating and regenerating myofibers, increased internalized nuclei, and increased fibrosis consistent with a dystrophic myopathy. These findings correlate with decreased performance on functional assessments of muscle strength and activity compared to wild-type controls. Preliminary data suggest that Col6A2 −/− mice show decreased grip strength normalized to body weight, run shorter distances on a treadmill before exhaustion, and show decreased overall mobility and activity. Col6A2 knockout mice serve as a novel animal model for collagen VI-related dystrophies. Similar to patients, they exhibit typical, albeit milder, histologic and functional changes and can be used to study pathogenic mechanisms of the disease and test efficacy of potential therapeutic interventions. http://dx.doi.org/10.1016/j.nmd.2015.06.292
G.P.269 Correlation between crural muscle fatty change and maximum motor function in Fukuyama congenital muscular dystrophy patients K. Ishigruo *,1, K. Ishigaki 1, T. Sato 1, T. Murakami 1, M. Shichiji 1, K. Saito 2, M. Osawa 1, S. Nagata 1 1 Tokyo Women’s Medical University, School of Medicine, Department of Pediatrics, Tokyo, Japan; 2 Tokyo Women’s Medical University, School of Medicine, Institute of Medical Genetics, Tokyo, Japan Recently, T1-weighted skeletal muscle magnetic resonance imaging (MRI), which can precisely detect fatty replacement as bright signals, has been recognized as a useful technique for differential diagnosis or assessing the progression of neuromuscular disorders. Several skeletal muscle MRI studies of the lower limbs in genetically distinct neuromuscular disorders have been performed with the aim of identifying the specific patterns of each disease. Fukuyama congenital muscular dystrophy (FCMD), the most common