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P.16.13 Myopathy with typical OPMD morphology without association with the PABPN1 gene locus
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Abstracts / Neuromuscular Disorders 23 (2013) 738–852
extremity functional is sensitive to detect a range of upper extremity impairments encountered in FSHD. http://dx.doi:10.1016/j.nmd.2013.06.648
P.16.12 OPMD from the myoblast’s and fibroblast’s point of view T. Gidaro 1, E. Negroni 1, P. Klein 1, M. Oloko 1, M. Lesnik 1, A. Bigot 1, K. Mamchaoui 1, S. Pe´rie´ 2, J.L. St Guily 2, G. Butler-Browne 1, V. Mouly 1, C. Trollet 1 1 UPMC Universite´ Paris 6, UM76, Institut de Myologie, INSERM U 974, Paris, France; 2 Service d’Oto-Rhino-Laryngologie et de Chirurgie CervicoFaciale, Faculte´ de Me´decine St Antoine, UPMC, Paris, France Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant inherited dystrophy due to an expansion of GCG repeats in the coding region of the ubiquitously expressed PABPN1 gene. The main muscular targets of OPMD are cricopharyngeal muscle (CPM) and elevator eyelid muscle whose progressive involvement leads to dysphagia and ptosis. We have recently demonstrated that OPMD CPM is characterized by atrophy, fibrosis and increased PAX7-positive cells compared to control CPM and to OPMD non-affected muscles such as quadriceps (QM). These results suggest that the specific involvement of affected muscles in OPMD correlates with an exacerbated fibrosis and a failure of the regenerative response. This led us to further study the skeletal muscle progenitor cells from CPM and their possible deregulation in OPMD. In vitro, primary cultures isolated from CPM biopsies of both OPMD (n = 4) and control (n = 4) subjects were characterized by a rapid fall of their myogenicity, whereas in primary cultures from control QM (n = 3) the myogenicity was maintained throughout the course of the lifespan. Several hypotheses for this drastic loss of myogenicity have been investigated, e.g. proliferative deregulation between resident fibroblasts and myoblasts. In addition, CPM cells regeneration capacity was explored in vivo. Each primary culture was injected into cryodamaged tibialis anterior (TA) muscle of an immunodeficient mouse model. One month after injection, a high number of human PAX7-positive satellite cells were found in TA muscles injected with CPM myoblasts compared to control injected QM myoblasts. Moreover, an elevated number of human cells were revealed in the interstitial space of TA muscle injected by CPM myoblasts. Altogether, these results show that muscle primary cultures represent a good model to further study the deregulations observed in OPMD CPM. Cellular and molecular mechanisms deregulated in both fibroblasts and myoblasts fractions are now being investigated. http://dx.doi:10.1016/j.nmd.2013.06.649
P.16.13 Myopathy with typical OPMD morphology without association with the PABPN1 gene locus C. Hedberg 1, P. Chinnery 2, C. Lindberg 3, T. Martinsson 4, A. Oldfors 1 1 Biomedicin, Pathology, Gothenburg, Sweden; 2 Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; 3 Biomedicin, Neurology, Gothenburg, Sweden; 4 Biomedicin, Clinical Genetics, Gothenburg, Sweden Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive ptosis of the eyelids and dysphagia. Intranuclear inclusions of tubulofilamentous (INIs) in skeletal muscle constitute a pathological hallmark for this disease. The filaments are up to 250 nm in length and have external diameter of 8.5 nm and an internal diameter of 3 nm. The only causative mutation described to date is a trip-
let repeat expansion consisting of 2–7 additional base triplets in a repeat sequence in exon 1 of the polyadenine binding protein nuclear 1 (PABPN1) gene localized on chromosome 14q11.2. This results in an increase in length of a polyalanine tract in the PABPN1 protein from 10 to 12– 17 residues. We describe the clinical, histopathological and genetically findings in three individuals from a Swedish family, with a dominantly inherited adult-onset myopathy characterized by ptosis and dysphagia. Muscle histopathological features included rimmed vacuoles and nuclei containing inclusions of unique 8.5 nm filaments and insoluble PABPN1 protein. The PABPN1 gene was excluded as the disease causative gene in this family both by direct DNA sequencing of the gene together with high density single nucleotide polymorphism (SNP) arrays covering the entire genome excluding the locus harbouring the PABPN1 gene. http://dx.doi:10.1016/j.nmd.2013.06.650
METABOLIC MYOPATHIES P.17.1 Phenotypic variation within 22 families with Pompe disease S.C.A. Wens 1, C.M. Van Gelder 2, M.E. Kruijshaar 2, J.M. De Vries 1, N.A.M. Van der Beek 1, A.J.J. Reuser 2, P.A. Van Doorn 1, A.T. Van der Ploeg 2, E. Brusse 1 1 Erasmus MC University Medical Centre, Neurology, Center for Lysosomal and Metabolic Diseases, Rotterdam, Netherlands; 2 Erasmus MC University Medical Centre, Center for Lysosomal and Metabolic Diseases, Rotterdam, Netherlands Pompe disease is an autosomal recessive disorder caused by a deficiency of acid a-glucosidase (GAA) leading to glycogen accumulation in different tissues. Pompe disease has a broad clinical spectrum, in which the phenotype can vary widely, even in patients with a similar GAA genotype. The aim of this study was to describe phenotypic variation among siblings with non-classic Pompe disease in the Netherlands. We identified 22 families consisting of two or three siblings (50 patients: 42 adults and eight children). All carried the most common mutation c.-32-13T>G in combination with another pathogenic mutation. Siblings typically all had symptom onset either in childhood or in adulthood, however, there was a wide variation in age of symptom onset between siblings (median difference of nine years). Presenting symptoms were similar across siblings in 14 families and limb girdle weakness was most frequently reported. In certain families ptosis, bulbar weakness or scapular winging were present in all siblings. The majority of wheelchair and/or ventilator dependent patients had an ambulant or non-ventilated sibling; half of these less affected siblings had a longer disease duration. Gender, GAA activity and co-morbidity did not appear to explain differences in phenotype between siblings. Since the course of disease and its severity in some families varied to the same extent as seen in unrelated patients with an identical genotype, other factors like epigenetic and environmental effects are likely to influence the clinical presentation and disease course. Additional studies are needed to identify these factors, as possible prognostic factors for disease course and outcome on ERT of an individual patient. http://dx.doi:10.1016/j.nmd.2013.06.651
P.17.2 Late onset Pompe disease with dilated cardiomyopathy T. Kurashige 1, N. Shiroma 1, A. Motoda 1, H. Ikenaga 1, N. Oda 1, T. Takahashi 1, M. Kosuga 2, Y. Kihara 1, K. Arihiro 1, M. Matsumoto 1 1 Hiroshima University, Hiroshima, Japan; 2 National Center for Child Health and Development, Tokyo, Japan
Abstracts / Neuromuscular Disorders 23 (2013) 738–852
extremity functional is sensitive to detect a range of upper extremity impairments encountered in FSHD. http://dx.doi:10.1016/j.nmd.2013.06.648
P.16.12 OPMD from the myoblast’s and fibroblast’s point of view T. Gidaro 1, E. Negroni 1, P. Klein 1, M. Oloko 1, M. Lesnik 1, A. Bigot 1, K. Mamchaoui 1, S. Pe´rie´ 2, J.L. St Guily 2, G. Butler-Browne 1, V. Mouly 1, C. Trollet 1 1 UPMC Universite´ Paris 6, UM76, Institut de Myologie, INSERM U 974, Paris, France; 2 Service d’Oto-Rhino-Laryngologie et de Chirurgie CervicoFaciale, Faculte´ de Me´decine St Antoine, UPMC, Paris, France Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant inherited dystrophy due to an expansion of GCG repeats in the coding region of the ubiquitously expressed PABPN1 gene. The main muscular targets of OPMD are cricopharyngeal muscle (CPM) and elevator eyelid muscle whose progressive involvement leads to dysphagia and ptosis. We have recently demonstrated that OPMD CPM is characterized by atrophy, fibrosis and increased PAX7-positive cells compared to control CPM and to OPMD non-affected muscles such as quadriceps (QM). These results suggest that the specific involvement of affected muscles in OPMD correlates with an exacerbated fibrosis and a failure of the regenerative response. This led us to further study the skeletal muscle progenitor cells from CPM and their possible deregulation in OPMD. In vitro, primary cultures isolated from CPM biopsies of both OPMD (n = 4) and control (n = 4) subjects were characterized by a rapid fall of their myogenicity, whereas in primary cultures from control QM (n = 3) the myogenicity was maintained throughout the course of the lifespan. Several hypotheses for this drastic loss of myogenicity have been investigated, e.g. proliferative deregulation between resident fibroblasts and myoblasts. In addition, CPM cells regeneration capacity was explored in vivo. Each primary culture was injected into cryodamaged tibialis anterior (TA) muscle of an immunodeficient mouse model. One month after injection, a high number of human PAX7-positive satellite cells were found in TA muscles injected with CPM myoblasts compared to control injected QM myoblasts. Moreover, an elevated number of human cells were revealed in the interstitial space of TA muscle injected by CPM myoblasts. Altogether, these results show that muscle primary cultures represent a good model to further study the deregulations observed in OPMD CPM. Cellular and molecular mechanisms deregulated in both fibroblasts and myoblasts fractions are now being investigated. http://dx.doi:10.1016/j.nmd.2013.06.649
P.16.13 Myopathy with typical OPMD morphology without association with the PABPN1 gene locus C. Hedberg 1, P. Chinnery 2, C. Lindberg 3, T. Martinsson 4, A. Oldfors 1 1 Biomedicin, Pathology, Gothenburg, Sweden; 2 Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; 3 Biomedicin, Neurology, Gothenburg, Sweden; 4 Biomedicin, Clinical Genetics, Gothenburg, Sweden Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive ptosis of the eyelids and dysphagia. Intranuclear inclusions of tubulofilamentous (INIs) in skeletal muscle constitute a pathological hallmark for this disease. The filaments are up to 250 nm in length and have external diameter of 8.5 nm and an internal diameter of 3 nm. The only causative mutation described to date is a trip-
let repeat expansion consisting of 2–7 additional base triplets in a repeat sequence in exon 1 of the polyadenine binding protein nuclear 1 (PABPN1) gene localized on chromosome 14q11.2. This results in an increase in length of a polyalanine tract in the PABPN1 protein from 10 to 12– 17 residues. We describe the clinical, histopathological and genetically findings in three individuals from a Swedish family, with a dominantly inherited adult-onset myopathy characterized by ptosis and dysphagia. Muscle histopathological features included rimmed vacuoles and nuclei containing inclusions of unique 8.5 nm filaments and insoluble PABPN1 protein. The PABPN1 gene was excluded as the disease causative gene in this family both by direct DNA sequencing of the gene together with high density single nucleotide polymorphism (SNP) arrays covering the entire genome excluding the locus harbouring the PABPN1 gene. http://dx.doi:10.1016/j.nmd.2013.06.650
METABOLIC MYOPATHIES P.17.1 Phenotypic variation within 22 families with Pompe disease S.C.A. Wens 1, C.M. Van Gelder 2, M.E. Kruijshaar 2, J.M. De Vries 1, N.A.M. Van der Beek 1, A.J.J. Reuser 2, P.A. Van Doorn 1, A.T. Van der Ploeg 2, E. Brusse 1 1 Erasmus MC University Medical Centre, Neurology, Center for Lysosomal and Metabolic Diseases, Rotterdam, Netherlands; 2 Erasmus MC University Medical Centre, Center for Lysosomal and Metabolic Diseases, Rotterdam, Netherlands Pompe disease is an autosomal recessive disorder caused by a deficiency of acid a-glucosidase (GAA) leading to glycogen accumulation in different tissues. Pompe disease has a broad clinical spectrum, in which the phenotype can vary widely, even in patients with a similar GAA genotype. The aim of this study was to describe phenotypic variation among siblings with non-classic Pompe disease in the Netherlands. We identified 22 families consisting of two or three siblings (50 patients: 42 adults and eight children). All carried the most common mutation c.-32-13T>G in combination with another pathogenic mutation. Siblings typically all had symptom onset either in childhood or in adulthood, however, there was a wide variation in age of symptom onset between siblings (median difference of nine years). Presenting symptoms were similar across siblings in 14 families and limb girdle weakness was most frequently reported. In certain families ptosis, bulbar weakness or scapular winging were present in all siblings. The majority of wheelchair and/or ventilator dependent patients had an ambulant or non-ventilated sibling; half of these less affected siblings had a longer disease duration. Gender, GAA activity and co-morbidity did not appear to explain differences in phenotype between siblings. Since the course of disease and its severity in some families varied to the same extent as seen in unrelated patients with an identical genotype, other factors like epigenetic and environmental effects are likely to influence the clinical presentation and disease course. Additional studies are needed to identify these factors, as possible prognostic factors for disease course and outcome on ERT of an individual patient. http://dx.doi:10.1016/j.nmd.2013.06.651
P.17.2 Late onset Pompe disease with dilated cardiomyopathy T. Kurashige 1, N. Shiroma 1, A. Motoda 1, H. Ikenaga 1, N. Oda 1, T. Takahashi 1, M. Kosuga 2, Y. Kihara 1, K. Arihiro 1, M. Matsumoto 1 1 Hiroshima University, Hiroshima, Japan; 2 National Center for Child Health and Development, Tokyo, Japan