- Email: [email protected]
G.P.36 An autosomal dominant distal myopathy
Abstracts / Neuromuscular Disorders 22 (2012) 804–908 affected HMERF patients. In addition, the mutation was identified in one British patient, in one Italian patient and in one additional Swedish family. The patients had the same phenotype with progressive muscle weakness in the lower limbs and respiratory muscles, cytoplasmic bodies and rimmed vacuolar myopathy in muscle biopsy. Muscle MRI findings are pathognomonic with fatty degenerative changes in semitendinosus, obturatorius, sartorius, gracilis and iliopsoas muscles with variable involvement of anterior and lateral compartment and tibialis posterior on the lower legs. All patients carried the same haplotype including markers D2S2173 and D2S385 at the mutational locus. The shared genomic region is less than 3.3 Mb in size suggesting an ancestral founder, and indicating the existence of many undiagnosed families with this mutation. http://dx.doi:10.1016/j.nmd.2012.06.057
G.P.36 An autosomal dominant distal myopathy J. Hu, Z. Zhao The Third Hospital of Hebei Medical University, Shijiazhuang, China The distal myopathies are a clinically and pathologically heterogeneous group of genetic disorders in which the distal muscles of limbs are selectively or disproportionately affected. Until date, at least 20 genes have been shown to be involved in distal myopathy. A 26-year-old Chinese male presented with progressive weakness of distal limbs for 2 years. His mother has the same symptoms. Neurological examination revealed wading gait, with no ataxia, predominantly distal limb weakness of four limbs was noticed. Sensory examination was unremarkable, no evidence of pyramidal tract signs. Serum creatine kinase was 656 IU/l. Electrocardiogram test was normal. Nerve conduction study showed normal sensory and motor nerve conduction. Needle electromyography showed decreased amplitude and short-duration motor unit action potentials and some myotonic discharges in some tested muscles. MRI scans of his legs revealed significantly fatty infiltration of anterior tibial muscles. Muscle biopsy of anterior tibial muscle revealed degenerating and necrotic fibers and many rimmed vacuoles were observed; type-fibers are predominant; glycogen and lipid contents appear normal; anti-dysferlin immunohistochemical stain was normal. MYH7 gene and Mex5–6 region of the TTN gene were sequenced. No pathogenic variant was detected. The patients we reported with distal muscular dystrophy was of early adult onset and presumably inherited in an autosomal dominant inheritance. It was characterized by a selective involvement of anterior tibial muscle, finger extensors muscle, and neck extension muscles. Serum CK level was mildly elevated. Histopathological findings revealed autophagic vacuoles and normal expression of dysferlin protein. Laing distal myopathy or tibial muscular dystrophy (TMD) was suspected according clinic, electrophysiological, and pathological findings. But no pathogenic variant was detected in MYH7 gene and Mex5–6 region of th. http://dx.doi:10.1016/j.nmd.2012.06.058
G.P.37 Muscle immunohistochemistry and pathology in Welander distal myopathy A. Vihola 1, M. Screen 1, O. Raheem 2, S. Huovinen 2, H. Haapasalo 2, P. Hackman 1, B. Udd 2 1 Folkhalsan Institute of Genetics and Haartman Institute, University of Helsinki, Department of Medical genetics, Helsinki, Finland; 2 Neuromuscular Research Unit, University Hospital of Tampere, Tampere, Finland Welander distal myopathy (WDM) is a dominant late-onset muscular dystrophy affecting primarily the extensor muscles of the fingers, and
819
progressing later to involve lower leg and all hand muscles. The muscle histopathology in WDM shows variable myopathic–dystrophic changes in the affected muscles with frequent rimmed vacuoles and autophagic degenerative pathology on electron microscopic examination. We have analyzed WDM muscle biopsies using immunohistochemistry, immunofluorescence and Western blotting to further elaborate which molecular pathways are affected in WDM. We have assessed the expression of the proteins involved in the autophagosomal–lysosomal pathway (LAMP2, Cathepsin B and LC3), the ubiquitin–proteasome-mediated protein degradation pathway and VCP, the linker between these pathways. In addition, we used common markers (SMI31, p62 and TDP-43) of the rimmed vacuolar pathologies such as s-IBM. Our results suggest that there is an increase of misfolded or aggregated, partly ubiquitinated proteins as shown with increase of sequestosome (p62), TDP-43 and SMI31 both in the rimmed vacuolar regions and patchy in all atrophic fibers. This is accompanied with activation of the autophagic system as judged by some increase of LAMP2 positive regions that are too large to represent normal mature lysosomes. In contrast, the rimmed vacuoles are more or less devoid of LAMP2 positive mature lysosomes, and are instead filled with LC3-positive autophagosomes. The primary mutation in WDM causes a downstream abnormality including both incapacity of the proteasomal system to degrade all ubiquitinated proteins, and apparent decompensation of the autophagic system despite its activation. http://dx.doi:10.1016/j.nmd.2012.06.059
MYOFIBRILLAR AND AUTOPHAGIC MYOPATHIES – POSTER PRESENTATIONS G.P.50 A nationwide survey of autophagic vacuolar myopathies characterized by autophagic vacuoles with sarcolemmal features (AVSF) in Japan K. Sugie 1, H. Komaki 2, D. Kaneda 3, T. Kurashige 4, M. Matsumoto 4, I. Nonaka 2, S. Ueno 1, I. Nishino 2 1 Nara Medical University, Department of Neurology, Nara, Japan; 2 National Center of Neurology and Psychiatry, Tokyo, Japan; 3 Osaka Red Cross Hospital, Neurology, Osaka, Japan; 4 Hiroshima University, Department of Neurology, Hiroshima, Japan Danon disease (DD), X-linked myopathy with excessive autophagy (XMEA), and related autophagic vacuolar myopathies (AVMs) are pathologically characterized by autophagic vacuoles with sarcolemmal features (AVSF). AVSF delineates a group of at least five clinically different myopathies, including DD and XMEA. However, the clinical features and the prevalences of these AVMs have not been well established. We sent questionnaires on these AVMs to 2617 hospitals in Japan that have departments of neurology, cardiology, or pediatrics. We reviewed clinical histories and muscle specimens provided by hospitals with AVM patients. In addition, we performed genetic analyses of the LAMP-2 and VMA21 genes. We identified 27 DD patients from 12 families, 3 XMEA patients from 1 family, 7 X-linked congenital AVM patients from 1 family, 2 infantile AVM patients, and 1 patient with adult-onset AVM with multiorgan involvement. All DD patients had LAMP-2 gene mutations. Lethal cardiomyopathy was evident in all DD patients. Hypertrophic cardiomyopathy (HCM) was documented in most men, while dilated cardiomyopathy was more common among women. All XMEA patients had VMA21 gene mutations. XMEA, infantile AVM, and congenital AVM patients had no cardiomyopathy. HCM developed in the adult with AVM. Pathologically, AVSF in all AVMs expressed virtually all sarcolemmal proteins on their vacuolar membranes. Multilayering of the basal lamina along vacuolar membranes was present in XMEA, infantile AVM, congenital AVM, and adult AVM. In addition, the locus for infantile AVM and congenital AVM was suggested to be the same region as that in XMEA. These AVMs are very rare muscular disorders and may be primarily caused by lysosomal
G.P.36 An autosomal dominant distal myopathy J. Hu, Z. Zhao The Third Hospital of Hebei Medical University, Shijiazhuang, China The distal myopathies are a clinically and pathologically heterogeneous group of genetic disorders in which the distal muscles of limbs are selectively or disproportionately affected. Until date, at least 20 genes have been shown to be involved in distal myopathy. A 26-year-old Chinese male presented with progressive weakness of distal limbs for 2 years. His mother has the same symptoms. Neurological examination revealed wading gait, with no ataxia, predominantly distal limb weakness of four limbs was noticed. Sensory examination was unremarkable, no evidence of pyramidal tract signs. Serum creatine kinase was 656 IU/l. Electrocardiogram test was normal. Nerve conduction study showed normal sensory and motor nerve conduction. Needle electromyography showed decreased amplitude and short-duration motor unit action potentials and some myotonic discharges in some tested muscles. MRI scans of his legs revealed significantly fatty infiltration of anterior tibial muscles. Muscle biopsy of anterior tibial muscle revealed degenerating and necrotic fibers and many rimmed vacuoles were observed; type-fibers are predominant; glycogen and lipid contents appear normal; anti-dysferlin immunohistochemical stain was normal. MYH7 gene and Mex5–6 region of the TTN gene were sequenced. No pathogenic variant was detected. The patients we reported with distal muscular dystrophy was of early adult onset and presumably inherited in an autosomal dominant inheritance. It was characterized by a selective involvement of anterior tibial muscle, finger extensors muscle, and neck extension muscles. Serum CK level was mildly elevated. Histopathological findings revealed autophagic vacuoles and normal expression of dysferlin protein. Laing distal myopathy or tibial muscular dystrophy (TMD) was suspected according clinic, electrophysiological, and pathological findings. But no pathogenic variant was detected in MYH7 gene and Mex5–6 region of th. http://dx.doi:10.1016/j.nmd.2012.06.058
G.P.37 Muscle immunohistochemistry and pathology in Welander distal myopathy A. Vihola 1, M. Screen 1, O. Raheem 2, S. Huovinen 2, H. Haapasalo 2, P. Hackman 1, B. Udd 2 1 Folkhalsan Institute of Genetics and Haartman Institute, University of Helsinki, Department of Medical genetics, Helsinki, Finland; 2 Neuromuscular Research Unit, University Hospital of Tampere, Tampere, Finland Welander distal myopathy (WDM) is a dominant late-onset muscular dystrophy affecting primarily the extensor muscles of the fingers, and
819
progressing later to involve lower leg and all hand muscles. The muscle histopathology in WDM shows variable myopathic–dystrophic changes in the affected muscles with frequent rimmed vacuoles and autophagic degenerative pathology on electron microscopic examination. We have analyzed WDM muscle biopsies using immunohistochemistry, immunofluorescence and Western blotting to further elaborate which molecular pathways are affected in WDM. We have assessed the expression of the proteins involved in the autophagosomal–lysosomal pathway (LAMP2, Cathepsin B and LC3), the ubiquitin–proteasome-mediated protein degradation pathway and VCP, the linker between these pathways. In addition, we used common markers (SMI31, p62 and TDP-43) of the rimmed vacuolar pathologies such as s-IBM. Our results suggest that there is an increase of misfolded or aggregated, partly ubiquitinated proteins as shown with increase of sequestosome (p62), TDP-43 and SMI31 both in the rimmed vacuolar regions and patchy in all atrophic fibers. This is accompanied with activation of the autophagic system as judged by some increase of LAMP2 positive regions that are too large to represent normal mature lysosomes. In contrast, the rimmed vacuoles are more or less devoid of LAMP2 positive mature lysosomes, and are instead filled with LC3-positive autophagosomes. The primary mutation in WDM causes a downstream abnormality including both incapacity of the proteasomal system to degrade all ubiquitinated proteins, and apparent decompensation of the autophagic system despite its activation. http://dx.doi:10.1016/j.nmd.2012.06.059
MYOFIBRILLAR AND AUTOPHAGIC MYOPATHIES – POSTER PRESENTATIONS G.P.50 A nationwide survey of autophagic vacuolar myopathies characterized by autophagic vacuoles with sarcolemmal features (AVSF) in Japan K. Sugie 1, H. Komaki 2, D. Kaneda 3, T. Kurashige 4, M. Matsumoto 4, I. Nonaka 2, S. Ueno 1, I. Nishino 2 1 Nara Medical University, Department of Neurology, Nara, Japan; 2 National Center of Neurology and Psychiatry, Tokyo, Japan; 3 Osaka Red Cross Hospital, Neurology, Osaka, Japan; 4 Hiroshima University, Department of Neurology, Hiroshima, Japan Danon disease (DD), X-linked myopathy with excessive autophagy (XMEA), and related autophagic vacuolar myopathies (AVMs) are pathologically characterized by autophagic vacuoles with sarcolemmal features (AVSF). AVSF delineates a group of at least five clinically different myopathies, including DD and XMEA. However, the clinical features and the prevalences of these AVMs have not been well established. We sent questionnaires on these AVMs to 2617 hospitals in Japan that have departments of neurology, cardiology, or pediatrics. We reviewed clinical histories and muscle specimens provided by hospitals with AVM patients. In addition, we performed genetic analyses of the LAMP-2 and VMA21 genes. We identified 27 DD patients from 12 families, 3 XMEA patients from 1 family, 7 X-linked congenital AVM patients from 1 family, 2 infantile AVM patients, and 1 patient with adult-onset AVM with multiorgan involvement. All DD patients had LAMP-2 gene mutations. Lethal cardiomyopathy was evident in all DD patients. Hypertrophic cardiomyopathy (HCM) was documented in most men, while dilated cardiomyopathy was more common among women. All XMEA patients had VMA21 gene mutations. XMEA, infantile AVM, and congenital AVM patients had no cardiomyopathy. HCM developed in the adult with AVM. Pathologically, AVSF in all AVMs expressed virtually all sarcolemmal proteins on their vacuolar membranes. Multilayering of the basal lamina along vacuolar membranes was present in XMEA, infantile AVM, congenital AVM, and adult AVM. In addition, the locus for infantile AVM and congenital AVM was suggested to be the same region as that in XMEA. These AVMs are very rare muscular disorders and may be primarily caused by lysosomal