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P2.05 Long-term measurement of muscle strength in distal myopathy with rimmed vacuoles (DMRV)
Abstracts / Neuromuscular Disorders 20 (2010) 596–680
mutations of GNE gene in HIBM are quite different among nationalities and ethnic origin, even among individuals from oriental countries. doi:10.1016/j.nmd.2010.07.074
P2.03 Natural course of distal myopathy with rimmed vacuoles (hereditary inclusion body myopathy) in Japan. The distal myopathy functional scale (DMFS) for assessment of clinical status M. Mori-Yoshimura 1, K. Momma 2, H. Nakamura 1, Y. Oya 1, M.V. Malicdan 2, S. Noguchi 2, Y.H. Hayashi 2, M. Murata 1, I. Nishino 2 1
National Center Hospital of Neurology and Psychiatry, Department of neurology, Kodaira, Tokyo, Japan, 2 National Institute of Neuroscience, National Center of Neurology and Psychiatry, Department of Neuromuscular Research, Kodaira, Tokyo, Japan Background: Distal myopathy with rimmed vacuoles (DMRV), or hereditary inclusion body myopathy (hIBM), is an adult-onset, moderately progressive autosomal recessive myopathy caused by GNE mutation. Clinical trials for DMRV should be based on detailed knowledge of the kind and severity of symptoms and the natural course of the genetically confirmed DMRV. Objective: to know the natural course of DMRV and to establish distal myopathy functional scale (DMSF). Methods: A detailed questionnaire covering the medical history and current status was developed and information was gathered from 66 Japanese patients with genetically-confirmed DMRV (males, 23 females, 43). DMSF, comprising nine items on daily living abilities, was made. Results: The mean (±SD) age of the patients was 43.4 ± 12.7 years. The initial symptoms appeared at 25.7 ± 9.4 years and were mostly related to drop foot and mobility. 64.4% were wheelchair users. To monitor the progression of disability and describe past and present symptoms, we tried to establish DMSF. The questionnaire sought information on the grade of DMRV, which was divided into five stages, ranging from completely normal to totally dependent. DMFS was useful instrument for the evaluation of functional state and functional changes in patients with DMRV/hIBM. It was also useful as a screening tool for entry into clinical trials, as a surrogate measure of function in situations when muscle strength cannot be measured directly, and possibly also to measure the therapeutic effects. Age at onset and age at starting wheelchair use, together with the final DMFS score indicated that patients with homozygous mutation mostly of p.V572L were more severely affected than those with compound heterozygous mutation. Thus, the genetic background should be considered when evaluating the clinical stage of DMRV-hIBM. Conclusions: DMSF is a useful tool to evaluate DMRV patients. Homozygous V572L mutations may be associated with a severe phenotype. doi:10.1016/j.nmd.2010.07.075
P2.04 DMRV and GNE mutations: genotype–phenotype correlation in 100 Japanese patients H. Tomimitsu 1, A. Arai 2, K. Murayama 3, J. Shimizu 4, N. Suzuki 5, T. Nagata 5, M. Aoki 5, H. Mizusawa 1, K. Tanaka 6, I. Nishino 3 1
Tokyo Medical and Dental University, Neurology and Neurological Science, Tokyo, Japan, 2 Niigata University, Neurology, Niigata, Japan, 3 National Center of Neurology and Psychiatry, Neuromuscular Research, National Institute of Neuroscience, Kodaira, Japan, 4 University of Tokyo, Neurology, Tokyo, Japan, 5 Tohoku University, Neurology, Sendai, Japan, 6 Kanazawa Medical University, Neurology, Kanazawa, Japan
619
Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder with preferential involvement of the distal muscles in lower extremities at young adulthood and spares quadriceps muscles. In DMRV patients, we previously identified homogeneous and compound heterozygous mutations in the UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is the causative gene in hereditary inclusion body myopathy (hIBM). Purpose: To investigate the correlation between phenotypes and genotypes in DMRV, we analyzed the information of 100 cases of this disease in Japan. Results: p.V572L is the most common mutation, followed by p.D176V. We cannot detect definite genotype–phenotype correlation in this study, but the symptoms tend to be milder in the compound heterozygous cases that have one mutation in the epimerase domain and another in kinase domain. Moreover, we found some cases with myocardial involvement and a few cases with abnormal findings in the brain, suggesting involvement of organs other than skeletal muscle in DMRV patients. Conclusion: Although we could not find the genotype–phenotype correlation in DMRV in this study, these symptoms other than skeletal muscles are very important for assessment of DMRV patients. doi:10.1016/j.nmd.2010.07.076
P2.05 Long-term measurement of muscle strength in distal myopathy with rimmed vacuoles (DMRV) Y.O. Oya 1, I.N. Nishino 2, M.K. Kawai 3 NCNP, Neurology, Kodaira city, Japan, 2 NCNP, Kodaira, Japan, 3 NHO Higashi-saitama Hosp, Neurology, Hasuda City, Japan 1
Distal myopathy with rimmed vacuoles (DMRV), also called Nonaka myopathy (OMIM #605820) or hereditary inclusion body myopathy, which is caused by UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene mutations, is a disorder of sialylation and can potentially be treated by giving sialic acids. We previously reported the outcome of trial of b2 adrenergic agonist clenbuterol in adult muscular dystrophy patients (Rinsho Shinkeigaku 2001), and we treated also patients with DMRV. We measured isometric muscle strength with a hand-held dynamometer (HHD) as well as grip and pinch strength. We report progressive deterioration of strength in patients with DMRV with or without clenbuterol treatment. In an 18-year-old male p.V572L homozygote, clenbuterol improved power and volume of well-preserved muscles of upper limbs transiently. He showed initially relative preservation of ankle dorsiflexion compared to plantar flexion. He showed linear decrease in leg muscle strength, especially knee extension; there were no muscle movements measurable with HHD in his legs in 3 years. A 24-yearold female p.V572L/D176V compound heterozygote had difficulty in standing and walking, and no leg movements measurable with HHD in 3 years. At the age of 32, only pinch strength was measurable. These two patients had the most or the second most common mutations, but the clinical manifestations were atypical in some aspects; knee flexion strength could be measured initially, and strength progressively decreased in all the limb muscles including the quadriceps. Some other patients showed almost no changes in strength in one or two years, with or without treatment. Knee extension was the only measurable movement in the legs in most such patients, but its strength gradually decreased. Disease progression is rapid in some patients, although other patients showed so-called quadriceps-sparing myopathy. There is wide variation in disease progression among DMRV patients. doi:10.1016/j.nmd.2010.07.077
mutations of GNE gene in HIBM are quite different among nationalities and ethnic origin, even among individuals from oriental countries. doi:10.1016/j.nmd.2010.07.074
P2.03 Natural course of distal myopathy with rimmed vacuoles (hereditary inclusion body myopathy) in Japan. The distal myopathy functional scale (DMFS) for assessment of clinical status M. Mori-Yoshimura 1, K. Momma 2, H. Nakamura 1, Y. Oya 1, M.V. Malicdan 2, S. Noguchi 2, Y.H. Hayashi 2, M. Murata 1, I. Nishino 2 1
National Center Hospital of Neurology and Psychiatry, Department of neurology, Kodaira, Tokyo, Japan, 2 National Institute of Neuroscience, National Center of Neurology and Psychiatry, Department of Neuromuscular Research, Kodaira, Tokyo, Japan Background: Distal myopathy with rimmed vacuoles (DMRV), or hereditary inclusion body myopathy (hIBM), is an adult-onset, moderately progressive autosomal recessive myopathy caused by GNE mutation. Clinical trials for DMRV should be based on detailed knowledge of the kind and severity of symptoms and the natural course of the genetically confirmed DMRV. Objective: to know the natural course of DMRV and to establish distal myopathy functional scale (DMSF). Methods: A detailed questionnaire covering the medical history and current status was developed and information was gathered from 66 Japanese patients with genetically-confirmed DMRV (males, 23 females, 43). DMSF, comprising nine items on daily living abilities, was made. Results: The mean (±SD) age of the patients was 43.4 ± 12.7 years. The initial symptoms appeared at 25.7 ± 9.4 years and were mostly related to drop foot and mobility. 64.4% were wheelchair users. To monitor the progression of disability and describe past and present symptoms, we tried to establish DMSF. The questionnaire sought information on the grade of DMRV, which was divided into five stages, ranging from completely normal to totally dependent. DMFS was useful instrument for the evaluation of functional state and functional changes in patients with DMRV/hIBM. It was also useful as a screening tool for entry into clinical trials, as a surrogate measure of function in situations when muscle strength cannot be measured directly, and possibly also to measure the therapeutic effects. Age at onset and age at starting wheelchair use, together with the final DMFS score indicated that patients with homozygous mutation mostly of p.V572L were more severely affected than those with compound heterozygous mutation. Thus, the genetic background should be considered when evaluating the clinical stage of DMRV-hIBM. Conclusions: DMSF is a useful tool to evaluate DMRV patients. Homozygous V572L mutations may be associated with a severe phenotype. doi:10.1016/j.nmd.2010.07.075
P2.04 DMRV and GNE mutations: genotype–phenotype correlation in 100 Japanese patients H. Tomimitsu 1, A. Arai 2, K. Murayama 3, J. Shimizu 4, N. Suzuki 5, T. Nagata 5, M. Aoki 5, H. Mizusawa 1, K. Tanaka 6, I. Nishino 3 1
Tokyo Medical and Dental University, Neurology and Neurological Science, Tokyo, Japan, 2 Niigata University, Neurology, Niigata, Japan, 3 National Center of Neurology and Psychiatry, Neuromuscular Research, National Institute of Neuroscience, Kodaira, Japan, 4 University of Tokyo, Neurology, Tokyo, Japan, 5 Tohoku University, Neurology, Sendai, Japan, 6 Kanazawa Medical University, Neurology, Kanazawa, Japan
619
Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder with preferential involvement of the distal muscles in lower extremities at young adulthood and spares quadriceps muscles. In DMRV patients, we previously identified homogeneous and compound heterozygous mutations in the UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is the causative gene in hereditary inclusion body myopathy (hIBM). Purpose: To investigate the correlation between phenotypes and genotypes in DMRV, we analyzed the information of 100 cases of this disease in Japan. Results: p.V572L is the most common mutation, followed by p.D176V. We cannot detect definite genotype–phenotype correlation in this study, but the symptoms tend to be milder in the compound heterozygous cases that have one mutation in the epimerase domain and another in kinase domain. Moreover, we found some cases with myocardial involvement and a few cases with abnormal findings in the brain, suggesting involvement of organs other than skeletal muscle in DMRV patients. Conclusion: Although we could not find the genotype–phenotype correlation in DMRV in this study, these symptoms other than skeletal muscles are very important for assessment of DMRV patients. doi:10.1016/j.nmd.2010.07.076
P2.05 Long-term measurement of muscle strength in distal myopathy with rimmed vacuoles (DMRV) Y.O. Oya 1, I.N. Nishino 2, M.K. Kawai 3 NCNP, Neurology, Kodaira city, Japan, 2 NCNP, Kodaira, Japan, 3 NHO Higashi-saitama Hosp, Neurology, Hasuda City, Japan 1
Distal myopathy with rimmed vacuoles (DMRV), also called Nonaka myopathy (OMIM #605820) or hereditary inclusion body myopathy, which is caused by UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene mutations, is a disorder of sialylation and can potentially be treated by giving sialic acids. We previously reported the outcome of trial of b2 adrenergic agonist clenbuterol in adult muscular dystrophy patients (Rinsho Shinkeigaku 2001), and we treated also patients with DMRV. We measured isometric muscle strength with a hand-held dynamometer (HHD) as well as grip and pinch strength. We report progressive deterioration of strength in patients with DMRV with or without clenbuterol treatment. In an 18-year-old male p.V572L homozygote, clenbuterol improved power and volume of well-preserved muscles of upper limbs transiently. He showed initially relative preservation of ankle dorsiflexion compared to plantar flexion. He showed linear decrease in leg muscle strength, especially knee extension; there were no muscle movements measurable with HHD in his legs in 3 years. A 24-yearold female p.V572L/D176V compound heterozygote had difficulty in standing and walking, and no leg movements measurable with HHD in 3 years. At the age of 32, only pinch strength was measurable. These two patients had the most or the second most common mutations, but the clinical manifestations were atypical in some aspects; knee flexion strength could be measured initially, and strength progressively decreased in all the limb muscles including the quadriceps. Some other patients showed almost no changes in strength in one or two years, with or without treatment. Knee extension was the only measurable movement in the legs in most such patients, but its strength gradually decreased. Disease progression is rapid in some patients, although other patients showed so-called quadriceps-sparing myopathy. There is wide variation in disease progression among DMRV patients. doi:10.1016/j.nmd.2010.07.077