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P.4.6 Useful differential diagnostic markers between congenital myotonic dystrophy and X-linked myotubular myopathy
Abstracts / Neuromuscular Disorders 23 (2013) 738–852 P.4.5 Muscle NMR imaging in the rare E650K mutation in the DNM2 gene in a centronuclear myopathy patient M. Vainzof 1, P. Calyjur 1, M.C.G. Otaduy 2, C.F. Almeida 1, A. MartinsBach 1, R.Y. Carlier 3, J. Gurgel-Giannetti 4, E. Amaro 2, P.G. Carlier 3 1 Human Genome Research Center, Institute of Biosciences, University of Sa˜o Paulo, Genetics and Evolutionary Biology, Sa˜o Paulo, Brazil; 2 InRadHospital das Clı´nicas, Faculty of Medicine of the University of Sa˜o Paulo, Magnetic Resonance, Sa˜o Paulo, Brazil; 3 Institute of Myology, AIM & CEA NMR Laboratory, Paris, France; 4 Pediatric Neurology Service, Medical School, Universidade Federal de Minas Gerais, Pediatrics, Belo Horizonte, Brazil Autosomal dominant centronuclear myopathy (CNM) is characterized by slowly progressive muscular weakness and wasting, and high frequency of centrally located nuclei in muscle fibers. The disorder involves mainly limb girdle, trunk and neck muscles but may also affect distal muscles. Ptosis and limitation of eye movements are frequent. Molecular analysis has identified recurrent mutations in exons 8 and 11 and rare heterozygous missense mutations in the dynamin-2 (DNM2) gene, which encodes a protein involved in endocytosis and membrane trafficking, actin assembly, and centrosome cohesion. We recently identified an isolated case of a 34 years old male patient, complaining of gait difficulties since the age of 14 years. Two years ago, the condition evolved to limb muscle weakness due to a predominantly distal severe lower limbs muscle atrophy associated to pes cavus. He also presented mild facial weakness with a discrete ptosis without ophtalmoparesis. By sequencing DNM2 exons, we found the rare heterozygous missense mutation c.1948G > A (p.E650K) in the DNM2 gene. This mutation was only described in one Chilean family. T1-weighted whole-body NMR imaging revealed fatty degenerative changes predominantly affecting the legs (score of 3 in a scale of 4), the face and the thighs. Thigh muscle displayed the particular reticular-punctuated pattern of fatty infiltration seen in CNM patients. The pattern of lesion distribution and the particular muscle texture observed in this patient are highly evocative of the disease. Therefore, NMR findings are showing comparable alterations in DNM2-related CNM patients, independently of the pathogenic mutation. FAPESP-CEPID, CNPQ-INCT, FINEP, CAPES-COFECUB. http://dx.doi:10.1016/j.nmd.2013.06.443
P.4.6 Useful differential diagnostic markers between congenital myotonic dystrophy and X-linked myotubular myopathy K. Hamanaka, S. Noguchi, Y.K. Hayashi, I. Nishino National Institute of Neurology and Psychiatry, Department of Neuromuscular Research, Tokyo, Japan Congenital myotonic dystrophy (CDM) and X-linked myotubular myopathy (XLMTM) share common clinical and pathological features at the neonatal stage. Clinically, both CDM and XLMTM patients show reduced fetal movements, polyhydramnios, severe hypotonia and respiratory failure from birth. Pathologically, they commonly show increased number of fibers with internalized nuclei, in addition to peripheral halo. To find useful markers to pathologically differentiate between two disorders, we compared 29 CDM and 40 XLMTM muscle samples younger than 4 years of age in terms of difference in the percentage of internalized-nuclei fibers, peripheral halo and type 2C fibers. We also characterized the pathological changes of CDM and XLMTM along the time course. In CDM, the frequency of type 2C fibers is significantly higher and peripheral halo is seen only in early stages. In XLMTM, type 2C fibers are not increased and peripheral halo is seen in age-independent matter. Furthermore, extremely small type 2 fibers are seen at higher ages in XLMTM. These observations suggest that CDM pathology most likely
761
reflects muscle fiber immaturity while XLMTM pathology is produced by structural derangement due to MTM1 mutation. http://dx.doi:10.1016/j.nmd.2013.06.444
P.4.7 The natural history of myotubular myopathy, summary of the first year of enrollment K. Amburgey, D. Julian, E. Howell, M. Britt, J.J. Dowling University of Michigan, Ann Arbor, United States Myotubular myopathy (MTM) is an X-linked disorder characterized by muscle weakness, hypotonia, external ophthalmoplegia, and respiratory failure. At this time, no treatments exist for MTM. To prepare for future therapy development, the natural history of a condition must be well established. This study sought to expand on the two previous natural history studies that were performed over one decade ago. A five year prospective natural history study was launched in 2011. Data was gathered through a patient-reported survey, physical examination, pulmonary function testing (PFT), repetitive stimulation testing, collection of medical records, and pedigree. In the first year, 37 MTM participants (20 living, 7 deceased) were enrolled ranging from 10 months to 41 years. The majority of participants were wheelchair (70%) and ventilator dependent (78%). Scoliosis was reported among 67% of participants, developing at an average age of 2.93 years. Similar to the study performed by Herman and colleagues (1999), additional medical problems were reported including cardiac (35%), liver (40%), kidney (20%), and clotting (25%). PFT’s (n = 4) and the Hammersmith Functional Motor Scale (n = 6) were performed on a subset of participants and were not found to be useful outcome measures. Additionally, repetitive stimulation was performed on a subset of participants (n = 8) and no evidence of neuromuscular junction abnormalities were detected. Our results are similar to the previous studies, showing increased survival of MTM patients and the identification of additional medical problems which may require screening. Preclinical data has shown abnormalities in the neuromuscular junction, however, this was not confirmed in our small cohort of participants. Lastly, the investigation of additional outcome measures will be needed in preparation for future clinical trials. http://dx.doi:10.1016/j.nmd.2013.06.445
P.4.8 X-linked benign form of myotubular myopathy (XLMTM) with necklace fibres: A case report C. Ortez 1, A. Nascimento 1, C. Jou 2, C. Jimenez-Mallebrera 1, S. Paco 1, J. Corbera 2, V. Viancalana 3, J. Colomer 1 1 Hospital Sant Joan de De´u – UB, Unitat Patologia Neuromuscular, Barcelona, Spain; 2 Hospital Sant Joan de De´u – UB, Servei d’Anatomia Patologica, Barcelona, Spain; 3 Faculte de Me`decine-CHRU, Laboratoire Diagnostic Ge´netique, Strasbourg, France X-linked myotubular myopathy (XLMTM) is usually a severe condition caused by mutations in myotubularin gen MTM1, (Xq28), a lipid inositide phosphatase acting in remodeling of membranes. Most of the affected patients present a severe neonatal form with hypotonia, weakness, facial diplegia, difficulties in sucking in addition to other symptoms dying within the first months. The biopsy features are consistent with the presence of central nuclei in most fibres. However, a more benign phenotype with a distinctive hallmark has recently been described. Herein, we present a four year old boy affected by this benign form.
P.4.6 Useful differential diagnostic markers between congenital myotonic dystrophy and X-linked myotubular myopathy K. Hamanaka, S. Noguchi, Y.K. Hayashi, I. Nishino National Institute of Neurology and Psychiatry, Department of Neuromuscular Research, Tokyo, Japan Congenital myotonic dystrophy (CDM) and X-linked myotubular myopathy (XLMTM) share common clinical and pathological features at the neonatal stage. Clinically, both CDM and XLMTM patients show reduced fetal movements, polyhydramnios, severe hypotonia and respiratory failure from birth. Pathologically, they commonly show increased number of fibers with internalized nuclei, in addition to peripheral halo. To find useful markers to pathologically differentiate between two disorders, we compared 29 CDM and 40 XLMTM muscle samples younger than 4 years of age in terms of difference in the percentage of internalized-nuclei fibers, peripheral halo and type 2C fibers. We also characterized the pathological changes of CDM and XLMTM along the time course. In CDM, the frequency of type 2C fibers is significantly higher and peripheral halo is seen only in early stages. In XLMTM, type 2C fibers are not increased and peripheral halo is seen in age-independent matter. Furthermore, extremely small type 2 fibers are seen at higher ages in XLMTM. These observations suggest that CDM pathology most likely
761
reflects muscle fiber immaturity while XLMTM pathology is produced by structural derangement due to MTM1 mutation. http://dx.doi:10.1016/j.nmd.2013.06.444
P.4.7 The natural history of myotubular myopathy, summary of the first year of enrollment K. Amburgey, D. Julian, E. Howell, M. Britt, J.J. Dowling University of Michigan, Ann Arbor, United States Myotubular myopathy (MTM) is an X-linked disorder characterized by muscle weakness, hypotonia, external ophthalmoplegia, and respiratory failure. At this time, no treatments exist for MTM. To prepare for future therapy development, the natural history of a condition must be well established. This study sought to expand on the two previous natural history studies that were performed over one decade ago. A five year prospective natural history study was launched in 2011. Data was gathered through a patient-reported survey, physical examination, pulmonary function testing (PFT), repetitive stimulation testing, collection of medical records, and pedigree. In the first year, 37 MTM participants (20 living, 7 deceased) were enrolled ranging from 10 months to 41 years. The majority of participants were wheelchair (70%) and ventilator dependent (78%). Scoliosis was reported among 67% of participants, developing at an average age of 2.93 years. Similar to the study performed by Herman and colleagues (1999), additional medical problems were reported including cardiac (35%), liver (40%), kidney (20%), and clotting (25%). PFT’s (n = 4) and the Hammersmith Functional Motor Scale (n = 6) were performed on a subset of participants and were not found to be useful outcome measures. Additionally, repetitive stimulation was performed on a subset of participants (n = 8) and no evidence of neuromuscular junction abnormalities were detected. Our results are similar to the previous studies, showing increased survival of MTM patients and the identification of additional medical problems which may require screening. Preclinical data has shown abnormalities in the neuromuscular junction, however, this was not confirmed in our small cohort of participants. Lastly, the investigation of additional outcome measures will be needed in preparation for future clinical trials. http://dx.doi:10.1016/j.nmd.2013.06.445
P.4.8 X-linked benign form of myotubular myopathy (XLMTM) with necklace fibres: A case report C. Ortez 1, A. Nascimento 1, C. Jou 2, C. Jimenez-Mallebrera 1, S. Paco 1, J. Corbera 2, V. Viancalana 3, J. Colomer 1 1 Hospital Sant Joan de De´u – UB, Unitat Patologia Neuromuscular, Barcelona, Spain; 2 Hospital Sant Joan de De´u – UB, Servei d’Anatomia Patologica, Barcelona, Spain; 3 Faculte de Me`decine-CHRU, Laboratoire Diagnostic Ge´netique, Strasbourg, France X-linked myotubular myopathy (XLMTM) is usually a severe condition caused by mutations in myotubularin gen MTM1, (Xq28), a lipid inositide phosphatase acting in remodeling of membranes. Most of the affected patients present a severe neonatal form with hypotonia, weakness, facial diplegia, difficulties in sucking in addition to other symptoms dying within the first months. The biopsy features are consistent with the presence of central nuclei in most fibres. However, a more benign phenotype with a distinctive hallmark has recently been described. Herein, we present a four year old boy affected by this benign form.