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Clinimetric studies in centronuclear myopathies
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212 describe the baseline data obtained from 8 sites in Europe. Currently, 24 patients (22 males and 2 symptomatic females) have been enrolled in France, Germany, Belgium and Spain. 25% are younger than 2 years old, 16.7% are between 2 and 6 years old and 58.3% are older than 6 years old. 7 patients are ambulant including the 2 women. Initial symptoms invariably include hypotonia (all 22 males enrolled), with respiratory distress (19/24) and muscle weakness (16/24) also frequently seen. Respiratory function is significantly altered. Six of the 8 nonambulant patients older than 6yo are ventilated via a tracheostomy. Forced vital capacity (FVC) of the 2 other patients are 7 and 19% of the predicted value. Ambulant male patients also have altered respiratory function (Mean FVC: 46.3 ± 16.2 % predicted value). Seven additional patients have been identified and will be enrolled in the coming months. http://dx.doi.org/10.1016/j.nmd.2016.06.114
P.93 MTM1-related myopathy carrier females manifest significant skeletal asymmetries and a spectrum of muscle involvement A. Reghan Foley 1, B. Cocanougher 2, L. Flynn 1, P. Yun 1, M. Jain 3, M. Waite 3, R. Vasavada 3, S. de Chastonay 4, S. Donkervoort 1, C. Bonnemann 1 1 National Institutes of Health, NINDS, Bethesda, USA; 2 Howard Hughes Medical Institute, Ashburn, USA; 3 National Institutes of Health, Bethesda, USA; 4 Cure CMD, Torrance, USA X-linked myotubular myopathy (XLMTM) results from mutations in MTM1 and manifests in males with severe congenital hypotonia, weakness and respiratory insufficiency. Carrier females are less well-characterized, with reports indicating a spectrum of disease, ranging from mild facial weakness to severe congenital weakness. We deeply phenotyped a cohort of ten females with causative mutations in MTM1, evaluating the severity of disease expression based on muscle weakness, pulmonary function (spirometry and dynamic breathing MRI), muscle imaging (ultrasound and MRI) and skeletal morphology. Neuromuscular examination revealed patterns of muscle involvement along a spectrum of weakness severity which we categorized as severe (non-ambulant) (n = 1); moderate (assisted ambulation) (n = 2); mild (independent ambulation but with evidence of muscle weakness) (n = 5) and non-manifesting (no evidence of muscle weakness) (n = 2). Both the severity of respiratory insufficiency and the degree of abnormal signal on muscle imaging were directly correlated to the degree of muscle weakness. Interestingly, we noted significant and consistent left-to-right asymmetries evident in all ten females evaluated in our cohort, even in the absence of muscle weakness. Asymmetries of muscle strength and skeletal morphology appeared to correlate with handedness, with evidence of weakness and atrophy of extremities contralateral to each individual’s dominant side. The degree of skeletal asymmetry did not necessarily correlate with the degree of weakness, however, potentially suggesting distinct pathways for MTM1-encoded myotubularin, an ubiquitously expressed phosphoinosotide phosphatase, in the development of skeletal morphology and skeletal muscles. Deep phenotyping of MTM1-related myopathy carrier females is particularly timely, as gene therapy trials for infant males with XLMTM are being planned, the outcome of which will determine whether this gene therapy may be extended to symptomatic carrier females. http://dx.doi.org/10.1016/j.nmd.2016.06.115
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associated with fatal respiratory failure. The disease is caused by loss-offunction mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals (including MTMR1 to 14). We recently demonstrated the therapeutic efficacy of intravenous delivery of recombinant adeno-associated viral vectors (rAAV) expressing myotubularin in murine and canine animal models of the disease. As an alternative approach, we tested in the present study whether Mtm1 closest homologues, Mtmr1 and Mtmr2, could also rescue the XLMTM phenotype. Recombinant serotype-9 AAV vectors encoding either MTMR1 or MTMR2 under the control of the desmin promoter were injected into the tibialis anterior muscle of two week-old Mtm1-deficient knockout mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtmr2 but not Mtmr1 overexpression. The histopathological hallmarks were normalized, and muscle hypotrophy and contractility were improved. Furthermore, systemic administration of a single dose of this rAAV9-Mtmr2 vector in mutant mice improved the motor activity and contractile force, and prolonged survival throughout a 3-month study. Altogether, our results establish the proof-of concept that skeletal muscle-targeted MTMR2 overexpression represents a novel target for therapeutic development in myotubular myopathy. http://dx.doi.org/10.1016/j.nmd.2016.06.116
P.95 Clinimetric studies in centronuclear myopathies T. Rosa, C. Iwabe-Marchese, L. Queiroz, M. França Jr, A. Nucci Universidade Estadual de Campinas-UNICAMP, Campinas, Brazil To describe the phenotype spectrum of patients with centronuclear myopathies (CNM) from a university hospital. The gold standard for diagnosis was muscle biopsy. Medical records were reviewed and patients underwent to clinimetric examination protocol: MRC scale, pulmonary function test, Portuguese version of motor function measure scale (MFM-P) and functional independence measure (FIM). We used the SYSTAT v.9.0 software to perform descriptive analysis and Pearson correlation coefficient (with Bonferroni correction) to evaluate possible correlations. Significance was considered as p < 0.05. A total of 13 cases were included, with a male/female ratio of 4/9 and a mean age of 30.2 years (range: 7–59 years). Disease was neonatal in 4 cases, had early (7) and adult (2) onset. There were 2 families: one with mother and 3 daughters affected and other with mother and daughter. MRC revealed widespread weakness, especially in axial cervical muscles, pelvic girdle and ankle dorsiflexors. All patients had abnormal vertebral column deviation and one was wheelchair bounded. Mean total MFM-P score was 65.7% ± 9.5 (range: 50%–85.4%). Dimensions 1 (D1), 2 (D2) and 3(D3) had 39.1 ± 23.1, 86.6 ± 10.8 and 77.8 ± 29.9 mean scores, respectively. FIM showed complete independence in 9/13 cases; modified dependence up to 25% and dependence up to 50% in 2/13 each. FVC was <50% in 5/13, 50–69% in 6/13 and >70% in 2/13 patients. There was no significant correlation between lung and motor functions. MFM-P and FIM had significant correlation in their total scores (r = 0.66; p = 0.014). Considering D1, it was also correlated to the following FIM sub-domains: mobility (r = 0.62; p = 0.021), locomotion (r = 0.61; p = 0.025) and self-care (r = 0.63; p = 0.021). Pulmonary function, MFM-P and FIM were useful to determine the phenotype severity in a cohort of CNM patients and also were capable to highlight intra-familial variability. http://dx.doi.org/10.1016/j.nmd.2016.06.117
P.94 AAV-mediated MTMR2 delivery prolongs survival and rescues the pathology in a mouse model of myotubular myopathy N. Danièle 1, C. Moal 1, L. Julien 1, T. Jamet 1, R. Joubert 1, S. Martin 2, A. Vignaud 1, M. Lawlor 3, A. Buj-Bello 1 1 Genethon, INSERM U951, Evry, France; 2 Genethon, Evry, France; 3 Medical College of Wisconsin, Milwaukee, USA X-linked myotubular myopathy (XLMTM) is a severe congenital disorder leading to generalized skeletal muscle weakness in male infants, frequently
P.96 A new homozygous frameshifting mutation in SPEG causes mild centronuclear myopathy A. Kaçar Bayram 1, H. Per 1, S. Zorludemir 2, H. Wang 3, H. Gumus 1, S. Çırak 3 1 Department of Pediatrics, Division of Pediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey; 2 Department of Pathology, School of Medicine, Çukurova University, Adana, Turkey; 3 Department of
P.93 MTM1-related myopathy carrier females manifest significant skeletal asymmetries and a spectrum of muscle involvement A. Reghan Foley 1, B. Cocanougher 2, L. Flynn 1, P. Yun 1, M. Jain 3, M. Waite 3, R. Vasavada 3, S. de Chastonay 4, S. Donkervoort 1, C. Bonnemann 1 1 National Institutes of Health, NINDS, Bethesda, USA; 2 Howard Hughes Medical Institute, Ashburn, USA; 3 National Institutes of Health, Bethesda, USA; 4 Cure CMD, Torrance, USA X-linked myotubular myopathy (XLMTM) results from mutations in MTM1 and manifests in males with severe congenital hypotonia, weakness and respiratory insufficiency. Carrier females are less well-characterized, with reports indicating a spectrum of disease, ranging from mild facial weakness to severe congenital weakness. We deeply phenotyped a cohort of ten females with causative mutations in MTM1, evaluating the severity of disease expression based on muscle weakness, pulmonary function (spirometry and dynamic breathing MRI), muscle imaging (ultrasound and MRI) and skeletal morphology. Neuromuscular examination revealed patterns of muscle involvement along a spectrum of weakness severity which we categorized as severe (non-ambulant) (n = 1); moderate (assisted ambulation) (n = 2); mild (independent ambulation but with evidence of muscle weakness) (n = 5) and non-manifesting (no evidence of muscle weakness) (n = 2). Both the severity of respiratory insufficiency and the degree of abnormal signal on muscle imaging were directly correlated to the degree of muscle weakness. Interestingly, we noted significant and consistent left-to-right asymmetries evident in all ten females evaluated in our cohort, even in the absence of muscle weakness. Asymmetries of muscle strength and skeletal morphology appeared to correlate with handedness, with evidence of weakness and atrophy of extremities contralateral to each individual’s dominant side. The degree of skeletal asymmetry did not necessarily correlate with the degree of weakness, however, potentially suggesting distinct pathways for MTM1-encoded myotubularin, an ubiquitously expressed phosphoinosotide phosphatase, in the development of skeletal morphology and skeletal muscles. Deep phenotyping of MTM1-related myopathy carrier females is particularly timely, as gene therapy trials for infant males with XLMTM are being planned, the outcome of which will determine whether this gene therapy may be extended to symptomatic carrier females. http://dx.doi.org/10.1016/j.nmd.2016.06.115
S117
associated with fatal respiratory failure. The disease is caused by loss-offunction mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals (including MTMR1 to 14). We recently demonstrated the therapeutic efficacy of intravenous delivery of recombinant adeno-associated viral vectors (rAAV) expressing myotubularin in murine and canine animal models of the disease. As an alternative approach, we tested in the present study whether Mtm1 closest homologues, Mtmr1 and Mtmr2, could also rescue the XLMTM phenotype. Recombinant serotype-9 AAV vectors encoding either MTMR1 or MTMR2 under the control of the desmin promoter were injected into the tibialis anterior muscle of two week-old Mtm1-deficient knockout mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtmr2 but not Mtmr1 overexpression. The histopathological hallmarks were normalized, and muscle hypotrophy and contractility were improved. Furthermore, systemic administration of a single dose of this rAAV9-Mtmr2 vector in mutant mice improved the motor activity and contractile force, and prolonged survival throughout a 3-month study. Altogether, our results establish the proof-of concept that skeletal muscle-targeted MTMR2 overexpression represents a novel target for therapeutic development in myotubular myopathy. http://dx.doi.org/10.1016/j.nmd.2016.06.116
P.95 Clinimetric studies in centronuclear myopathies T. Rosa, C. Iwabe-Marchese, L. Queiroz, M. França Jr, A. Nucci Universidade Estadual de Campinas-UNICAMP, Campinas, Brazil To describe the phenotype spectrum of patients with centronuclear myopathies (CNM) from a university hospital. The gold standard for diagnosis was muscle biopsy. Medical records were reviewed and patients underwent to clinimetric examination protocol: MRC scale, pulmonary function test, Portuguese version of motor function measure scale (MFM-P) and functional independence measure (FIM). We used the SYSTAT v.9.0 software to perform descriptive analysis and Pearson correlation coefficient (with Bonferroni correction) to evaluate possible correlations. Significance was considered as p < 0.05. A total of 13 cases were included, with a male/female ratio of 4/9 and a mean age of 30.2 years (range: 7–59 years). Disease was neonatal in 4 cases, had early (7) and adult (2) onset. There were 2 families: one with mother and 3 daughters affected and other with mother and daughter. MRC revealed widespread weakness, especially in axial cervical muscles, pelvic girdle and ankle dorsiflexors. All patients had abnormal vertebral column deviation and one was wheelchair bounded. Mean total MFM-P score was 65.7% ± 9.5 (range: 50%–85.4%). Dimensions 1 (D1), 2 (D2) and 3(D3) had 39.1 ± 23.1, 86.6 ± 10.8 and 77.8 ± 29.9 mean scores, respectively. FIM showed complete independence in 9/13 cases; modified dependence up to 25% and dependence up to 50% in 2/13 each. FVC was <50% in 5/13, 50–69% in 6/13 and >70% in 2/13 patients. There was no significant correlation between lung and motor functions. MFM-P and FIM had significant correlation in their total scores (r = 0.66; p = 0.014). Considering D1, it was also correlated to the following FIM sub-domains: mobility (r = 0.62; p = 0.021), locomotion (r = 0.61; p = 0.025) and self-care (r = 0.63; p = 0.021). Pulmonary function, MFM-P and FIM were useful to determine the phenotype severity in a cohort of CNM patients and also were capable to highlight intra-familial variability. http://dx.doi.org/10.1016/j.nmd.2016.06.117
P.94 AAV-mediated MTMR2 delivery prolongs survival and rescues the pathology in a mouse model of myotubular myopathy N. Danièle 1, C. Moal 1, L. Julien 1, T. Jamet 1, R. Joubert 1, S. Martin 2, A. Vignaud 1, M. Lawlor 3, A. Buj-Bello 1 1 Genethon, INSERM U951, Evry, France; 2 Genethon, Evry, France; 3 Medical College of Wisconsin, Milwaukee, USA X-linked myotubular myopathy (XLMTM) is a severe congenital disorder leading to generalized skeletal muscle weakness in male infants, frequently
P.96 A new homozygous frameshifting mutation in SPEG causes mild centronuclear myopathy A. Kaçar Bayram 1, H. Per 1, S. Zorludemir 2, H. Wang 3, H. Gumus 1, S. Çırak 3 1 Department of Pediatrics, Division of Pediatric Neurology, School of Medicine, Erciyes University, Kayseri, Turkey; 2 Department of Pathology, School of Medicine, Çukurova University, Adana, Turkey; 3 Department of