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G.P.9.10 Standardized platform for testing therapeutics in a neonatal mouse model of spinal muscular atrophy
Abstracts / Neuromuscular Disorders 19 (2009) 543–660
(AD) inheritance. Most affected family members have mild weakness, limited to the lower limbs, with a history congenital talipes with or without congenital hip dysplasia. All remain ambulant. Features seen on EMG and muscle biopsy suggest an overall reduction in the number of motor units. Nerve conduction velocities are normal. On muscle MRI there is atrophy of most distal leg muscles, with preservation of the anterior compartment, and mild hypertrophy of the adductor longus and semitendinosus, a pattern that has been previously reported in distal SMA. A detailed post-mortem study of a 14 month old affected girl from this family, who died from meningococcal meningitis, provides rare insight into the pathological basis of this condition. There was a paucity of anterior horn cells, in the absence of signs of active cell degeneration, which supports the hypothesis that the loss of anterior horn cells is limited to early development. Analysis of linkage to 12q23-q24, and other loci previously linked to AD distal SMA is in progress. doi:10.1016/j.nmd.2009.06.169
G.P.9.09 A new type of autosomal dominant adult onset spinal motor neuronopathy M. Jokela1, B. Udd 2, S. Penttilä 3, A.M. Saukkonen 4, J. Toivanen 4, T. Suominen 3 University of Turku, Turku, Finland, 2 Tampere University Hospital, Neurology, Tampere, Finland, 3 University of Tampere, Neuromuscular Research Center, Tampere, Finland, 4 Joensuu Central Hospital, Neurology, Joensuu, Finland 1
We describe the clinical features of an apparently new late onset lower motor neuron disease without major atrophy of muscles. The mode of inheritance is autosomal dominant and the average age of onset 41 years. Twelve patients from three North Carelian families were personally examined by the authors and data on four other affected family members was obtained from their medical records. Proximal weakness was present in 13 and distal weakness in 10 patients (proximo-distal in 10). The first manifestations of the disease were painful cramps and fasciculations. Later, a slowly progressive limb muscle weakness developed starting in the lower limbs in the majority of patients. No prominent bulbar or facial involvement was observed in any patient and upper motor neuron signs were absent in all. Nerve conduction velocities were within normal range and electromyography showed chronic neurogenic alterations. Myotonic bursts on EMG were obtained in one patient, although, none of the patients had clinical myotonia. CK value was slightly elevated in 12 of the patients. Muscle biopsy showed neurogenic findings with atrophic fibers, group atrophy and fiber type grouping. Many biopsies showed features also compatible with myogenic change such as increased number of internal nuclei, some fiber splitting, occasional fiber necrosis, and, in one muscle biopsy changes compatible with inclusion body myositis, including rimmed vacuolar degeneration, minor lymphocyte infiltrates and COX-negative fibres. Sensory abnormalities were rare, such as mildly reduced sensory amplitudes or loss of tarsal vibration sensation, except in one patient, who had a coexisting diabetes. Based on the age of onset, the mode of inheritance and symptoms and signs, the disease does not clearly fit into any of the known hereditary spinal motor neuron disorders and may thus represent a novel kind of autosomal dominant lower motor neuron disease. Linkage studies are currently in progress. doi:10.1016/j.nmd.2009.06.170
597
G.P.9.10 Standardized platform for testing therapeutics in a neonatal mouse model of spinal muscular atrophy B. El-Khodor 1, S. Ramboz 1, A. Chen 1, H. Bowling 2, K. Chen 2, M. Winberg2 1
PsychoGenics, Inc., Tarrytown, NY, United States, Atrophy Foundation, New York, NY, United States
2
Spinal Muscular
SMA is a genetic disorder characterized by motor neuron loss and muscle atrophy, due to a deficit of SMN protein expression. While there is as yet no approved treatment for SMA, development of cellular and animal models has allowed extensive in vitro and in vivo screening for drugs and treatment mechanisms. A uniform mouse testing platform has been implemented as a valuable tool in prioritizing drug development efforts. We have surveyed candidate drugs and probe compounds in a severe, early onset mouse model (smn / ; hSMN2+/+; hSMN2delta7+/+) using primary (survival) and secondary (weight and motor) outcome parameters that were established for proofof-concept efficacy testing. Candidate compounds were selected on the basis of previous animal or human studies, broadly surveying neuromuscular and neurodegenerative diseases. Some are known to increase SMN expression in vitro, while others are expected to act through non-SMN trophic, protective or regenerative mechanisms for neurons and/or muscle. More than 50 compounds have been tested. Doses and formulations were chosen based on published rodent studies, or empirically determined maximally tolerated doses in wildtype and SMA-mutant neonatal mice. Efficacy testing has been performed for each drug in parallel with corresponding vehicle controls. While many compounds have yielded modest responses in at least one of the outcomes tested, few compounds have shown significant responses across multiple outcomes. The severity of this particular mouse model may contribute to the paucity of favorable results. Positive hits are the subject of further investigation to be described. Additionally, we are now testing combinations of therapeutics to simultaneously address pathology in multiple neuromuscular compartments, seeking additive or synergistic benefits. Furthermore, pilot studies in a less severe, and perhaps more responsive, mouse model are underway. doi:10.1016/j.nmd.2009.06.171
THE EXTRACELLULAR MATRIX IN NORMAL AND DISEASED MUSCLE; INVITED LECTURES EM.I.1 Laminin functions along the neuromuscular axis P.D. Yurchenco, K.M. McKee, S. Capizzi, D.H. Yang Robert Wood Johnson Medical School, Pathology and Laboratory Medicine, Piscataway, NJ, United States Laminins are key organizers of basement membranes, promoting peripheral nerve and skeletal muscle maturation and function. Their significance is revealed by the dystrophic myofibers, abnormal synapses, and axonal amyelination that develop from laminin mutations in human congenital muscular dystrophies and mouse models. Basement membrane assembly and receptor interactions have been investigated in Schwann cells (SCs) and myotubes both in culture using recombinant basement membrane components and in genetically-modified mice. A model supported by the data is that the assembly is a cooperative process in which laminins initially adhere to cell surface sulfated glycolipids, polymerize to form a
(AD) inheritance. Most affected family members have mild weakness, limited to the lower limbs, with a history congenital talipes with or without congenital hip dysplasia. All remain ambulant. Features seen on EMG and muscle biopsy suggest an overall reduction in the number of motor units. Nerve conduction velocities are normal. On muscle MRI there is atrophy of most distal leg muscles, with preservation of the anterior compartment, and mild hypertrophy of the adductor longus and semitendinosus, a pattern that has been previously reported in distal SMA. A detailed post-mortem study of a 14 month old affected girl from this family, who died from meningococcal meningitis, provides rare insight into the pathological basis of this condition. There was a paucity of anterior horn cells, in the absence of signs of active cell degeneration, which supports the hypothesis that the loss of anterior horn cells is limited to early development. Analysis of linkage to 12q23-q24, and other loci previously linked to AD distal SMA is in progress. doi:10.1016/j.nmd.2009.06.169
G.P.9.09 A new type of autosomal dominant adult onset spinal motor neuronopathy M. Jokela1, B. Udd 2, S. Penttilä 3, A.M. Saukkonen 4, J. Toivanen 4, T. Suominen 3 University of Turku, Turku, Finland, 2 Tampere University Hospital, Neurology, Tampere, Finland, 3 University of Tampere, Neuromuscular Research Center, Tampere, Finland, 4 Joensuu Central Hospital, Neurology, Joensuu, Finland 1
We describe the clinical features of an apparently new late onset lower motor neuron disease without major atrophy of muscles. The mode of inheritance is autosomal dominant and the average age of onset 41 years. Twelve patients from three North Carelian families were personally examined by the authors and data on four other affected family members was obtained from their medical records. Proximal weakness was present in 13 and distal weakness in 10 patients (proximo-distal in 10). The first manifestations of the disease were painful cramps and fasciculations. Later, a slowly progressive limb muscle weakness developed starting in the lower limbs in the majority of patients. No prominent bulbar or facial involvement was observed in any patient and upper motor neuron signs were absent in all. Nerve conduction velocities were within normal range and electromyography showed chronic neurogenic alterations. Myotonic bursts on EMG were obtained in one patient, although, none of the patients had clinical myotonia. CK value was slightly elevated in 12 of the patients. Muscle biopsy showed neurogenic findings with atrophic fibers, group atrophy and fiber type grouping. Many biopsies showed features also compatible with myogenic change such as increased number of internal nuclei, some fiber splitting, occasional fiber necrosis, and, in one muscle biopsy changes compatible with inclusion body myositis, including rimmed vacuolar degeneration, minor lymphocyte infiltrates and COX-negative fibres. Sensory abnormalities were rare, such as mildly reduced sensory amplitudes or loss of tarsal vibration sensation, except in one patient, who had a coexisting diabetes. Based on the age of onset, the mode of inheritance and symptoms and signs, the disease does not clearly fit into any of the known hereditary spinal motor neuron disorders and may thus represent a novel kind of autosomal dominant lower motor neuron disease. Linkage studies are currently in progress. doi:10.1016/j.nmd.2009.06.170
597
G.P.9.10 Standardized platform for testing therapeutics in a neonatal mouse model of spinal muscular atrophy B. El-Khodor 1, S. Ramboz 1, A. Chen 1, H. Bowling 2, K. Chen 2, M. Winberg2 1
PsychoGenics, Inc., Tarrytown, NY, United States, Atrophy Foundation, New York, NY, United States
2
Spinal Muscular
SMA is a genetic disorder characterized by motor neuron loss and muscle atrophy, due to a deficit of SMN protein expression. While there is as yet no approved treatment for SMA, development of cellular and animal models has allowed extensive in vitro and in vivo screening for drugs and treatment mechanisms. A uniform mouse testing platform has been implemented as a valuable tool in prioritizing drug development efforts. We have surveyed candidate drugs and probe compounds in a severe, early onset mouse model (smn / ; hSMN2+/+; hSMN2delta7+/+) using primary (survival) and secondary (weight and motor) outcome parameters that were established for proofof-concept efficacy testing. Candidate compounds were selected on the basis of previous animal or human studies, broadly surveying neuromuscular and neurodegenerative diseases. Some are known to increase SMN expression in vitro, while others are expected to act through non-SMN trophic, protective or regenerative mechanisms for neurons and/or muscle. More than 50 compounds have been tested. Doses and formulations were chosen based on published rodent studies, or empirically determined maximally tolerated doses in wildtype and SMA-mutant neonatal mice. Efficacy testing has been performed for each drug in parallel with corresponding vehicle controls. While many compounds have yielded modest responses in at least one of the outcomes tested, few compounds have shown significant responses across multiple outcomes. The severity of this particular mouse model may contribute to the paucity of favorable results. Positive hits are the subject of further investigation to be described. Additionally, we are now testing combinations of therapeutics to simultaneously address pathology in multiple neuromuscular compartments, seeking additive or synergistic benefits. Furthermore, pilot studies in a less severe, and perhaps more responsive, mouse model are underway. doi:10.1016/j.nmd.2009.06.171
THE EXTRACELLULAR MATRIX IN NORMAL AND DISEASED MUSCLE; INVITED LECTURES EM.I.1 Laminin functions along the neuromuscular axis P.D. Yurchenco, K.M. McKee, S. Capizzi, D.H. Yang Robert Wood Johnson Medical School, Pathology and Laboratory Medicine, Piscataway, NJ, United States Laminins are key organizers of basement membranes, promoting peripheral nerve and skeletal muscle maturation and function. Their significance is revealed by the dystrophic myofibers, abnormal synapses, and axonal amyelination that develop from laminin mutations in human congenital muscular dystrophies and mouse models. Basement membrane assembly and receptor interactions have been investigated in Schwann cells (SCs) and myotubes both in culture using recombinant basement membrane components and in genetically-modified mice. A model supported by the data is that the assembly is a cooperative process in which laminins initially adhere to cell surface sulfated glycolipids, polymerize to form a