Hereditary Canine Spinal Muscular Atrophy

Cork, Linda C.; Griffin, John W.; Munnell, J. F.; Lorenz, Michael D.; Adams, Robert J.; Price, Donald L.

doi:10.1097/00005072-197905000-00002

Cited by 84 publications

(33 citation statements)

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“…Affected dogs, homozygous for the as yet unidentified HCSMA mutation, can be identified 6 to 8 weeks after birth by the appearance of weakness in the tail muscles; they survive for 4 to 6 months. 3 In this study, data obtained from homozygous animals have been compared with data from symptom-free members of the HCSMA pedigree of similar age (Table). Symptom-free animals may be either heterozygotes or wildtype because at the ages used in this study, HCSMA heterozygotes lack motor symptoms and do not begin exhibiting signs about 10 months after birth.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…1,2 Clinically, HCSMA exhibits a rapidly progressive course that produces muscle weakness in an apparent proximal-to-distal gradient. 3 During experiments in which the mechanical properties of single motor units were studied in HCSMA homozygotes, we observed that some motor units failed to maintain force output during tetanic activation, a phenomenon called tetanic failure. 4 Understanding the mechanisms underlying motor unit tetanic failure is important because its appearance signals the onset of weakness and loss of motor unit function, which are central problems in all motor neuron diseases.…”

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confidence: 99%

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Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

et al. 2000

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Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal‐to‐distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom‐free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration. Ann Neurol 2000;47:596–605

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Section: Materials and Methods Animalsmentioning

confidence: 99%

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confidence: 99%

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

et al. 2000

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“…Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons in which affected animals exhibit progressive weakness and eventually become quadraparetic (Cork et al, 1979(Cork et al, , 1982Sack et al, 1984). The progression of muscular weakness exhibits a distinct spatiotemporal gradient: proximal and caudal muscles (such as tail muscles) become weak early, and more distally and rostrally located muscles become weak at later stages.…”

Section: Abstract: Neuromuscular Disease; Synaptic Transmission; Tramentioning

confidence: 99%

Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

et al. 1997

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Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotransmission. The drug 4-aminopyridine (4AP) blocks voltagedependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.

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“…Where they have been subject to study, these disorders invariably demonstrate a familial pattern, occurring in specific breeds of animals such as Brittany Spaniel dogs [1], Brown Swiss cattle [2] and Yorkshire pigs [3]. Clinical deficits are evident in the first year of life and often by a few months of age.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E deficiency and risk of equine motor neuron disease

et al. 2007

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BackgroundEquine motor neuron disease (EMND) is a spontaneous neurologic disorder of adult horses which results from the degeneration of motor neurons in the spinal cord and brain stem. Clinical manifestations, pathological findings, and epidemiologic attributes resemble those of human motor neuron disease (MND). As in MND the etiology of the disease is not known. We evaluated the predisposition role of vitamin E deficiency on the risk of EMND.MethodsEleven horses at risk of EMND were identified and enrolled in a field trial at different times. The horses were maintained on a diet deficient in vitamin E and monitored periodically for levels of antioxidants – α-tocopherols, vitamins A, C, β-carotene, glutathione peroxidase (GSH-Px), and erythrocytic superoxide dismutase (SOD1). In addition to the self-control another parallel control group was included. Survival analysis was used to assess the probability of developing EMND past a specific period of time.ResultsThere was large variability in the levels of vitamins A and C, β-carotene, GSH-Px, and SOD1. Plasma vitamin E levels dropped significantly over time. Ten horses developed EMND within 44 months of enrollment. The median time to develop EMND was 38.5 months. None of the controls developed EMND.ConclusionThe study elucidated the role of vitamin E deficiency on the risk of EMND. Reproducing this disease in a natural animal model for the first time will enable us to carry out studies to test specific hypotheses regarding the mechanism by which the disease occurs.

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Hereditary Canine Spinal Muscular Atrophy

Cited by 84 publications

References 0 publications

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

Vitamin E deficiency and risk of equine motor neuron disease

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