Frequent atrophic groups with mixed-type myofibers is distinctive to motor neuron syndromes

Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, St. Louis, Missouri, USA.
Muscle & Nerve (Impact Factor: 2.28). 07/2007; 36(1):107-10. DOI: 10.1002/mus.20755
Source: PubMed


This study was performed to determine whether there are distinctive features to the pattern of muscle denervation in motor neuron disease. We first compared muscle biopsies from patients with amyotrophic lateral sclerosis (ALS) or Kennedy's disease with other causes of denervation. Groups of atrophic muscle fibers, with individual groups containing both fiber types I and II, occurred frequently in motor neuron disease but not other causes of denervation. We then identified 11 additional muscle biopsies with frequent atrophic groups containing mixed fiber types. Chart review revealed that 10 patients had a final diagnosis of motor neuron disease or ALS and one had multifocal motor neuropathy. We conclude that muscle biopsy may have diagnostic utility early in the course of motor neuron disease. The muscle biopsy pattern of frequent atrophic groups containing mixed fiber types should suggest a diagnosis of a motor neuron syndrome or motor neuropathy.

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    • "Neurogenic atrophy in muscle from ALS patients was often found to be accompanied by fiber type grouping, which is thought to occur when denervated myofibers are reinnervated by collateral sprouts from neighboring axons (Andersen et al., 1996; Fischer et al., 2004; Schaefer et al., 2005; Soraru et al., 2008). However, in muscle biopsies from ALS patients muscle fiber atrophy without fiber type grouping can also be observed (Baloh et al., 2007). It is difficult to explain the reasons for this discrepancy using the available data, but ALS actually encompasses a spectrum of disorders, and it is possible that fiber type grouping occurs in some forms of the disease and not others (Soraru et al., 2008). "
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    ABSTRACT: Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS.
    Zoology 10/2015; DOI:10.1016/j.zool.2015.09.003 · 1.67 Impact Factor
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    • "ated to occur when denervated myofibers are reinnervated by collateral sprouts from neighboring axons ( Andersen et al . , 1996 ; Fischer et al . , 2004 ; Schaefer et al . , 2005 ; Soraru et al . , 2008 ) . On the other hand , it has also been reported that muscle biopsies from ALS patients exhibit muscle fiber atrophy but no fiber type grouping ( Baloh et al . , 2007 ) . The reason for this seeming discrepancy is not apparent from the data available , but ALS actually encompasses a spectrum of disorders , and it is possible that fiber type grouping occurs in some forms of the disease and not others ( Soraru et al . , 2008 ) . Because no type grouping in intercostal muscle ( this study ) or in pelvic"
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    ABSTRACT: Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions, accompanied by atrophic changes in the descending spinal cord tracts. Some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure from severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression, providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology, we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model. © 2013 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 12/2013; 91(12). DOI:10.1002/jnr.23287 · 2.59 Impact Factor
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    • "Further, in Sod1 À/À mice, measurements of steady state redox potential of glutathione (which is routinely used as indicator of the intracellular redox state) in tibial nerve and gastrocnemius muscle showed a selective involvement of the nerve at 4 months, again indicating the primary involvement of the axon (Fischer et al., 2012). Thus muscle changes in Sod1 À/À mice are secondary to denervation; they are non-specific and also present in muscle biopsies from patients with ALS (Baloh et al., 2007a). "
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    ABSTRACT: Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a-still unknown-toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1-amyotrophic lateral sclerosis. From analysing published data from patients with SOD1-amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1-amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.
    Brain 05/2013; 136(8). DOI:10.1093/brain/awt097 · 9.20 Impact Factor
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