Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During 2003, numerous research advances in both clinical neuromuscular disease and in the basic pathophysiology of these disorders were published and/or presented. In this review, we present a few categorical highlights of the year, discussing a new potential treatment of McArdle's disease, proposed new diagnostic criteria for the inflammatory myopathies and their clinical implications, the emerging anti-MuSK antibody syndrome in patients with myasthenia gravis, potential new therapies for the most common hereditary neuropathy (Charcot-Marie-Tooth type 1A), the successful pharmacologic manipulation and its therapeutic implications of the genetic mechanisms underlying spinal muscular atrophy, and several emerging therapeutic strategies in amyotrophic lateral sclerosis. As these reports indicate, clinical and basic research in neuromuscular disease continues to yield important and clinically relevant insights, which are now being rapidly translated into new clinical trials showing therapeutic promise for diseases previously thought untreatable.
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PMID:Advances in neuromuscular disease 2003: the year in review. 1907 38

Amyotrophic lateral sclerosis (ALS) is a devastating disease that progresses from detachment of motor nerve terminals to complete muscle paralysis and lethal respiratory failure within 5 years of diagnosis. Genetic studies have linked mutations in several genes to ALS, and mice bearing mutations in SOD1 recapitulate hallmark features of the disease. We investigated whether disease symptoms can be ameliorated by co-opting the retrograde signaling pathway that promotes attachment of nerve terminals to muscle. We crossed SOD1G93A mice with transgenic mice that express MuSK, a receptor tyrosine kinase that is required for retrograde signaling, and we used histological and behavioral assays to assess motor innervation and behavior. A 3-fold increase in MuSK expression delayed the onset and reduced the extent of muscle denervation, improving motor function for more than a month without altering survival. These findings suggest that increasing MuSK activity by pharmacological means has the potential to improve motor function in ALS.
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PMID:Increasing MuSK activity delays denervation and improves motor function in ALS mice. 2293 80

The aim was to examine potential joint disease mechanisms for myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) through the examination of long-term patient cohorts for comorbidity. Recent studies support early involvement of the neuromuscular junction in ALS patients with subsequent degeneration of motor neurons. Medical records at Haukeland University Hospital from 1987 to 2012 were examined for International Classification of Diseases diagnostic codes for MG and ALS. Sera were re-tested for antibodies to acetylcholine receptor, titin, MuSK and GM1. We report one patient with both MG and ALS, and another 3 patients with suggestive evidence of both conditions. This is far more than expected from prevalence and incidence figures in this area if the disorders were unrelated. Our data suggest that immunological mechanisms in the neuromuscular junction are relevant in ALS pathogenesis. Attention should be given to possible therapeutic targets in the neuromuscular junction and muscle in ALS patients.
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PMID:Myasthenia gravis and amyotrophic lateral sclerosis: A pathogenic overlap. 2710 3

Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated that activation of muscle-specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs. Here, we show that therapeutic administration of an adeno-associated virus vector encoding the human DOK7 gene suppressed motor nerve terminal degeneration at NMJs together with muscle atrophy in the SOD1-G93A ALS mouse model. Ultimately, we show that DOK7 gene therapy enhanced motor activity and life span in ALS model mice.
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PMID:DOK7 gene therapy enhances motor activity and life span in ALS model mice. 2849 May 73

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated SOD1-G93A mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of SOD1-G93A mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle.
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PMID:Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody. 2955 67