Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report seven patients with immune-mediated rippling muscle disease (iRMD) and AChR-antibody positive myasthenia gravis (MG) without germline caveolin-3 gene mutations. We describe the follow-up of two patients and the clinical features of five new patients (1 female, 4 male, aged 32 to 69 years). These presented with significant generalized, exercise-induced and electrically-silent muscle rippling with myalgia, combined with generalized MG. In two of the seven patients, MG appeared before iRMD. Mediastinal imaging excluded thymic alterations in all, although two had other coincident tumours. Myalgia and rippling were aggravated by acetylcholinesterase-inhibitor treatment. Generalized MG and iRMD were successfully treated with plasma exchange, steroids and azathioprine in the two patients followed long-term. Muscle morphology of five patients showed a minimal myopathic pattern with rare lymphohistiocytic infiltration. In four patients, sarcolemmal caveolin-3, and dysferlin immunofluorescence staining was moderately reduced in a mosaic pattern, but caveolin-3 protein on Western blots was clearly reduced only in two. Notably, electron microscopy showed that caveolae were almost completely lost at the sarcolemma in the three biopsies examined but not in endothelium. Antibodies targeting high molecular weight muscle proteins, likely associated with the neuromuscular endplate and sarcolemma, were found in the iRMD patients but also in age-matched MG patients without iRMD. Since the generalized MG and iRMD improved with immunosuppressive treatments, it is likely that both are caused by autoantibodies, but the target for pathogenic antibodies in iRMD requires further study.
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PMID:Immune-mediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two. 1920 78

Dysferlin is a member of the evolutionarily conserved ferlin gene family. Mutations in Dysferlin lead to Limb Girdle Muscular Dystrophy 2B (LGMD2B), an inherited, progressive and incurable muscle disorder. However, the molecular mechanisms underlying disease pathogenesis are not fully understood. We found that both loss-of-function mutations and muscle-specific overexpression of C. elegans fer-1, the founding member of the Dysferlin gene family, caused defects in muscle cholinergic signaling. To determine if Dysferlin-dependent regulation of cholinergic signaling is evolutionarily conserved, we examined the in vivo physiological properties of skeletal muscle synaptic signaling in a mouse model of Dysferlin-deficiency. In addition to a loss in muscle strength, Dysferlin -/- mice also exhibited a cholinergic deficit manifested by a progressive, frequency-dependent decrement in their compound muscle action potentials following repetitive nerve stimulation, which was observed in another Dysferlin mouse model but not in a Dysferlin-independent mouse model of muscular dystrophy. Oral administration of Pyridostigmine bromide, a clinically used acetylcholinesterase inhibitor (AchE.I) known to increase synaptic efficacy, reversed the action potential defect and restored in vivo muscle strength to Dysferlin -/- mice without altering muscle pathophysiology. Our data demonstrate a previously unappreciated role for Dysferlin in the regulation of cholinergic signaling and suggest that such regulation may play a significant pathophysiological role in LGMD2B disease.
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PMID:FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in C. elegans and mice. 2424 62