Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’

School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Bath, Newcastle upon Tyne, UK.
Brain (Impact Factor: 9.2). 09/2006; 129(Pt 8):2061-76. DOI: 10.1093/brain/awl200
Source: PubMed

ABSTRACT The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

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Available from: Clarke R Slater, Jan 24, 2014
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    • "This variable response to cholinesterase inhibitors has been previously reported in literature. Slater et al. had observed some patients with “limb girdle myasthenia” who showed initial motor strength improvement following initiation of pyridostigmine with subsequent secondary deterioration seen after a few days to weeks while on treatment.[4] A reduced quantal release of acetylcholine (ACh) in addition to altered structural integrity of the neuromuscular junction has been proposed to be the reason for impaired neuromuscular transmission in limb girdle myasthenia. "
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    ABSTRACT: Congenital myasthenic syndromes (CMS) are frequently misdiagnosed due to their wide clinical heterogeneity. Molecular defects in various end-plate associated proteins are being identified. Better understanding of the molecular pathogenesis and genotype-phenotype correlations can help evolve newer therapeutic targets. We present a report of two siblings with familial limb girdle myasthenia who showed significant objective clinical improvement after initiation of terbutaline. The possible mechanism of action and utility of terbutaline in the setting of CMS are described. Terbutaline is a potential treatment option in certain subtypes of CMS refractory to conventional medicines. However, long-term follow-up is required to determine the overall efficacy and safety profile.
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    • "In addition, patients did not have prominent daytime-fatigable weakness, but rather experienced prolonged periods of exacerbations lasting weeks or months as described in other cases [2] [12]. "
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    ABSTRACT: DOK7 mutations cause a congenital myasthenic syndrome (OMIM 254300) characterized by a "limb-girdle" phenotype. We identified 7 French-Canadian patients with a previously undiagnosed proximal myopathy. A genome wide scan was performed. Homozygosity mapping identified a locus on chromosome 4p16.2 containing DOK7. Sequencing of DOK7 revealed homozygous 1124_1127dupTGCC mutations in all individuals. SNP genotyping of 42kb surrounding DOK7 in our cohort and in 9 patients of various European origins demonstrated a shared haplotype suggesting a common ancestral European mutation. In our cohort, fatigability was not prominent; rather patients reported prolonged periods of increased weakness. Abnormalities on repetitive nerve stimulation and single fiber EMG were not invariably present. There was considerable intra-familial phenotypic variability, and we report an asymptomatic individual. DOK7 mutations should be considered in patients with early-onset myopathy, even in the absence of symptoms suggesting a possible myasthenia.
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    • "The light-microscope studies which focused on the cholinesterase reactivity demonstrated that our patient had a reduction of the endplate size, a finding that has also been reported in patients with limb girdle myasthenia, and suggestive of incomplete development of endplates (29). Indeed, the electron microscopy studies revealed prominent simplification of the postsynaptic membranes, and the intracellular microelectrode studies showed reduction of amplitudes of miniature synaptic potentials and currents consistent with postsynaptic failure (30). "
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