Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’
1 School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne Bath 2 Department of Clinical Neurophysiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne Bath 3 Department of Paediatric Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne Bath 4 Department of Neurology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne Bath 5 Department of Neurology, Royal United Hospital Bath 6 Department of Pharmacy and Pharmacology, University of Bath Bath 7 Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital Headington, Oxford, UK
Correspondence to: Prof. C. R. Slater, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK E-mail: c.r.slater{at}ncl.ac.uk
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 
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 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 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.
Key Words: congenital myasthenic syndrome; human; limb-girdle myasthenia; neuromuscular transmission; neuromuscular junction
Abbreviations: AChE, acetylcholinesterase; AChR, acetylcholine receptor; ADM, abductor digiti minimi; ANC, anconeus; CMAP, compound muscle action potential; DELT, deltoid; EDC, extensor digitorum communis; EPC, end-plate current; EPP, end-plate potential; LGM, limb-girdle myasthenia; MCD, mean of consecutive differences; mEPC, miniature EPC; mEPP, miniature EPP; NMJ, neuromuscular junction; VL, vastus lateralis
Received March 20, 2006. Revised April 25, 2006. Accepted May 3, 2006.
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