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

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.

The Therapy of Congenital Myasthenic Syndromes

“…The side effects include nervousness, insomnia, palpitation, and hypertension. 37,45 • There may be no similarly affected relatives • The symptoms can be episodic 7,13,44 • EMG abnormalities may not be present in all muscles, or are present only intermittently 7,13 • Weakness may not involve cranial muscles 40 Clinical • Proximal greater than distal limb and axial muscle weakness, mild facial weakness and ptosis, and normal ocular ductions in the majority • Bulbar muscles affected in some patients • May deteriorate on exposure to pyridostigmine AChE, acetylcholinesterase; AChR, acetylcholine receptor; CMAP, compound muscle fiber action potential; EP, endplate; MuSK, muscle specific tyrosine kinase. *There are no clinical clues to the diagnosis of the fast channel CMS, primary EP AChR deficiency, and most cases of rapsyn deficiency.…”

“…Ephedrine improved five out of five patients but in one the improvement was temporary. 40,15 Paucity of synaptic vesicles associated with reduced quantal release…”

Therapeutic Strategies in Congenital Myasthenic Syndromes

“…26 More and more detailed information during recent years about these mechanisms and about the neural agrin-Dok-7-MuSK-Rapsyn-AChR pathway can help in developing specific agents that block aberrant pathological reactions or enhance single necessary steps in these cascades. [27][28][29][30] To date, ten different types of CMS are known, and further CMS subtypes and their genetic cause may be disclosed with future investigation. Prognosis in CMS is variable and largely depends on the pathophysiological and genetic defect.…”

Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] The frequency and the prevalence of the disease are not known.…”

“…3,8,[10][11][12]14,15 The multisystem presentation (28 patients) is, as a rule, a severe disease. Twenty-three patients died between 6 weeks and 5 years.…”