CONGENITAL MYASTHENIC SYNDROMES IN 2 KINSHIPS WITH END-PLATE ACETYLCHOLINE-RECEPTOR AND UTROPHIN DEFICIENCY

We studied two families with five affected members suffering from ptos is and slowly progressive limb-girdle muscle weakness. All patients ha d abnormal decremental response on low-frequency nerve stimulation, bu t there were no repetitive responses to single stimuli. The patients i mproved on anti-acetylcholinesterase drugs. Intercostal muscle was obt ained for special studies from one patient of each family. In vitro mi croelectrode studies were done in Patient 1, Miniature end-plate poten tials were of low amplitude, and the quantal content of the evoked end -plate potentials was normal. Light microscopy revealed a marked type 1 fiber predominance. Acetylcholinesterase reactivity was dispersed ov er increased length of individual fibers in Patient 2. On morphometry of the end-plate ultrastructure, the number of secondary synaptic clef ts per neuromuscular junction and the expansion of the postsynaptic ar ea were markedly reduced. In Patient 1, but not in Patient 2, the enve lopment of the nerve terminal by Schwann cell was increased. Acetylcho line-receptor (AChR) density was reduced as judged by the reduced immu noreactivity to antibodies against different receptor subunits. Immuno histochemical analysis of proteins known to be involved in orchestrati ng the end-plate structure showed deficiency of the AChR-associated pr otein utrophin, These patients appear to have a defect in the developm ent or maintenance of the postsynaptic clefts; whether this defect res ults from or causes a reduced expression of utrophin or AChR is unclea r.