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Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency

From the Department of Neurology (Drs. Sieb and Ries and Mrs. Dörfler) and the Department of Surgery (Dr. Jakschik), University Hospital, Bonn, Germany; Department of Biochemistry (Dr. Tzartos), Hellenic Pasteur Institute, Athens, Greece; Institute of Molecular Pathology (Dr. Wewer), University of Copenhagen, Denmark; Department of Pharmacology (Dr. Rüegg), Biozentrum of the University of Basel, Switzerland; Department of Neurology (Dr. Meyer), General Hospital Nordstadt, Hannover, Germany; private practice in neurology(Dr. Baumann), Markranstädt/Leipzig, Germany; and the Department of Neurology (Dr. Lindemuth), University Hospital, Homburg/Saar, Germany.

Address correspondence and reprint requests to Dr Sieb, Department of Neurology, University Hospital, Sigmund-Freud-St 25, D-53105 Bonn, Germany.

We studied two families with five affected members suffering from ptosis and slowly progressive limb-girdle muscle weakness. All patients had abnormal decremental response on low-frequency nerve stimulation, but there were no repetitive responses to single stimuli. The patients improved on anti-acetylcholinesterase drugs. Intercostal muscle was obtained for special studies from one patient of each family. In vitro microelectrode studies were done in Patient 1. Miniature end-plate potentials 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 over increased length of individual fibers in Patient 2. On morphometry of the end-plate ultrastructure, the number of secondary synaptic clefts per neuromuscular junction and the expansion of the postsynaptic area were markedly reduced. In Patient 1, but not in Patient 2, the envelopment of the nerve terminal by Schwann cell was increased. Acetylcholine-receptor (AChR) density was reduced as judged by the reduced immunoreactivity to antibodies against different receptor subunits. Immunohistochemical analysis of proteins known to be involved in orchestrating the end-plate structure showed deficiency of the AChR-associated protein utrophin. These patients appear to have a defect in the development or maintenance of the postsynaptic clefts; whether this defect results from or causes a reduced expression of utrophin or AChR is unclear.

Dr. Sieb's laboratory is supported in part by grants from the Deutsche Forschungsgemeinschaft (Si 472/2-1), from the Deutsche Gesellschaft für Muskelkranke, Freiburg i.Br., from the University of Bonn (BONFOR program), and from the Gesellschaft von Freunden und Förderern der Universität Bonn, Germany.

Received February 10, 1997. Accepted in final form July 30, 1997.

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