Brain, Vol. 116, No. 3, 633-653, 1993
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Congential Endplate acetylocholinesterase deficiency
1Department of Neurology Rouchester, Minnesota 2Department of Paediatric Neurology Rouchester, Minnesota 3Department of Orthopaedic Surgery, Mayo Clinic Rouchester, Minnesota 4Department of Pharmacology, University of California San Diego, California 5Department of Neurology, Temple University Philadelphia, Pennsylvania, USA
Correspondence to:
Correspondence to: Dr A. G. Engel, Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Endplate acetylcoinsterase (AChE) consists of globular catalytic subunits attached to the basal lamina by a collagen-like tail. Different Genes encode the catalytic subunit and the tail portion of the enzyme. Endplate AChE deficiency was reported previously in a single case (Engel et al., 1977, patient 1). We describe here our observations in four additional patients (patients 2–5). Three cases were sporadic; patients 2 and 3 were sisters. All had generalized weakness increased by exertion but ophthalmoparesis was not a constant feature. All had mild slowing of the pupillary light reflex; other dysautonomic features were absent. None benefited from anticholinesterace therapy.
All patients had a decremental electromyogram response; in four of the five patients, single nerve stimult evoked a repetitive response. Miniature endplate potential amplitude was reduced in patient 5 only. Endplate amplitudes and currents were prolonged but the open-time of the acctylcholine receptor ion channel was normal. In patients 1–4 the quantal content of the endplate potential was reduced due to a reduced number of readily releasable quanta.
Quantitative electron microscopy revealed abnormally small nerve terminals, abnormal encasement of the presynaptic membrane by Schwann cells and degeneration of junctional folds and of organelles in the junctional sarcoplasm.
Acetylcholinesterace was absent from all endplates of all patients by cytochemical and immunocytochemical criteria. Density gradient ultracentricugation of muscle extracts from patients 1, 3, 4 and 5 revealed an absebce of the collagen-tailed from of the ezyme in patients 1, 3 and 4 but not in patient 5. The kinetic properties of the residual AChE in muscle were normal. Erythrocyte AChE activity and Km values, determined in three patients, were also normal. Studies of the cataytic subunit gene of AChE in patients 2 and 3 revealed no abnormality in those exons that encode the domain to which the tail subunit binds.
In patients 1–4 the molecular defect is likely to reside in the gene encoding the tail subunit of AChE, or in a protein necessary to assemble the catalytic and tail subunits. In patient 5, the absence of AChE from thye endplate may be due to a faculty tail subunit, a defect in the basal lamina site that binds the tail subunit or failure of transport of the assembled asymmetric enzyme from the cell interior to the basal lamins.
The cause of the weakness in these patients is not fully understood but possible mechanisms are discussed.
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Received July 23, 1992. Revised November 9, 1992. Accepted November 11, 1993.
*Present address: Department of Neurology, Newcastle General Hospital, Newcastle upon Tyne, UK.
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