CONGENITAL END-PLATE ACETYLCHOLINESTERASE DEFICIENCY

Endplate acetylcholinesterase (AChE) consists of globular catalytic su bunits 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 (E ngel et al., 1977, patient 1). We describe here our observations in fo ur additional patients (patients 2-5). Three cases were sporadic; pati ents 2 and 3 were sisters. All had generalized weakness increased by e xertion but ophthalmoparesis was not a constant feature. All had mild slowing of the pupillary light reflex; other dysautonomic features wer e absent. None benefited from anticholinesterase therapy. All patients had a decremental electromyogram response; in four of the five patien ts, single nerve stimuli evoked a repetitive response. Miniature endpl ate potential amplitude was reduced in patient 5 only. Endplate amplit udes and currents were prolonged but the open-time of the acetylcholin e receptor ion channel was normal. In patients 1-4 the quantal content of the endplate potential was reduced due to a reduced number of read ily releasable quanta. Quantitative electron microscopy revealed abnor mally small nerve terminals, abnormal encasement of the presynaptic me mbrane by Schwann cells and degeneration of junctional folds and of or ganelles in the junctional sarcoplasm. Acetylcholinesterase was absent from all endplates of all patients by cytochemical and immunocytochem ical criteria. Density gradient ultracentrifugation of muscle extracts from patients 1, 3, 4 and 5 revealed an absence of the collagen-taile d form of the enzyme in patients 1, 3 and 4 but not in patient 5. The kinetic properties of the residual AChE in muscle were normal. Erythro cyte AChE activity and K(m) values, determined in three patients, were also normal. Studies of the catalytic subunit gene of AChE in patient s 2 and 3 revealed no abnormality in those exons that encode the domai n to which the tail subunit binds. In patients 1 -4 the molecular defe ct 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 the endplate may be due to a f aulty tail subunit, a defect in the basal lamina site that binds the t ail subunit or failure of transport of the assembled asymmetric enzyme from the cell interior to the basal lamina. The cause of the weakness in these patients is not fully understood but possible mechanisms are discussed.