Evaluation of electrophysiological and clinical tests in an exploratory trial of Org 2766 in motor neuron disease.

Twenty four patients with motor neuron disease (MND) participated in a double-blind, placebo-controlled trial with the ACTH 4-9 analog, Org 2766. Patients were examined three times during an 8 week treatment period, using a summated score for several manually and functionally tested muscles (sum score), myometry, jitter, fibre density (FD), macro motor unit potential (MUP), and supramaximal evoked muscle action potentials. No differences were found between Org 2766 and placebo treated patients. In an open 1 yr follow-up study, 5 out of 13 patients treated with Org 2766 died; the others showed continued progression of weakness. The methods used for assessment of muscle function were compared. The highest interest reliability was obtained in the sum score and myometry. Mean differences that might be detectable were relatively small for the sum score and myometry, and large for FD and MUP. We concluded that clinical function testing and myometry are superior to electromyographic measurements for assessment of changes in MND patients.

A non-immunogenic myasthenia gravis model and its application in a study of transsynaptic regulation at the neuromuscular junction.

A non-immunological model for myasthenia gravis was developed in rats: 'toxin-induced myasthenia gravis'. Rats were injected once every 48 h with 3-5 micrograms alpha-bungarotoxin for periods of up to 5 weeks. This treatment caused weakness, especially of facial muscles. Respiration, however, was unaffected. Miniature endplate potentials and 125I-alpha-bungarotoxin binding in the extensor digitorum longus muscles were severely reduced. Acetylcholine release evoked by electrical and chemical (50 mM KCl) stimulation was higher in diaphragms from alpha-bungarotoxin-treated rats than in those from control animals. Histological investigation of the tibialis anterior muscle provided no evidence that the endplates were enlarged. It is concluded that the activity of acetylcholine receptors influences the rate of transmitter release in the neuromuscular junction and it is suggested that a transsynaptic regulation process may be active in myasthenia gravis. The present animal model for myasthenia gravis seems very suitable for studying such a regulation of transmitter release.

A light and electron microscopical study of B-50 (GAP-43) in human intramuscular nerve and neuromuscular junctions during development.

The growth associated protein B-50 (GAP-43) is demonstrated in human intramuscular nerves and neuromuscular junctions by light microscopy and electron microscopy. Nearly all fetal endplates are shown to be immunoreactive for B-50. The percentage of B-50 positive endplates decreases significantly during the peri- and neonatal period, but in children and adults a low percentage of B-50 positive endplates remains present. These data indicate that also in the human peripheral nervous system the expression of B-50 is developmentally regulated.

Reduction of urinary bile alcohol excretion and serum cholestanol in patients with cerebrotendinous xanthomatosis after oral administration of deoxycholic acid.

Deoxycholic acid and chenodeoxycholic acid were administered alternately to four patients with cerebrotendinous xanthomatosis. During this oral therapy serum cholestanol and urinary bile alcohols were determined. Both showed a marked decrease after the start of the two different therapies. It can be concluded that not only chenodeoxycholic acid but also deoxycholic acid is able to suppress endogenous human bile acid synthesis, which is in accordance with other experiments describing the effect of feeding of various bile acids on endogenous bile acid synthesis.

Deficiency of acetylcholine receptors in a case of end-plate acetylcholinesterase deficiency: a histochemical investigation.

A young boy is described who, since early infancy, suffered from weakness of predominantly proximal limb muscles. Electromyography revealed impairment of neuromuscular transmission. There were no antibodies against acetylcholine receptors. The amplitude of miniature end-plate potentials was reduced. Neuromuscular junctions showed somewhat coarse postsynaptic junctional folds and degeneration products in the synaptic clefts and in postsynaptic areas. Using qualitative and semiquantitative histochemical methods, at light- and electronmicroscopical levels, acetylcholinesterase (AChE) activity and acetylcholine receptors (AChRs) were demonstrated to be deficient. This patient demonstrates that the clinical picture of congenital myasthenia may closely resemble a congenital myopathy. The findings provide evidence that AChR deficiency offers protection from some of the effects of AChE deficiency. The clinical features of AChE deficiency depend, not only on the level of residual enzyme activity, but also on the degree of AChR reduction, if present.

Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors.

The aim of this study was to establish the time scale of developmental changes in innervation of skeletal muscle fibers in man. Specimens of thigh and intercostal muscle from 19 embryos and 18 infants were examined with histological methods which enabled the discrimination between fetal (gamma) and adult (epsilon) types of acetylcholine receptors (AChRs). At 8 weeks of development, AChRs were distributed diffusely in the myotube membranes. Following onset of innervation in approximately the ninth week the length of the AChR positive area diminished and reached its shortest size at the sixteenth developmental week. At the sixteenth and eighteenth week some nerve terminals opposed the muscle membrane outside the AChR positive area. Decrease in the number of nerve terminals, strongly suggesting elimination of polyneuronal innervation, started in the sixteenth week and was completed in the twenty-fifth week. This fetal (gamma) type of AChR could no longer be demonstrated after the thirty-first week. The length of the end-plates as determined by the presence of AChRs increased again in the last week before birth and reached a plateau size by the end of the first year after birth. It is concluded that in man the transition from poly- to mononeuronal innervation takes place between the sixteenth and twenty-fifth weeks of development. The evidence available suggests that the retraction of nerve terminals is preceded by loss of AChRs from the muscle membrane facing the terminals. There is no relationship between retraction of nerve terminals and the switch from fetal to adult type of AChR. The size of the presynaptic apparatus changes little after the first year of life.

Secondary changes of the motor endplate in Lambert-Eaton myasthenic syndrome: a quantitative study.

Underlying the Lambert-Eaton myasthenic syndrome (LEMS) is a decrease in the release of the neurotransmitter acetylcholine. Only few reports on light and transmission electron microscopical observations of motor endplates in LEMS are available and changes reported so far differ from those found in experimental blocking of acetylcholine release. We performed a quantitative study on intercostal muscle biopsies of five patients. The main light microscopical finding was an enlargement of the area of contact between nerve and muscle, which was interpreted as a compensatory phenomenon. At the ultrastructural level we found the mean postsynaptic area and membrane length of the neuromuscular junctions to be decreased, putatively due to small postsynaptic regions of newly created neuromuscular junctions. The secondary changes in LEMS endplates as seen in this study are similar to those reported in experimental blocking of acetylcholine release.