Ultrastructural abnormalities of muscle and neuromuscular junction differentiation in a bovine congenital neuromuscular disease.

The syndrome of arthrogryposis and palatoschisis (SAP), an inherited syndrome of muscular hypotonia in Charolais cattle, was used as an experimental model to study neuromuscular differentiation. The ultrastructural development of muscle, peripheral nerve, and neuromuscular junctions was studied to determine the sequence of events preceding hypotrophic changes in the skeletal muscles of affected calves at birth. Dorsiflexion of the metatarsophalangeal joints in the hindlimbs occurred in fetuses older than 3 months of age, but hypotrophic changes in skeletal muscle, manifested as small fibers scattered among larger and occasional degenerating fibers, was not apparent until late in gestation, affecting 8-month-old fetuses and neonatal calves. Electron microscope and enzyme histochemistry studies disclosed differentiation of skeletal muscle into fiber types which is consistent with changes expected from disuse and does not indicate a primary myopathic abnormality. Abnormal differentiation of neuromuscular junctions (NMJ), composed of several separated axonal endings terminating in shallow synaptic gutters, indicated impaired maturation of the synapse. The earliest indication of abnormal NMJ was observed in a 5-month-old SAP fetus. The clinical signs and pathologic changes found in the neuromuscular junction and skeletal muscle of SAP fetuses are consistent with an embryologic defect occurring during development of the central nervous system (CNS) that affects the integrated function of the motor neurons to the limbs. However, diversification of myofibers by histochemistry and ultrastructural parameters is evidence that the intrinsic physiologic properties of spinal motor neurons were retained.