Can old observations explain the pathogenesis of SMA?

Abstract

A characteristic feature of spinal muscular atrophy (SMA) is the death of motoneurones in the anterior horn of the spinal cord first observed in autopsies from children displaying symptoms of the disease [1,2]. Ever since, the death of motoneurones is held responsible for the ensuing paralysis. Recent exciting results that identified the genetic mutation [3] that is the cause of the disease allowed the study of the possible cellular function of the gene and its product the SMN protein. This has opened up new possibilities that could explain old observations on the neuromuscular system of SMA patients. The findings that the SMN protein plays a key role in the formation of spliceosomal complexes, and its absence causes widespread premRNA splicing defects in numerous transcripts of diverse genes in different tissues [4] indicates that in SMA in addition to the motoneurones other parts of the motor unit may also be affected. Extensive research on various animal models with a manipulated SMN gene and the study of their phenotype promised to answer questions about the pathophysiology of SMA. Although the experiments on animal models of SMA provided a large amount of interesting information as to the changes that take place in the neuromuscular system in the absence of the full complement of the SMN protein in mice, they were disappointing in that they failed to reproduce the main feature of the human disease, i.e. massive death of motoneurones [5,6]. Thus the animal models used to study the pathophysiology of SMA are inadequate since they do not display the main feature typical of the disease in humans, i.e. death of motoneurones. It seems therefore pertinent to try and explain the pathophysiology of SMA by information from studies collected over many years from SMA patients and try to explain them using