Review Critical period of neuromuscular development: Importance for a new treatment of SMA Gerta Vrbová a, *, Urszula Slawin´ska b a Division of Life Sciences, University College London, Gower Str., London,WC1 6BT, UK b Department of Neurophysiology, Nencki Institute of Experimental Biology PAS, 3 Pasteur Str., 02-093,Warsaw, Poland Received 25 October 2017; received in revised form 5 January 2018; accepted 8 March 2018 Abstract Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion. There is a critical period during which the presence of the SMN protein is mandatory for the survival of the motor unit and the individual. This period coincides with the most important events involved in the development of the motor unit. Results from normal genetically unaffected rats and mice show that during a critical period of development the function of the nerve terminal and the release of transmitter play a crucial role in the development of the motor neurone and muscle. The possibility that targeting the function of the nerve terminal to overcome its inability to release transmitter could benefit patients with the deletion of the SMN gene. © 2018 Elsevier B.V.All rights reserved. Keywords: SMA animal models; Smn gene; SMN protein; Motor neurone; Motor unit 1. Introduction Spinal muscular atrophy (SMA) is an autosomal recessive inherited disorder with variable clinical severity. The severe infantile form was already documented by Beevor [1] at the turn of the last century, whereas it was not until the 1950s that an adolescent and adult mild ambulant form was distinguished from limb girdle muscular dystrophy by Kugelberg and Welander in1956 [2]. In 1964 Dubowitz [3] documented 10 personal cases of an intermediate severity with ability to sit unaided but not to stand or walk and noted that some of them had a sibling dying in infancy with severe SMA. He subsequently suggested [4] that there might be a continuum of severity ranging from the severe infantile form through an intermediate severity with ability to sit unaided but not to stand independently or to walk, to the later onset milder ambulant form. The severe form has a very characteristic clinical picture with severe symmetrical weakness affecting the legs more than the arms, the proximal muscles more than distal, sparing the facial muscles and having a unique pattern of gross weakness of the intercostal muscles but sparing the diaphragm giving the characteristic abdominal breathing which is pathognomonic of spinal muscular atrophy and does not occur in any other neuromuscular disorder. The gene for spinal muscular atrophy was initially located on Chromosome 5q by Gilliam et al and Brzustowicz et al in 1990 [5,6] in a cohort of intermediate severity cases from an inbred Amish community and confirmation in the severe form followed soon after. Because of the complexity of their duplicated region of chromosome 5 it took several years for Melki’s group [7–10] to identify the gene. They named it survival motor neurone gene (SMN). An even more severe form with intrauterine death or severe weakness and respiratory deficit at birth was subsequently also linked to the SMN gene. What now required resolution was the pathogenesis of the extremely variable disease in relation to the age of onset and also the frequent history of an infant with severe SMA of postnatal onset being perfectly normal and active initially and then having a seemingly rapid onset of weakness, often overnight, and then remaining fairly stable. The main feature in SMA is the death of motor neurones already mentioned by Beevor [1] and subsequently by a number of other authors. Focusing on this it became of paramount importance to establish the possible cause of death of * Corresponding author. Division of Life Sciences, University College London, Gower Str., London, WC1 6BT, UK. E-mail address: g.vrbova@ucl.ac.uk (G. Vrbová). https://doi.org/10.1016/j.nmd.2018.03.007 0960-8966/© 2018 Elsevier B.V.All rights reserved. ARTICLE IN PRESS Please cite this article in press as: Gerta Vrbová, Urszula Slawin´ska, Critical period of neuromuscular development: Importance for a new treatment of SMA, Neuromuscular Disorders (2018), doi: 10.1016/j.nmd.2018.03.007 Available online at www.sciencedirect.com Neuromuscular Disorders ■■ (2018) ■■–■■ www.elsevier.com/locate/nmd ScienceDirect