The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis

Abstract

Since the topic of motor neuron diseases was last covered in Neurotherapeutics in 2008, increasing insight into genetic causes and underlying disease mechanisms has fueled several advances that have paved the way for new therapeutic strategies that are currently in development or being tested in clinical trials. In this special issue, we present reviews by leading investigators in the field that detail these advances for spinal muscular atrophy (SMA), an inherited neuromuscular disease associated with motor neuron degeneration and muscle atrophy that presents early in life, and amyotrophic lateral sclerosis (ALS), a fatal adult-onset neuromuscular disease also characterized by loss of motor neurons. The papers are divided into 4 main sections that cover 1) SMA advances, 2) ALS challenges and recent biological advances, 3) ALS clinical trial design considerations and outcome measures, and 4) emerging ALS treatments. Together, these articles offer a timely and comprehensive look into the recent research advances, current clinical considerations, and therapeutic prospects currently in development or being tested for motor neuron diseases.The issue begins with 2 papers focused on SMA. In the first article, Drs. Michelle Farrar and Matthew Kiernan [1] provide a detailed overview of the genetic basis of SMA forms and variants and present common pathophysiological mechanisms, including discussion of the function of the survival motor neuron protein. They then discuss considerations for therapeutic development and testing before reviewing potential molecular biomarkers for outcome assessments and trial design. Next, Drs. Constantin d'Ydewalle and Charlotte Sumner [2] present an eloquent synopsis of promising SMA treatments currently in advanced stages of development, a discussion that is prefaced by an overview of the available in vivo mouse SMA models. The treatment strategies include some originally designed for applications in ALS, approaches to induce survival motor neuron, and new treatment paradigms harnessing epigenetic targets, antisense oligonucleotides, and gene therapy approaches. Notably, both articles also discuss important issues that remain to be addressed for current progress, such as how well preclinical models recapitulate the human phenotype, how to factor in disease heterogeneity and identify and define potential therapeutic windows, and how to best analyze effects on disease progression. We believe the recent novel insights and current advances bode well for continued progress and the identification of much needed treatment options in SMA.The second section of the issue begins with a review by Drs. Jeffrey Rosenfeld and Michael Strong [3], which specifies the current challenges underlying therapeutic development that accompany the recent expansions in our understanding of the complex, multifaceted nature of ALS. Briefly, establishing firm diagnostic and prognostic criteria, determining what role frontotemporal dysfunction plays in the classification of ALS, identifying an accepted biomarker, determi...

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“…The spectrum of MNDs involves varying degrees of upper and lower motor neuron involvement and is differentiated from neuropathies by the pattern of motor and/or sensory involvement. These disorders range from spinal muscular atrophy (frequent in childhood) to amyotrophic lateral sclerosis (ALS) in adults ( 84 ). The most prevalent MND is ALS, which can be inherited or sporadic, and is characterized by mixed upper and lower MND, with sensory sparing ( 85 ).…”