Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an 
increasingly recognized preclinical prodrome. A wide spectrum of investigative 
approaches has identified loss of inhibitory function at the heart of ALS. In 
developing an explanation for the onset of ALS, it remains a consideration that 
ALS has its origins in neonatal derangement of the γ-aminobutyric acid 
(GABA)-ergic system, with delayed conversion from excitatory to mature 
inhibitory GABA and impaired excitation/inhibition balance. If this is so, the 
resulting chronic excitotoxicity could marginalize cortical network functioning 
very early in life, laying the path for neurodegeneration. The possibility that 
adult-onset neurodegenerative conditions might have their roots in early 
developmental derangements is worthy of consideration, particularly in relation 
to current models of disease pathogenesis. Unraveling the very early molecular 
events will be crucial in developing a better understanding of ALS and other 
adult neurodegenerative disorders. Muscle Nerve, 2019.