Juvenile-onset Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder that affects the upper and lower motor neurons, slower than adult onset ALS and causes progressive muscle weakness, disability and eventually death.  5-10 % of cases are familial of which 15-30% are caused by pathologic variants in the Superoxide Dismutase-1 gene (SOD1).  Over 180 mutations of the SOD1 gene have been reported. 

The p.D125G mutation represents a rare pathologic variant in the SOD1 gene presenting as juvenile onset ALS. This mutation, in prior studies, has been shown to be a non-conserved amino acid substitution that likely impacts  the conformation of the protein and resulting in abnormal aggregation. Functional studies in addition show this variant causing chronic stress to the endoplasmic reticulum by exposure to the Derlin-1 binding region. Reduced penetrance and interfamilial variability as well dorsal root ganglion degeneration, seen in prior reports of ALS are also exemplified in our case.