Pathogenic variants in SOD1, encoding
superoxide dismutase 1, are responsible for about 20% of all familial
amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including
cDNA analysis,
SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial
hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1.
cDNA analysis predicted the loss of a single
valine residue from a tandem pair (p.Val119/Val120) in the wild-type
protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and
protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable
SOD1 protein in the child, whereas the parents had ∼50%
protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the
valine residues at positions V119-120, and suggest possible implications for future
therapeutics research.