Complete Loss of SOD1 Function Leads to Severe Motor Problems, Study Says in Warning to Researchers

Mutations causing a complete loss of function of the SOD1 gene lead to severe motor problems, a case study reports, calling for caution in research into silencing this gene as a  potential treatment for people with amyotrophic lateral sclerosis (ALS).

The case study, “SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis,” was published in BRAIN a Journal of Neurology.

The superoxide dismutase 1, or SOD1, gene provides instructions to make an enzyme called superoxide dismutase, which regulates the production of reactive oxygen species (ROS) — toxic substances that are byproducts of a cell’s normal metabolism and need to be broken down regularly to avoid oxidative stress (cellular damage that occurs as a consequence of high levels of oxidant molecules).

“SOD1 variants [mutations] are causative for a significant proportion of familial ALS cases, ranging from about 13% in western to up to 30% in Asian populations. While initially believed to exert mainly gain-of-function effects on the enzyme’s activity, it has become clear that the described variants result in a variety of effects,” the researchers wrote.

The scientists, with the University of Münster in Germany, described the case of a boy who carried two copies of a genetic mutation in SOD1 that led to total loss of activity of superoxide dismutase.

The 6-year-old, of Afghan origin, was the third child of consanguineous parents (first-degree cousins) delivered by an emergency cesarean section at 39 weeks of pregnancy.

When he arrived at a care center, he had a combination of severe developmental delays (i.e., he was not able to stand upright or sit without help) and abnormal physical features (like clustered toes, and ears rotated backwards).

Physical examination revealed the boy had severe spasticity (muscle tightness) in both arms and legs, and hyperekplexia-like symptoms. (Hyperekplexia is a medical condition in which individuals with an abnormally high muscle tone have an exaggerated startle reaction to unexpected stimuli, especially loud noises. When startled, these patients become rigid and unable to move.)

Magnetic resonance imaging (MRI) brain scans performed when he was 2 years old and again at age 6 showed signs of mild brain atrophy (shrinkage).

Genetic and biochemical analyses confirmed he carried two copies of a frameshift mutation (c.335dupG) in SOD1 that led to the production of an abnormally short and non-functional superoxide dismutase enzyme. Both parents and his older brother carried one copy of the same mutation, and had lower superoxide dismutase activity compared to healthy individuals. However, none of them had any neurological symptoms.

Of note, a frameshift mutation is caused by insertions or deletions that change the number of nucleotides, the building blocks of DNA, in the sequence.

“Antioxidant supplementation may represent a therapeutic approach, although further research is needed to characterize the effects of the variant on a deeper level. The results of this study call for a cautious approach to SOD1 silencing as a therapeutic concept for ALS,” they wrote.