What is SOD1-ALS?

For certain individuals with ALS, the condition is thought to be caused by abnormal superoxide dismutase 1 (SOD1) protein. Variants in the SOD1 gene are thought to cause abnormal SOD1 protein to be made, which is likely harmful to cells and possibly causes nerve cells to break down and die. There are many different kinds of SOD1 gene variants.1 The ATLAS Study is studying some, but not all, SOD1 gene variants.

As you may know, ALS is a rare neurodegenerative disease in which the nerve cells that control muscles (also known as motor neurons) break down and die over time. This results in progressive loss of muscle mass, strength, and function.

Understanding SOD1-ALS penetrance and progression.

What is penetrance?

Penetrance refers to the likelihood someone with a gene variant will show signs or symptoms of the disease associated with the gene. Not everyone with a SOD1 gene variant will have a known family history of ALS. Sometimes this is because not everyone with a SOD1 gene variant will develop ALS in their lifetime. When this occurs, this is called reduced penetrance. Today, there is no way to know with certainty if or when someone with a SOD1 gene variant will develop signs or symptoms of ALS – a person may never develop signs or symptoms of ALS. However, research suggests that some SOD1 gene variants have a higher possibility of developing signs or symptoms of ALS, which may be associated with high or complete penetrance.2 To be eligible for the ATLAS Study, participants need to carry a SOD1 gene variant associated with high or complete penetrance.

What is disease progression?

Additional research indicates that some SOD1 gene variants are associated with a faster progression of symptoms and disability, and shorter survival. But this is not always the case. Therefore, having a SOD1 gene variant known to be associated with a rapid disease progression does not predict with certainty how quickly disease progresses if or when signs or symptoms of ALS develop.3

How is the SOD1 gene variant inherited?

Everyone has two copies of most genes, including the SOD1 gene: one copy that we inherit from our mother, and one copy that we inherit from our father. If an individual has a SOD1 gene variant, that typically means they have one abnormal copy of the SOD1 gene and one normal copy. Having one abnormal copy of the SOD1 gene may be enough to cause an increased risk of developing ALS. This is called autosomal dominant inheritance (see graphic below), and it’s how the majority of SOD1-ALS is inherited. In other words, the abnormal copy of the SOD1 gene dominates over the normal copy; therefore, having only one abnormal copy may cause an increased risk for ALS.

When an individual has children, they pass on one copy of each of their genes to each child. This means that if a parent has a single SOD1 gene variant, there is a 50% chance that the SOD1 gene variant will be passed down to each child. Alternatively, there is a 50% chance that the normal copy of the SOD1 gene will be passed down to each child. If an individual does not inherit the SOD1 gene variant from their parent, that means they will not pass on the SOD1 gene variant to their children either. Men and women have equal chances of not only inheriting a SOD1 gene variant from their parents but also passing it on to their children. In rare cases, de novo variants in the SOD1 gene have been reported, meaning that the variant occurred for the first time in that individual and was not inherited from a parent.4

Autosomal dominant inheritance.

References.

  1. ALS Association (n.d.). SOD1 (copper zinc superoxide dismutase 1) and ALS. www.alsa.org/research/focus-areas/genetics/sod1.html.
  2. MedlinePlus Genetics (n.d.). Help me understand genetics. medlineplus.gov/genetics/.
  3. ALS Association (n.d.). Stages of ALS. www.als.org/understanding-als/stages.
  4. MedlinePlus (n.d.). Genetics. medlineplus.gov/genetics/.