Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that attacks nerve cells controlling voluntary muscles, leading to loss of muscle control and eventual paralysis. The vast majority (about 90%) are Sporadic ALS (SALS), occurring without a clear family history. Familial ALS (FALS) accounts for 5 to 10% of cases and is directly inherited through genetic mutations. While FALS often appears in consecutive generations, it can sometimes seem to skip a generation.
The Genetic Basis of Familial ALS
Familial ALS is caused by mutations in certain genes passed down from a parent to a child. The most frequent genetic cause of FALS is a mutation in the C9orf72 gene, which accounts for about 40% of familial cases. Another common cause is a mutation in the SOD1 gene, responsible for approximately 20% of FALS diagnoses.
Most FALS cases follow an autosomal dominant inheritance pattern. This means a child only needs to inherit one copy of the altered gene from either parent to be at risk for the condition. For each pregnancy, a parent carrying the mutation has a 50% chance of passing that gene alteration to their child.
Reduced Penetrance: Why Generations Appear Unaffected
The concept that explains why an inherited condition might skip a generation is known as Reduced Penetrance. Penetrance describes the likelihood that a person who possesses a disease-causing gene mutation will develop the symptoms of that disease.
In the case of FALS, penetrance is often incomplete, or reduced, which means the disease can appear to skip a generation. An individual may inherit the gene alteration and pass it on to their children, yet remain asymptomatic throughout their own lifetime. This person is an obligate gene carrier, but because they never developed the condition, the family history appears interrupted.
The penetrance varies depending on the specific gene involved and a person’s age. For example, population-level studies estimate that the maximum penetrance for the C9orf72 mutation is around 33%, and for SOD1 mutations, it is approximately 54%.
Age is a significant factor in penetrance for late-onset conditions like ALS, as the risk of developing the disorder is cumulative over time. An individual carrying the gene may pass away from an unrelated cause before they reach the age where the gene would have expressed the disease. The variability in penetrance also suggests that other factors, such as genetic modifiers or environmental exposures, influence whether the mutation ultimately leads to disease.
Seeking Clarity: Genetic Testing and Family Planning
For individuals with a family history of FALS, genetic testing can provide clarity on their own genetic status. Predictive genetic testing can determine if an unaffected person has inherited a known FALS-associated gene mutation. A positive result indicates a higher risk of developing the disease, but due to reduced penetrance, it does not predict with certainty when, or if, the condition will manifest.
Genetic counseling is an important step before and after testing to help interpret the complex results and implications. A genetic counselor can assess the family history, discuss the specific risks and benefits of testing, and help individuals understand the concept of reduced penetrance in their particular situation. This process ensures the person makes an informed decision about proceeding with testing.
Understanding one’s genetic status allows for discussions about family planning options. Reproductive specialists can offer techniques such as preimplantation genetic diagnosis (PGD) in combination with in vitro fertilization (IVF). This allows for the selection of embryos that have not inherited the FALS-associated gene mutation, effectively preventing the transmission of the risk to the next generation.