Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord. These nerve cells control voluntary movement by sending signals to the muscles throughout the body. As the disease advances, motor neurons degenerate and die, leading to progressive muscle weakness, atrophy, and the inability to move, speak, or breathe. While a definitive cause remains unknown for most cases, genetic factors play a significant role in a minority of diagnoses.
Sporadic Versus Familial ALS
ALS is classified into two types based on family history: sporadic and familial. Sporadic ALS (SALS) is the most common form, accounting for approximately 90% to 95% of all diagnoses. In SALS cases, the individual has no known family history of the disease.
The cause of SALS is not fully understood, but it is believed to result from a complex interplay of genetic susceptibility, environmental factors, and age. About 10% of SALS patients still have a genetic mutation known to be linked to ALS. These mutations may arise spontaneously, meaning they occur for the first time in that individual and are not inherited.
Familial ALS (FALS) represents the remaining 5% to 10% of cases, occurring when two or more people in the same family are diagnosed. FALS is strongly linked to an inherited genetic mutation passed down through generations. Researchers have identified over 40 genes associated with ALS, with the C9orf72 and SOD1 genes being the most frequent contributors to FALS.
Genetic Inheritance and Apparent Generational Skipping
Whether ALS can seemingly skip a generation depends on the specific mode of genetic inheritance involved. Most familial ALS cases follow an autosomal dominant inheritance pattern. In this pattern, a person needs to inherit only one copy of the mutated gene from either parent to have an increased risk of developing the disease.
Since only a single mutated gene copy is sufficient, autosomal dominant conditions generally appear in every generation of a family. An affected parent has a 50% chance of passing the mutation to each child.
The appearance of skipping a generation in dominant inheritance is often explained by reduced penetrance. This occurs when a person carries the gene mutation but does not develop symptoms within their lifetime.
The mechanism that most directly accounts for generational skipping is autosomal recessive inheritance, though this is a much rarer pattern for ALS. Recessive conditions require a person to inherit two copies of the mutated gene—one from each parent—to manifest the disease.
Parents who each carry only one copy of the mutation are known as carriers. They are typically unaffected themselves because the single functioning gene copy compensates for the mutated one. A child born to two unaffected carriers has a 25% chance of inheriting a mutation from both parents and developing ALS. In this scenario, the disease appears to skip the carrier parents’ generation, only emerging in their child. Identifying the specific mutation, such as those in the SOD1 gene, helps determine if a family’s FALS is following this recessive pattern.
Navigating Genetic Risk and Counseling
Understanding genetic risk begins with a consultation with a genetic counselor. Counselors evaluate a family’s detailed medical history to construct a pedigree, which visually represents the disease across generations. This process clarifies the likely inheritance pattern and determines the individual’s specific risk level.
If a specific ALS-linked mutation has been identified in an affected family member, genetic testing can be offered to at-risk relatives. This is known as presymptomatic or predictive testing, which determines if a person without symptoms carries the mutation. Testing is available for key genes like C9orf72 and SOD1, which account for a large portion of FALS cases.
The decision to undergo presymptomatic testing carries ethical and psychological considerations. A positive result indicates a high probability of developing the disease but cannot predict the age of onset or the severity of symptoms.
Genetic counseling is required before testing to ensure the individual is prepared to process the complex implications of their results. Knowing the genetic status can provide access to clinical trials or approved treatments, such as those targeting SOD1 mutations. The primary goal of counseling is to provide non-directive support, allowing the individual to make an informed choice that aligns with their personal values.