Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition that targets the motor neurons, the nerve cells in the brain and spinal cord controlling voluntary muscle movement. The loss of these cells leads to muscle weakness, atrophy, and eventually the inability to move, speak, swallow, and breathe. Most ALS cases arise without a clear genetic link, occurring randomly. However, a small number of cases are directly inherited, meaning a specific gene mutation is passed down from a parent.
Differentiating Sporadic and Familial ALS
ALS cases are categorized into two main groups based on their origin and family history. Sporadic ALS (SALS) is the most common form, accounting for 90% to 95% of all diagnoses worldwide. SALS occurs randomly in individuals with no known family history, and its cause is thought to be a complex interaction between genetic risk factors and environmental exposures.
Familial ALS (FALS) accounts for the remaining 5% to 10% of cases. FALS is diagnosed when two or more family members have ALS, indicating a specific genetic mutation is responsible and passed down through generations.
The Genes Responsible for Familial ALS
Inherited ALS involves changes in specific genes that govern motor neuron function. The most frequent genetic cause of FALS is a mutation in the C9orf72 gene, responsible for 30% to 40% of familial cases. This mutation involves an abnormal expansion of a DNA sequence that disrupts normal cellular processes. The C9orf72 mutation is also associated with Frontotemporal Dementia (FTD), leading to ALS-FTD in some individuals.
Another gene is SOD1 (Superoxide Dismutase 1), accounting for 10% to 20% of FALS cases. SOD1 provides instructions for an enzyme that manages free radicals. When mutated, the protein misfolds and accumulates, becoming toxic to motor neurons. Less frequently, other genes like TARDBP and FUS are involved. These genes produce proteins essential for processing RNA, and their disruption leads to the buildup of damaged proteins.
Inheritance Patterns and Personal Risk
FALS typically follows an Autosomal Dominant pattern of inheritance. The mutation is located on a non-sex chromosome, and only one copy of the altered gene from one parent is sufficient to confer risk. Therefore, a person carrying the mutation has a 50% chance of passing that genetic change to each child.
Inheriting the mutation does not guarantee the disease will manifest, a concept known as incomplete penetrance. Penetrance describes the likelihood that an individual with the mutation will develop the disease. For ALS, penetrance is not absolute, suggesting that factors like age, environment, or other genetic variants influence symptom appearance. The age of onset and disease severity can also vary among family members with the same mutation; this is called variable expressivity.
Genetic Testing and Counseling Considerations
Genetic testing is a standard part of the diagnostic process for individuals with a family history of ALS or those newly diagnosed. Consensus guidelines recommend that all persons with an ALS diagnosis be offered genetic testing using a panel that includes at minimum the C9orf72, SOD1, FUS, and TARDBP genes. This testing identifies the precise cause of the disease, which may inform eligibility for future gene-targeted therapies.
Genetic counseling is important before and after testing, especially for asymptomatic individuals with a family history. Counselors help individuals understand complex inheritance patterns and the implications of results for themselves and their family. This process includes reviewing medical history and discussing the psychological and social ramifications of knowing one’s genetic status. Predictive testing for asymptomatic individuals requires careful consideration and is preceded by neurological and psychological assessments to ensure informed consent and preparation for the emotional impact of the results.