Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. This damage leads to the loss of muscle control, progressively impairing a person’s ability to move, speak, swallow, and eventually breathe. Advancements in research have confirmed genetic components in many cases, leading to genetic testing as a tool for diagnosis, research, and treatment guidance. Genetic testing for ALS is widely available, but it is specific and often recommended in conjunction with comprehensive genetic counseling.
The Role of Genetics in ALS Classification
ALS is primarily classified into two groups based on family history: Sporadic ALS (SALS) and Familial ALS (FALS). SALS accounts for the vast majority of cases (approximately 90% to 95%), appearing in individuals with no known family history. FALS represents about 5% to 10% of all cases, involving the disease occurring in families with multiple affected relatives.
Genetic research has increasingly blurred the lines between these two classifications, revealing that a significant portion of SALS cases also have an underlying genetic cause. Approximately 10% of individuals diagnosed with sporadic ALS are found to have a mutation in a gene known to be linked to the disease. This discovery suggests that many cases previously classified as SALS may actually be genetic in origin, but lack a clear family history due to factors like reduced gene penetrance or early death of family members.
Several specific genes are commonly associated with familial ALS, with a few accounting for the majority of known inherited cases. The C9orf72 gene is the most frequent genetic cause, responsible for between 25% and 40% of familial cases and a small percentage of sporadic cases. Mutations in the SOD1 gene are the second most common, accounting for 10% to 20% of familial cases. Other genes, including TARDBP and FUS, also contribute to a smaller percentage of familial and sporadic ALS, indicating that a complex genetic landscape underlies the disease.
When Genetic Testing is Recommended
Genetic testing for ALS is now broadly recommended for all individuals who have received an ALS diagnosis, regardless of their family history. Testing can help confirm the diagnosis and provide specific information that guides current medical management. The test analyzes genes known to be associated with ALS.
Specific clinical indicators make genetic testing especially relevant, such as having a known family history of ALS or a related neurological disorder like frontotemporal dementia (FTD). FTD shares genetic links with ALS, particularly through the C9orf72 gene, making a family history of dementia relevant for testing. Earlier age of onset, particularly before age 50, is another factor that increases the suspicion of a genetic cause, prompting a recommendation for testing.
The primary purpose of testing for a person with an ALS diagnosis is to identify a specific genetic variant that may qualify them for gene-targeted therapies or clinical trials. For example, the discovery of an SOD1 mutation can make a patient eligible for FDA-approved gene-targeted treatments. Furthermore, a positive genetic test result can support a clinical diagnosis, sometimes allowing for a definitive diagnosis even when a patient does not meet all clinical criteria based on symptoms alone.
Understanding Genetic Test Results
A genetic test for ALS can yield one of three main results, each carrying different implications for the patient and their family. A positive result indicates the identification of a pathogenic variant, or mutation, in a gene known to cause ALS. This confirms that the person’s ALS is linked to a specific genetic cause, which can be valuable for treatment decisions and for understanding the risk to blood relatives. However, a positive result does not predict the exact severity of the disease or the rate of its progression, as these factors can vary widely even among individuals with the same mutation.
A negative result means that no pathogenic variants were found in the genes included on the testing panel. A negative result does not rule out the diagnosis of ALS, nor does it guarantee that the disease is not genetic. Many genetic causes of ALS remain undiscovered, and the testing panel only searches for currently known mutations.
The third possible outcome is a Variant of Unknown Significance (VUS), which is a change in a gene where the clinical effect is not yet clear. A VUS is a common finding in genetic testing and means that there is not enough scientific evidence to determine if the change is related to the disease or is simply a harmless variation. Healthcare providers typically do not base medical decisions on a VUS, and these variants often require future research or re-analysis to clarify their significance.
The Importance of Genetic Counseling
Genetic counselors are specialized professionals who provide support and detailed information before, during, and after testing. Pre-test counseling is designed to ensure the individual fully understands the potential benefits, risks, and limitations of the testing.
During this initial counseling session, the counselor takes a detailed medical and family history and discusses the inheritance patterns of ALS-linked genes. They also prepare the patient for the potential emotional and social consequences of the results, including the impact on at-risk relatives. Post-test counseling involves interpreting the complex results and explaining what they mean for the patient’s care and for family planning decisions.
Counseling is also crucial for addressing the ethical considerations of predictive testing for asymptomatic relatives, who may wish to know their own risk. Furthermore, counselors can discuss the potential for genetic discrimination related to life or disability insurance, although federal protections exist for health insurance and employment.