Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects the nerve cells in the brain and spinal cord, which control voluntary muscle movement. This deterioration of motor neurons leads to muscle weakness, atrophy, and eventual paralysis. While most ALS cases occur without an apparent family history, genetic testing is available and is an important part of diagnosis and care for a subset of affected individuals. Identifying a genetic cause helps inform treatment decisions and provides critical information to the patient and their family members.
Understanding the Genetic Basis of ALS
ALS cases are broadly categorized into two types: familial and sporadic. Familial ALS (FALS) is the inherited form, accounting for 5% to 10% of total cases, caused by an inherited genetic mutation passed down through the family.
The vast majority of diagnoses (90% to 95%) are classified as sporadic ALS (SALS), occurring in people with no known family history. While SALS is not inherited in the traditional sense, a genetic cause can still be identified in a small percentage of these cases. This suggests that genetics play a role in a wider range of cases, and the distinction between FALS and SALS is becoming less rigid as more genetic factors are discovered.
Specific Genetic Tests Available
Genetic testing for ALS involves analyzing DNA for mutations within genes associated with the disease. The sample is typically collected via a blood draw or a cheek swab, isolated, and sent to a specialized laboratory for analysis. This process looks for specific gene variants associated with a higher risk or direct cause of ALS.
Testing can focus on a single gene, but it is more commonly performed using a multi-gene panel. These panels simultaneously screen for mutations in multiple genes. Current clinical guidelines strongly recommend testing for a minimum set of genes in all individuals diagnosed with ALS.
The most frequent genetic cause is an abnormal expansion in the C9orf72 gene, accounting for up to 40% of familial cases and a small percentage of sporadic cases. Mutations in the SOD1 gene are the second most common cause, responsible for 12% to 20% of familial ALS, and were the first genes identified. Other significant genes included on testing panels are TARDBP and FUS, each contributing to a smaller fraction of cases.
Clinical Rationale for Seeking Testing
Genetic testing is offered to individuals with an ALS diagnosis for several important reasons. The primary purpose is diagnostic, as identifying a specific gene mutation confirms the diagnosis and provides insight into the disease’s potential progression. A positive genetic test can also qualify a patient for gene-targeted therapies, such as the FDA-approved treatment for the SOD1 mutation, or for participation in gene-specific clinical trials.
Testing is also pursued by unaffected individuals in families where an ALS-linked mutation has been identified. This is called predictive or pre-symptomatic testing, which provides information about a person’s future risk of developing the disease before symptoms appear. Individuals with an early onset of symptoms or a co-occurring condition like frontotemporal dementia (FTD) often have an identifiable genetic cause.
Interpreting Results and Addressing Uncertainty
A positive genetic test result means a known ALS-causing mutation was found, such as in C9orf72 or SOD1. For the individual with ALS, this result determines eligibility for gene-specific treatments and clinical trials. For unaffected family members, a positive result indicates an increased lifetime risk of developing the disease.
The concept of penetrance is crucial when interpreting a positive result. Penetrance describes the likelihood that a person with the mutation will develop the disease. It is often age-dependent and incomplete, meaning not everyone who inherits the mutation will become ill. For example, the penetrance of the C9orf72 expansion is estimated to be 91% by age 80, but some carriers never develop ALS.
A negative result indicates that none of the known ALS-linked genes were found to have a mutation. This does not completely rule out a genetic cause, however, as many sporadic and some familial cases are caused by genes not yet discovered or not included in current testing panels. In such cases, the ALS is considered to be of unknown cause.
Because of the life-altering implications of the results, pre- and post-test genetic counseling with a specialist is recommended. A genetic counselor helps the individual understand the complex results, the risks of passing the mutation to children, and the emotional impact of the diagnosis, including potential discrimination regarding certain types of insurance.