Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that targets the motor neurons in the brain and spinal cord. These specialized nerve cells control voluntary muscle movement, and their deterioration leads to a loss of communication between the nervous system and the muscles. This breakdown results in muscle weakness, twitching, and atrophy, eventually affecting the ability to walk, speak, swallow, and breathe. Research has made significant progress in identifying the underlying genetic factors that contribute to the disease’s onset.
The Distinction Between Familial and Sporadic ALS
ALS cases are broadly classified into two main types based on family history, though this distinction is often blurred by genetic discoveries. 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, and the cause often appears random, potentially stemming from environmental and genetic risk factors.
Familial ALS (FALS) represents the remaining 5% to 10% of cases. FALS is defined by the presence of at least one first- or second-degree relative who has also been diagnosed with the condition. However, a significant portion of individuals with SALS are now known to carry a mutation in an ALS-linked gene, even without a clear family history. This suggests that many cases previously labeled as sporadic have a genetic component, meaning the classification often reflects observable inheritance patterns rather than true genetic origin.
Major Genes Implicated in ALS Development
The most frequent genetic cause of ALS is a mutation in the C9orf72 gene, responsible for about 40% of familial cases and 5% to 10% of sporadic cases. The mutation involves an abnormal expansion of a hexanucleotide repeat (GGGGCC) hundreds or thousands of times. This expansion occurs in a non-coding region of the gene, meaning it does not directly change the structure of the C9orf72 protein itself.
The second most common cause is a mutation in the SOD1 gene, accounting for 12% to 20% of familial cases and about 2% of sporadic cases. SOD1 provides instructions for the enzyme Superoxide Dismutase 1, which breaks down harmful superoxide radicals. Unlike the C9orf72 expansion, SOD1 mutations are typically point mutations—a change to a single base pair—resulting in a misfolded, toxic protein.
Two other genes, TARDBP and FUS, are also genetic contributors. TARDBP mutations are found in approximately 3% of familial cases and less than 1% of sporadic cases, with FUS mutations present in similar proportions. These genes encode proteins involved in processing RNA, the molecule that translates genetic instructions into proteins.
How Genetic Mutations Cause Motor Neuron Damage
Genetic mutations converge on a few destructive cellular processes that ultimately lead to motor neuron death. One primary mechanism is the accumulation of toxic protein aggregates, or clumps, which disrupt normal cell function.
In SOD1 mutations, the misfolded Superoxide Dismutase 1 protein becomes toxic, causing it to clump inside motor neurons and support cells. This misfolding initiates damage, including oxidative stress and mitochondrial dysfunction, which impairs the cell’s energy production. Similarly, the proteins produced by mutated TARDBP (TDP-43) and FUS genes also form toxic aggregates. These aggregates typically relocate from the nucleus to the cell’s cytoplasm, interfering with essential cellular processes.
The C9orf72 expansion causes damage through two distinct mechanisms: RNA toxicity and dipeptide repeat protein toxicity. The expanded GGGGCC repeat sequence is transcribed into an abnormal RNA molecule. This toxic RNA sequesters necessary proteins, preventing them from performing their normal functions (RNA toxicity). This toxic RNA is also translated into short, harmful dipeptide repeat proteins, which contribute to cellular stress.
These molecular pathologies impair the cell’s ability to maintain internal balance. Furthermore, mutations in genes like C9orf72, TARDBP, and FUS are associated with defects in axonal transport—the process of moving materials along the motor neuron’s long projections. Motor neurons are particularly vulnerable to disruption in this transport system, which is necessary for delivering nutrients and removing waste.
Genetic Screening and Counseling for ALS
The growing knowledge of ALS genetics has led to a greater emphasis on genetic screening for diagnosed individuals. Genetic testing is now recommended for all newly diagnosed patients, regardless of family history. Identifying a specific gene mutation helps patients understand the cause of their disease and determines eligibility for gene-targeted therapies or clinical trials.
For individuals who have a family member with ALS but show no symptoms, predictive genetic testing is available. This complex process requires genetic counseling beforehand to ensure the person fully understands the risks, benefits, and emotional implications of the results. Counselors address the potential for psychological distress and ethical concerns, such as discrimination in insurance or employment.
A central concept discussed in counseling is genetic penetrance, which is the likelihood that an individual carrying a specific gene mutation will develop the disease. Penetrance is highly variable in ALS and is often age-dependent; a person’s risk increases with age but may never reach 100%. For example, some SOD1 mutations have high penetrance, while the C9orf72 expansion can show reduced penetrance, explaining why some gene carriers never develop symptoms.