Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. These nerve cells, called motor neurons, control voluntary muscle movement. As motor neurons deteriorate, they stop sending messages to muscles, leading to loss of muscle control and eventual paralysis.
Forms of ALS
ALS primarily presents in two main forms: sporadic and familial. Sporadic ALS is the most common, accounting for approximately 90% to 95% of all cases. This form occurs randomly in individuals with no known family history of the disease. The exact cause of sporadic ALS is not fully understood, but it is believed to involve a combination of genetic and environmental factors.
Familial ALS occurs when the disease runs in families, indicating a clear genetic link. This form makes up about 5% to 10% of all ALS cases. Individuals with familial ALS often begin experiencing symptoms at an earlier age compared to those with sporadic ALS. The key distinction lies in the inheritance pattern.
How Familial ALS Genes Are Passed Down
Familial ALS is predominantly inherited through an autosomal dominant pattern. This means a person needs to inherit only one copy of an altered gene from either parent to be at risk. When a parent has a genetic mutation causing autosomal dominant ALS, there is a 50% chance that each child will inherit that specific mutation. This applies equally to both male and female children.
The concept of ALS appearing to “skip a generation” can be explained by incomplete penetrance. This means an individual may inherit the gene mutation but might not develop symptoms during their lifetime. The gene mutation is still present and can be passed on to subsequent generations. The likelihood of developing symptoms for many ALS gene mutations generally increases with age.
Several genes are commonly associated with familial ALS, including C9orf72, SOD1, TARDBP, and FUS. Mutations in the C9orf72 gene are a frequent genetic cause of familial ALS and often show variable penetrance. While most familial ALS cases follow an autosomal dominant pattern, less common inheritance patterns, such as autosomal recessive, also exist. In autosomal recessive inheritance, two copies of a mutated gene, one from each parent, are required for the disease to develop. Parents who carry only one copy typically do not show symptoms, which can also give the impression that the disease has skipped a generation.
Genetic Testing and Family Planning
Genetic testing offers insights for individuals with a family history of ALS. It can identify known genetic mutations associated with the disease. Testing is often considered in families where multiple members have been affected by ALS or related neurological conditions. Recent guidelines recommend that all individuals diagnosed with ALS be offered genetic testing, regardless of family history, as genetic mutations can be found in both familial and sporadic cases.
Genetic testing results can help individuals understand potential disease progression and inform eligibility for gene-targeted therapies or clinical trials. However, genetic testing has limitations; not all familial cases have identified mutations, meaning a negative result does not always rule out a genetic cause. Researchers continue to discover new genes linked to ALS. Genetic counseling is highly recommended before and after testing. Genetic counselors can help interpret results, discuss implications for the individual and family, and provide support for family planning decisions.
Other Considerations for ALS Risk
Beyond direct genetic inheritance, other factors can influence ALS risk. Age is a consistent risk factor, with the likelihood of developing ALS increasing with age, typically peaking between 60 and 80 years. Men have a higher risk than women before age 65, though this difference tends to equalize in older age groups. Ethnicity can also play a role, with some studies indicating higher rates among Caucasians.
Environmental factors are also under investigation as potential contributors to ALS risk, though their precise role is less understood compared to genetic mutations. These factors are thought to interact with an individual’s genetic predisposition. Suspected environmental influences include smoking, exposure to certain heavy metals like lead or mercury, pesticides, and solvents. Military service and traumatic injuries, including head trauma, have also been explored as potential risk factors. These environmental elements are not as definitively linked to ALS causation as specific genetic mutations in familial cases.