Amyotrophic Lateral Sclerosis (ALS), often known as Lou Gehrig’s disease, is a progressive neurodegenerative condition that targets motor neurons in the brain and spinal cord. The degeneration and eventual death of these cells lead to muscle weakness, atrophy, and paralysis, affecting a person’s ability to move, speak, swallow, and breathe. The underlying causes of ALS are complex, involving a mix of genetic and environmental factors, meaning the inheritance pattern does not have a single, simple answer.
Sporadic Versus Familial ALS
Understanding ALS genetics requires distinguishing between the two major categories of the disease. The vast majority of diagnoses, about 90% to 95% of cases, are classified as sporadic ALS (sALS), where the individual has no known family history. These cases are thought to arise from a combination of genetic susceptibility and environmental factors.
The remaining 5% to 10% of cases are familial ALS (fALS), meaning the disease runs in the family and is typically inherited through a genetic mutation. Genetic mutations associated with ALS can be identified in approximately 10% of seemingly sporadic cases. This overlap indicates that genetics contribute significantly to the disease’s development, even without a clear family history.
Autosomal Dominant Inheritance
The most frequent inheritance pattern observed in familial ALS is autosomal dominant inheritance. In this pattern, only one copy of the mutated gene is necessary to increase the risk of developing the disease. Since the mutation resides on a non-sex chromosome (autosome), it affects both males and females equally.
An individual with an autosomal dominant mutation has a 50% chance of passing that gene on to each child. Many well-known ALS-associated genes, such as C9orf72 and SOD1, follow this dominant model. The C9orf72 repeat expansion is the most common genetic cause of ALS, accounting for up to 40% of familial cases in some populations. Mutations in the SOD1 gene, the first ALS gene identified, are also inherited in an autosomal dominant manner.
In families with dominant inheritance, the disease often presents across multiple generations. The dominant mutation may be associated with an earlier age of onset or specific features, such as the increased likelihood of co-occurring frontotemporal dementia seen with the C9orf72 expansion. However, the severity and progression of the disease can vary significantly, even among family members who share the same mutation.
Recessive and Complex Inheritance Patterns
While less common than the dominant form, true autosomal recessive inheritance occurs in ALS, often involving specific genes. For a person to develop ALS through an autosomal recessive pattern, they must inherit two copies of the altered gene, one from each parent. The parents, who carry only one copy of the mutation, are typically unaffected carriers.
The genetics of ALS also encompass complex inheritance, particularly in sporadic cases. This involves genetic risk factors where multiple genes, each contributing a small risk, work together to increase susceptibility. This concept, known as oligogenic or polygenic risk, suggests the disease results from the cumulative effect of several genetic variations rather than a single mutation.
The concept of penetrance further complicates the inheritance picture. Penetrance refers to the likelihood that a person who has inherited a disease-causing mutation will actually develop the condition. Some ALS-linked genes show incomplete penetrance, meaning not every person who carries the mutation will develop ALS, though the probability increases with age.
Genetic Screening and Counseling
For individuals concerned about their risk for ALS, particularly those with a family history, genetic screening and counseling are available. Genetic testing can identify whether a person carries a known ALS-associated genetic mutation. Testing is frequently recommended for people with a family history of ALS or those who develop symptoms at an early age.
Genetic counseling is an essential step, especially before predictive testing for asymptomatic individuals. A genetic counselor provides guidance by reviewing the family medical history and explaining the potential benefits and limitations of testing. They interpret the complex results, which may involve dominant, recessive, or complex risk factors.
Counseling also helps individuals navigate the emotional, social, and financial consequences of knowing their genetic status. Counselors assist with family planning decisions and discuss the implications for the individual and their family members.