Motor Neurone Disease (MND), known as Amyotrophic Lateral Sclerosis (ALS) in the United States, is a progressive neurological disorder that selectively destroys the motor neurons responsible for controlling voluntary muscle movement. This degeneration leads to increasing muscle weakness, atrophy, and eventual paralysis, affecting a person’s ability to speak, swallow, move, and breathe. While the majority of cases occur with no family history, a significant minority are directly inherited, meaning a genetic change is passed down through a family.
Sporadic Versus Familial MND
Motor Neurone Disease is broadly divided into two classifications based on whether a family history of the disorder exists. The vast majority of cases, approximately 90%, are classified as sporadic MND (SMND or SALS), meaning the affected individual has no known family history of the disease or a related condition. Sporadic cases are thought to arise from a complex interplay between an individual’s genetic predisposition and environmental or lifestyle factors that have not yet been fully identified.
The remaining 5% to 10% of cases are known as familial MND (FMND or FALS), which is the inherited form of the disease. Familial MND is diagnosed when two or more individuals in the same family have been diagnosed with MND, or a known gene mutation has been identified. Even in sporadic cases, a smaller percentage of people may carry a gene mutation typically associated with familial disease, suggesting that a genetic component may still be present despite the lack of a clear family history.
Major Genes Linked to Inherited MND
Identifying specific genes provides insight into the biological mechanisms causing familial MND. These genes instruct the production of proteins crucial for motor neuron health, and mutations can lead to malfunction and death. Genetic factors are now known to account for roughly 60% to 70% of all familial MND cases.
The most common genetic cause of MND worldwide is an expansion in the C9orf72 gene, which is responsible for approximately 30% to 40% of familial cases and about 7% of sporadic cases. This mutation involves a specific segment of DNA that is repeated too many times, leading to the accumulation of toxic proteins that damage motor neurons. The second most frequently identified gene is SOD1, which was the first MND-related gene discovered and accounts for around 15% to 20% of familial cases.
Other genes also play a role, including TARDBP and FUS, each accounting for less than 5% of familial cases. Mutations in these genes disrupt the normal processing of RNA, which is a necessary step in making proteins, ultimately leading to the aggregation of abnormal proteins within the motor neurons. The identification of a specific gene can be important because it may affect a person’s eligibility for gene-specific clinical trials or future targeted therapies.
How Genetic Mutations Are Passed Down
Most familial MND cases follow an autosomal dominant inheritance pattern. In this pattern, a person only needs to inherit one copy of the mutated gene to have an increased risk of developing the disorder.
If a parent carries a dominant gene mutation for MND, each child has a 50% chance of inheriting the mutated copy of the gene. Conversely, each child also has a 50% chance of inheriting the normal copy and not being at increased risk. The inheritance of the mutated gene does not guarantee that the individual will develop MND, due to a concept known as incomplete penetrance, where other factors may influence whether the disease manifests.
A smaller number of familial MND cases are inherited in an autosomal recessive pattern, requiring a person to inherit a mutated copy from both parents to be affected. Because the dominant pattern is more common, detailed family history and genetic analysis are necessary to determine the specific inheritance risk. This understanding provides the foundation for risk assessment and predictive testing.
Genetic Counseling and Risk Assessment
Genetic counseling is an important resource for individuals with a family history of MND or those diagnosed with the disease. A genetic counselor is a specialized healthcare professional who interprets genetic information and discusses implications for the affected individual and their relatives. Counseling is recommended when there is a known family history or when an individual with MND considers diagnostic genetic testing.
The counseling process involves reviewing family medical history to construct a pedigree, determining the likelihood of an inherited mutation and its pattern. The counselor explains testing options, including diagnostic testing for symptomatic individuals or predictive testing for asymptomatic people with a known familial mutation. Predictive testing is a highly personal and voluntary decision because a positive result can carry significant emotional weight and may impact life insurance coverage or employment.
Genetic counselors provide emotional support and facilitate informed decision-making by discussing potential testing outcomes before a sample is collected. The goal is to ensure the individual fully understands their risk and the consequences of a test result for themselves and their family. Counseling helps families navigate the complexities of genetic risk and communicate this sensitive information to other at-risk relatives.