Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting nerve cells in the brain and spinal cord. It leads to the gradual loss of voluntary muscle control, affecting a person’s ability to move, speak, eat, and breathe. This condition results from the degeneration of motor neurons, which are the nerve cells responsible for sending signals from the brain to the muscles, causing them to weaken and waste away.
Understanding ALS Types
ALS cases are broadly categorized into two main types: sporadic and familial. Sporadic ALS (sALS) is the most common form, accounting for approximately 90% to 95% of all diagnoses. This type occurs randomly, with no identifiable family history of the disease. Familial ALS (fALS), by contrast, involves a clear genetic component and a history of the disease within a family. While the clinical presentation and symptoms of fALS are generally similar to sALS, familial cases often exhibit an earlier age of symptom onset.
The Familial Connection
A small percentage of ALS cases are familial, typically ranging from 5% to 10%. This means that the vast majority of individuals diagnosed with ALS do not have a known family history of the condition. Even among sporadic cases, about 10% are now understood to have an underlying genetic mutation linked to the disease, despite no apparent family history. This highlights the complex interplay of genetic factors in ALS.
Genes Involved in Familial ALS
The genetic basis of familial ALS involves mutations in several genes. Four genes, C9orf72, SOD1, TARDBP (also known as TDP-43), and FUS, collectively account for up to 70% of familial ALS cases, particularly in European populations. Mutations in these genes can disrupt normal cellular processes, leading to motor neuron degeneration.
The C9orf72 gene is the most frequent genetic cause of familial ALS, accounting for 25% to 40% of cases. Mutations in C9orf72 involve an abnormal hexanucleotide repeat expansion, which can lead to the production of toxic proteins and protein clumping within cells. This gene is also recognized for its genetic link to frontotemporal dementia.
Mutations in the SOD1 gene are the second most common cause of familial ALS, identified in 10% to 20% of cases. This gene was the first to be associated with familial ALS when discovered in 1993.
The TARDBP gene, which codes for the TDP-43 protein, is implicated in approximately 5% of familial ALS cases. Mutations in TARDBP result in the abnormal aggregation of the TDP-43 protein, contributing to the death of motor neurons.
Similarly, mutations in the FUS gene are found in about 5% of familial ALS cases. These mutations can cause the FUS protein to move out of its normal location within the cell nucleus and form harmful clumps in the cytoplasm.
Most familial ALS cases follow an autosomal dominant inheritance pattern, meaning that a child of an affected parent has a 50% chance of inheriting the mutated gene. Rarely, other inheritance patterns, such as autosomal recessive or X-linked, may be observed.
Family Considerations
For families with a history of ALS, especially those where a genetic component is suspected, genetic counseling offers valuable support and information. Genetic counselors are healthcare professionals who can help individuals understand their family medical history and the intricacies of ALS genetics. They provide guidance on the potential benefits and risks associated with genetic testing, allowing families to make informed decisions.
Genetic testing is an option for family members who may be at risk, particularly if a specific gene mutation has been identified in an affected relative. This type of testing can clarify whether an individual carries a genetic mutation linked to ALS, providing insights for personal and family planning. However, a positive test result does not predict the exact age of disease onset or its severity.
The decision to pursue genetic testing is deeply personal and involves complex considerations. While it can offer a sense of clarity and enable participation in certain research studies or clinical trials, there are also emotional and social implications. Genetic counselors can facilitate discussions about these topics, helping families navigate the potential emotional impact and future planning associated with genetic information.