Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that attacks motor neurons in the brain and spinal cord, leading to the loss of voluntary muscle control. While most ALS cases occur randomly, a small fraction is known as Familial ALS (FALS), meaning the disease is inherited within a family. FALS accounts for approximately 5 to 10% of all ALS diagnoses, representing a form where a genetic mutation is passed down through generations. Understanding the causes, inheritance patterns, and confirmation of FALS is important for individuals with a family history of the disorder.
Distinguishing Familial ALS
The primary factor separating Familial ALS (FALS) from Sporadic ALS (SALS), the non-inherited form, is the presence of a known disease history within a family. SALS accounts for 90 to 95% of cases and occurs without an apparent family history. A diagnosis of FALS is considered when at least two first-degree relatives have been diagnosed with the condition.
Although the clinical symptoms and disease progression of FALS and SALS are often similar, there can be subtle differences in the age of onset. People with FALS often begin showing symptoms slightly earlier, typically in their late forties or early fifties. SALS usually presents in the late fifties or early sixties. Despite these differences, the underlying pathology in both forms involves the progressive loss of motor neurons, leading to muscle weakness, atrophy, and eventual paralysis.
Genetic research shows the distinction between FALS and SALS is becoming more nuanced. Researchers have found that about 10% of SALS cases have a genetic mutation linked to ALS, despite lacking a family history. Conversely, 30 to 40% of FALS cases do not have an identified genetic mutation, suggesting more ALS-linked genes are yet to be discovered. This overlap suggests all forms of ALS may have a genetic component.
Genetic Basis of FALS
Familial ALS is caused by pathogenic mutations passed down from one generation to the next, primarily following an autosomal dominant inheritance pattern. This means the mutated gene is located on a non-sex chromosome, and inheriting just one copy of the altered gene is sufficient to cause the disorder. A parent who carries such a mutation has a 50% chance of passing the mutated gene to any of their children.
The most common genetic cause of FALS is a mutation in the C9orf72 gene, accounting for 35 to 40% of all familial cases in North America and Europe. This mutation involves a hexanucleotide repeat expansion, where a six-letter segment of DNA is repeated hundreds or thousands of times. The expansion disrupts normal cellular function. The C9orf72 mutation is also strongly associated with frontotemporal dementia (FTD), meaning individuals may develop ALS, FTD, or both conditions.
The second most common cause of FALS is mutations in the SOD1 gene, which are responsible for about 12 to 20% of familial cases worldwide. The SOD1 gene provides instructions for making the superoxide dismutase 1 enzyme, which neutralizes harmful free radicals in cells. Over 150 different mutations in SOD1 have been described, and these mutations lead to toxic protein aggregation, contributing to motor neuron death.
Other genes are linked to a smaller percentage of FALS cases, including TARDBP and FUS. Mutations in TARDBP are associated with 1 to 5% of familial cases, while FUS mutations are found in about 5% of familial ALS. These genes are involved in processes like RNA metabolism and protein transport. Their disruption can cause proteins to clump together in motor neurons, leading to dysfunction.
Diagnostic Confirmation
The process of confirming a FALS diagnosis begins with a detailed clinical evaluation by a neurologist, focusing on signs of both upper and lower motor neuron degeneration. Symptoms like muscle weakness, spasticity, and difficulty swallowing are assessed to determine if they align with the disease progression characteristic of ALS. This clinical picture is the foundation of the diagnosis, as there is no single test that can definitively diagnose ALS.
Specialized tests are then used to rule out other conditions that can mimic ALS symptoms. Electromyography (EMG) and Nerve Conduction Studies (NCS) measure the electrical activity of muscles and nerves, providing objective evidence of motor neuron damage. These tests help build a case for an ALS diagnosis based on physical and functional evidence.
Genetic testing provides the final confirmation for FALS, identifying a specific mutation in an ALS-linked gene. Testing is performed using a blood or saliva sample to analyze the DNA for mutations in genes like C9orf72 or SOD1. A positive result confirms the hereditary nature of the disease, which can be important for accessing gene-targeted therapies or clinical trials.
Genetic counseling is highly recommended for anyone considering genetic testing, especially those with a family history of ALS. A counselor helps interpret the complex results, discusses the inheritance risk for family members, and addresses the psychological and social implications of a positive finding. Genetic testing for FALS offers clarity on the cause of the disease and provides information for family planning and early detection strategies.