SNP Shot: Genomic Insights

Amyotrophic lateral sclerosis (ALS) is a progressive disease that damages motor neurons. These specialized nerve cells, located in the brain and spinal cord, control muscle movement. In ALS, these motor neurons gradually die (atrophy), causing muscle weakness, loss of muscle mass, and difficulty controlling movement.

ALS presents in various forms, distinguished by their specific symptoms, genetic causes, or the absence of a clear genetic link. The majority of ALS cases are sporadic, meaning they occur in individuals without a family history of the disease. Sporadic ALS typically manifests in individuals in their late fifties or early sixties. However, a smaller percentage (5-10%) have familial ALS, meaning there's a family history of ALS or frontotemporal dementia (FTD), a brain disorder impacting personality, behavior, and language. Familial ALS usually starts in the late forties or early fifties. Rarely, familial ALS begins in childhood or adolescence, known as juvenile ALS.

The initial signs of ALS can be subtle and easily overlooked. Early symptoms include muscle twitching, cramps, stiffness, or weakness. Individuals may develop slurred speech (dysarthria) and later, difficulty chewing or swallowing (dysphagia). Many ALS patients experience malnutrition due to reduced food intake from dysphagia and increased energy needs (metabolism) due to the illness. As the disease advances, muscles weaken, and limbs appear thinner due to muscle atrophy. Eventually, individuals lose muscle strength and the ability to walk, requiring wheelchairs and assistance with daily activities. Over time, hand and arm function is lost. Breathing becomes difficult as respiratory muscles weaken. Most people with ALS die from respiratory failure within 2 to 10 years of symptom onset, although the disease's progression varies significantly.

Approximately 20% of individuals with ALS also develop FTD. Changes in personality and behavior can impair social interaction. Communication skills deteriorate as the disease progresses. The relationship between ALS and FTD development remains unclear. Individuals with both conditions are diagnosed with ALS-FTD.

A rare, often familial form of ALS is the ALS-parkinsonism-dementia complex (ALS-PDC). This disorder combines ALS symptoms with parkinsonism (movement abnormalities) and progressive intellectual decline (dementia). Parkinsonism signs include slow movements (bradykinesia), stiffness, and tremors. Affected family members may exhibit different combinations of these symptoms.

Inheritance:

About 90-95% of ALS cases are sporadic, meaning they are not inherited. An estimated 5-10% are familial, caused by mutations in specific genes. The inheritance pattern varies depending on the gene. Most familial ALS is inherited in an autosomal dominant pattern, where one copy of the mutated gene is sufficient to cause the disease. Typically, an affected individual has one parent with the condition. However, some individuals who inherit an ALS-causing gene mutation may never develop the disease (reduced penetrance). The reason for this variability is unclear. Less frequently, ALS is inherited in an autosomal recessive pattern, requiring two copies of the mutated gene. In these cases, the parents are carriers, each possessing one copy of the mutated gene, but typically show no symptoms. Because the parents are unaffected, autosomal recessive ALS is often mistaken for sporadic ALS. Very rarely, ALS is inherited in an X-linked dominant pattern. X-linked conditions occur when the disease-associated gene is on the X chromosome. In females (two X chromosomes), one mutated copy is enough to cause the disorder. In males (one X chromosome), a single mutated copy will cause the disorder. Males with X-linked dominant ALS tend to develop the disease earlier and have a shorter life expectancy than females. A key feature of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.