---
title: "ALS"
chunk: 4/11
source: "https://en.wikipedia.org/wiki/ALS"
category: "reference"
tags: "science, encyclopedia"
date_saved: "2026-05-05T11:04:10.701513+00:00"
instance: "kb-cron"
---

=== Cognitive, emotional, and behavioral symptoms ===
Cognitive impairment or behavioral dysfunction is present in 30–50% of individuals with ALS, and can appear more frequently in later stages of the disease. Language dysfunction, executive dysfunction, and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in ALS. Cognitive impairment is found more frequently in patients with C9orf72 gene repeat expansions, bulbar onset, bulbar symptoms, family history of ALS and/or a predominantly upper motor neuron phenotype.
Pseudobulbar affect and emotional lability are a type of symptom in which patients cry, smile, yawn, or laugh, either in the absence of emotional stimuli, or when they are feeling the opposite emotion to that being expressed. Approximately half of ALS patients experience this; it is more common in those with bulbar-onset ALS. While more or less benign relative to other symptoms, it can cause increased stigma and social isolation as people around the patient struggle to react appropriately to what can be frequent and inappropriate outbursts in public.
In addition to mild changes in cognition that may only emerge during neuropsychological testing, around 10–15% of individuals have signs of frontotemporal dementia (FTD). Repeating phrases or gestures, apathy, and loss of inhibition are the most frequently reported behavioral features of ALS. ALS and FTD are now considered to be part of a common disease spectrum (ALS–FTD) because of genetic, clinical, and pathological similarities.
Cognitive and behavioral issues are associated with a poorer prognosis as they may reduce adherence to medical advice and deficits in empathy and social cognition, which may increase caregiver burden.

== Cause ==
Sporadic ALS has no known cause and is described as an idiopathic disease. Though its exact cause is unknown, genetic and environmental factors are thought to be of roughly equal importance. The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A multi-step liability threshold model for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life. ALS can strike at any age, but its likelihood increases with age. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. ALS is 20% more common in men than women, but this difference in sex distribution is no longer present in patients with onset after age 70.

=== Genetics and genetic testing ===

ALS can be classified as either familial or sporadic, depending on whether there is a known family history of the disease and/or whether an ALS-associated genetic mutation has been identified via genetic testing. Familial ALS is thought to account for 10–15% of cases overall and can include monogenic, oligogenic, and polygenic modes of inheritance.
There is considerable variation among clinicians on whether to conduct genetic testing in ALS, particularly if there is no discernible family history of the disease. In the past, genetic counseling and testing was only offered to those with obviously familial ALS. It is increasingly recognized that cases of sporadic ALS may also be due to disease-causing de novo mutations in SOD1, or C9orf72, or inherited mutations which were overlooked due to incomplete family history or incomplete penetrance. The lack of positive family history may be caused by lack of historical records, having a smaller family, older generations dying earlier of causes other than ALS, genetic non-paternity, and uncertainty over whether certain neuropsychiatric conditions (e.g. frontotemporal dementia, other forms of dementia, suicide, psychosis, schizophrenia) should be considered significant when determining a family history. There have been calls in the research community to routinely counsel and test all diagnosed ALS patients for familial ALS, especially due to the availability of gene therapy (tofersen) for carriers of SOD1 ALS. A shortage of genetic counselors and limited clinical capacity to see such at-risk individuals make this challenging in practice, as does the unequal access to genetic testing around the world.
More than 40 genes have been associated with ALS, of which four account for nearly half of familial cases, and around 5% of sporadic cases: C9orf72 (40% of familial cases, 7% sporadic), SOD1 (12% of familial cases, 1–2% sporadic), FUS (4% of familial cases, 1% sporadic), and TARDBP (4% of familial cases, 1% sporadic), with the remaining genes mostly accounting for fewer than 1% of either familial or sporadic cases. Notably, repeat expansions in the C9orf72 gene account for about 40% of genetic ALS and 25% of genetic FTD, leading to the redefinition of ALS and FTD as lying on a shared disease spectrum. ALS genes identified to date explain the cause of about 70% of familial ALS and about 15% of sporadic ALS. Overall, first-degree relatives of an individual with ALS have a ~1% risk of developing ALS themselves.
SOD (superoxide dismutase) refers to a group of enzymes that target and reduce the presence of harmful reactive oxygen species (ROS) to protect cells. Subsequently, SOD enzymes are often critical in ensuring appropriate conditions for neuronal/neural pathway development. SOD1, a subspecies within the main SOD gene family, is a metalloenzyme characterized by the two main metal groups it contains—Zinc (Zn) and Copper (Cu). The Cu-Zn superoxide dismutase metabolizes superoxide radicals to oxygen and hydrogen peroxide, defending organisms against oxygen toxicity. Various gene inhibition and knockdown experiments in model organisms such as Drosophila melanogaster have indicated the key role of SOD enzyme activity in neuronal remodeling.SOD gene mutation has been linked to inhibited motor function and ability, as well as a decreased capacity for affected organisms to function and perform physical behaviors normally due to dysfunctional movement and muscle degeneration. These downregulated transcripts are responsible for mediating axon extension and guidance functions; mutations in SOD1 genes are linked with neuronal defects/neuroinflammation similar to the symptoms of ALS.