Overview Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig's disease, is a rare progressive neurodegenerative disorder affecting the nerve cells in the brain and spinal cord that control voluntary muscle movement. Global estimates of ALS range from 1.9 per 100,000 to 6 per 100,000. ALS shot to public attention because of the viral "ice bucket challenge" in 2014. Though the exact impact of the viral challenge remains unknown with opinions divided on whether the challenge truly had a real world impact, it is undeniable that it catapulted the disease to the public's attention. Individuals well-known in their respective fields have been afflicted by this disorder, perhaps one of the most famous ones being the theoretical physicist Stephen Hawking. ALS leads to the gradual degeneration and death of motor neurons, which are the nerve cells responsible for transmitting signals from the brain to the muscles. As motor neurons deteriorate, voluntary muscle control and movement are progressively impaired, leading to muscle weakness, twitching (fasciculations), stiffness, and eventually paralysis. The symptoms of ALS can vary widely among individuals and may initially affect different muscle groups. Common early symptoms include weakness in the hands, arms, legs, or muscles involved in speech, swallowing, or breathing. As the disease progresses, muscle weakness and atrophy spread to other parts of the body. 102 ALS can also affect the muscles involved in speech, swallowing, and breathing, leading to difficulties in speaking, chewing, swallowing (dysphagia), and breathing (respiratory compromise). Bulbar symptoms often contribute to significant disability and can pose lifethreatening complications in advanced stages of the disease. In some cases, ALS may be associated with cognitive and behavioral changes, including difficulties with executive function, language, decision-making, and emotional regulation. This constellation of symptoms is referred to as frontotemporal dementia (FTD) or ALS-FTD, which represents a spectrum of overlapping neurodegenerative disorders. ALS currently has no cure, and the underlying mechanisms driving the disease remain incompletely understood. Most cases of ALS are sporadic, meaning they occur without a clear family history, while a smaller percentage are inherited (familial ALS) due to genetic mutations. Several genes have been implicated in familial ALS, including C9orf72, SOD1, TARDBP, FUS, and others. Diagnosis of ALS is typically based on a thorough medical history, neurological examination, electromyography (EMG), nerve conduction studies, and exclusion of other possible causes of muscle weakness and motor dysfunction. Magnetic resonance imaging (MRI) and other imaging tests may also be used to rule out other conditions. While there is no cure for ALS, various treatments and supportive interventions can help manage symptoms, improve quality of life, and prolong survival. These may include medications to alleviate muscle cramps, spasticity, or excessive saliva production, as well as physical therapy, occupational therapy, speech therapy, and assistive devices to maintain mobility and communication abilities. In some cases, non-invasive ventilation or feeding tubes may be necessary to support respiratory and nutritional needs. The US Food and Drug Administration (FDA) has approved a few medications for treating symptoms related to ALS including the benzothiazole Riluzole (Rilutek, Exservan, Tiglutik) in 1995, the antioxidant Edaravone (Radicava) 128 in 2017, and Sodium phenylbutyrate-Taurursodiol (Relyvrio) , a combination of a histone deacetylase inhibitor and a bile acid, in 2022. Sadly, Relyvrio has been just reported to have failed Phase III trial. The Phase 3b trial of Radicava has been also discontinued in 2023, as well as its extension study. The prognosis for ALS varies, with most individuals experiencing progressive disability over time. The rate of disease progression and life expectancy can vary widely among individuals, ranging from a few years to more than a decade from the onset of symptoms. Respiratory failure is the most common cause of death in ALS.