als als amyotrophic lateral sclerosis (als), also known as motor neurone disease (mnd) or lou gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. als is the most common form of the motor neuron diseases. early symptoms of als include stiff muscles, muscle twitches, and gradual increasing weakness and muscle wasting. limb-onset als begins with weakness in the arms or legs, while bulbar-onset als begins with difficulty speaking or swallowing. around half of people with als develop at least mild difficulties with thinking and behavior, and about 15% develop frontotemporal dementia. motor neuron loss continues until the ability to eat, speak, move, and finally the ability to breathe is lost. "motor neuron disease" and "motor neurone disease" redirect here. for a group of muscle-wasting disorders, see motor neuron diseases. amyotrophic lateral sclerosisother nameslou gehrig's diseasecharcot's diseasemotor neurone disease (mnd)the parts of the nervous system affected by als, highlighting the upper motor neurons, lower motor neurons, and frontotemporal regions of the brain. these cause progressive symptoms in skeletal muscles throughout the body.specialtyneurologysymptomsearly: stiff muscles, muscle twitches, gradual increasing weakness, typically in a limb later: difficulty in speaking, swallowing, and breathing; respiratory failure about 25-30% of cases start in the mouth + throat region. 10-15% of cases also have frontotemporal dementiacomplicationsfalling (accident); respiratory failure; pneumonia; malnutritionusual onset45 – 75 years causesunknown (most), genetic (about 15%)risk factorsgenetic risk factors including unc13a, ataxin-2; age; male sex; smoking; physical exercise; head injury; occupational and environmental exposures diagnostic methodclinical diagnosis of exclusion, based on the presence of symptoms in the upper and lower motor neurons with progressive muscular weakness in which no other explanation can be found. supportive evidence from electromyography, genetic testing, and neuroimagingdifferential diagnosismultifocal motor neuropathy, kennedy's disease, hereditary spastic paraplegia, nerve compression syndrome, diabetic neuropathy, post-polio syndrome, myasthenia gravis, multiple sclerosistreatmentwalker (mobility); wheelchair; non-invasive ventilation; feeding tube; augmentative and alternative communication; symptomatic managementmedicationriluzole, edaravone; sodium phenylbutyrate/ursodoxicoltaurine; dextromethorphan/quinidineprognosislife expectancy highly variable but most often 2–4 years from diagnosis frequencyincidence: 1.6/100,000 individuals per year; prevalence: 4.4/100,000 living individuals lifetime risk, 1 in 400 individuals most cases of als (about 90% to 95%) have no known cause, and are known as sporadic als. however, both genetic and environmental factors are believed to be involved. the remaining 5% to 10% of cases have a genetic cause, often linked to a history of the disease in the family, and these are known as genetic als. about half of these genetic cases are due to one of two specific genes. the diagnosis is based on a person's signs and symptoms, with testing done to rule out other potential causes. there is no known cure for als. the goal of treatment is to slow the disease and improve symptoms. treatments that slow als include riluzole (extends life by two to three months) and sodium phenylbutyrate/ursodoxicoltaurine (extends life by around seven months). non-invasive ventilation may result in both improved quality and length of life. mechanical ventilation can prolong survival but does not stop disease progression. a feeding tube may help maintain weight and nutrition. death is usually caused by respiratory failure. the disease can affect people of any age, but usually starts around the age of 60. the average survival from onset to death is two to four years, though this can vary, and about 10% survive longer than ten years. descriptions of the disease date back to at least 1824 by charles bell. in 1869, the connection between the symptoms and the underlying neurological problems was first described by french neurologist jean-martin charcot, who in 1874 began using the term amyotrophic lateral sclerosis. classification als is a motor neuron disease, which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body. other motor neuron diseases include primary lateral sclerosis (pls), progressive muscular atrophy (pma), progressive bulbar palsy, pseudobulbar palsy, and monomelic amyotrophy (mma). als itself can be classified in a few different ways: by which part of the motor neurons are affected; by the parts of the body first affected; whether it is genetic; and the age at which it started. subtypes of motor neuron degeneration typical or "classical" als involves neurons in the brain and spinal cord (upper motor neurons, highlighted green), as well as the lower motor neurons, which go from the spinal cord to the muscles, highlighted blue. the image on the left shows a side-on view of the brain and spinal cord, the image on the right shows a cross-sectional view (as if from above) through the spinal cord. als can be classified by the types of motor neurons that are affected. to successfully control any voluntary muscle in the body, a signal must be sent from the motor cortex in the brain down the upper motor neuron as it travels down the spinal cord. there, it connects via a synapse to the lower motor neuron which connects to the muscle itself. damage to either the upper or lower motor neuron, as it makes its way from the brain to muscle, causes different types of symptoms. damage to the upper motor neuron typically causes spasticity, stiffness, brisk reflexes, and/or clonus, while damage to the lower motor neuron typically causes weakness, atrophy, and fasciculation. "typical als" or "classical als" involves degeneration to both the upper motor neurons in the brain and the lower motor neurons in the spinal cord. primary lateral sclerosis (pls) involves degeneration of only the upper motor neurons, and progressive muscular atrophy (pma) involves only the lower motor neurons. there is debate over whether pls and pma are separate diseases or simply variants of als. main als subtypes upper motor neuron degeneration lower motor neuron degeneration classical als yes yes primary lateral sclerosis (pls) yes no progressive muscular atrophy (pma) no yes classical als accounts for about 70% of all cases of als and can be subdivided into limb-onset als (also known as spinal-onset) and bulbar-onset als. limb-onset als begins with weakness in the hands, arms, feet, and/or legs and accounts for about two-thirds of all classical als cases. bulbar-onset als begins with weakness in the muscles of speech, chewing, and swallowing and accounts for about one-third of classical als cases. a rarer type of classical als affecting around 3% of patients is respiratory-onset, in which the initial symptoms are difficulty breathing (dyspnea) upon exertion, at rest, or while lying flat (orthopnea). primary lateral sclerosis (pls) is a subtype of the overall als category which accounts for about 5% of all cases and affects only affects the upper motor neurons in the arms, legs, and bulbar region. however, more than 75% of people with apparent pls go on to later develop lower motor neuron signs within four years of symptom onset, meaning that a definitive diagnosis of pls cannot be made until several years have passed. pls has a better prognosis than classical als, as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss than classical als. progressive muscular atrophy (pma) is another subtype that accounts for about 5% of the overall als category and affects lower motor neurons in the arms, legs, and bulbar region. while pma is associated with longer survival on average than classical als, it is still progressive over time, eventually leading to respiratory failure and death. as with pls developing into classical als, pma can also develop into classical als over time if the lower motor neuron involvement progresses to include upper motor neurons, in which case the diagnosis might be changed to classic als. rare isolated variants of als isolated variants of als have symptoms that are limited to a single region for at least a year; they progress more slowly than classical als and are associated with longer survival. these regional variants of als can only be considered as a diagnosis should the initial symptoms fail to spread to other spinal cord regions for an extended period of time (at least 12 months). flail arm syndrome is characterized by lower motor neuron damage affecting the arm muscles, typically starting with the upper arms symmetrically and progressing downwards to the hands. flail leg syndrome is characterized by lower motor neuron damage leading to asymmetrical weakness and wasting in the legs starting around the feet. isolated bulbar als is characterized by upper or lower motor neuron damage in the bulbar region (in the absence of limb symptoms for at least 20 months), leading to gradual onset of difficulty with speech (dysarthria) and swallowing (dysphagia). illustration showing the range of upper and lower motor neuron involvement in the two most common types of als (top row) and three of the most common rare subtypes of als (bottom row) age of onset als can also be classified based on the age of onset. while the peak age of onset is 58 to 63 for sporadic als and 47 to 52 for familial als, about 10% of all cases of als begin before age 45 ("young-onset" als), and about 1% of all cases begin before age 25 (juvenile als). people who develop young-onset als are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of the disease. juvenile als is more likely to be familial than adult-onset als; genes known to be associated with juvenile als include als2, setx, spg11, fus, and sigmar1. although most people with juvenile als live longer than those with adult-onset als, some of them have specific mutations in fus and sod1 that are associated with a poor prognosis. late onset (after age 65) is associated with a more rapid functional decline and shorter survival. signs and symptoms the disorder causes muscle weakness, atrophy, and muscle spasms throughout the body due to the degeneration of the upper motor and lower motor neurons. sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with als maintain hearing, sight, touch, smell, and taste. initial symptoms the start of als may be so subtle that the symptoms are overlooked. the earliest symptoms of als are muscle weakness or muscle atrophy, typically on one side of the body. other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. the parts of the body affected by early symptoms of als depend on which motor neurons in the body are damaged first. in limb-onset als, the first symptoms are in the arms or the legs. if the legs are affected first, people may experience awkwardness, tripping, or stumbling when walking or running; this is often marked by walking with a "dropped foot" that drags gently on the ground. if the arms are affected first, they may experience difficulty with tasks requiring manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock. in bulbar-onset als, the first symptoms are difficulty speaking or swallowing. speech may become slurred, nasal in character, or quieter. there may be difficulty with swallowing and loss of tongue mobility. a smaller proportion of people experience "respiratory-onset" als, where the intercostal muscles that support breathing are affected first. over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia), including an overactive gag reflex. while the disease does not cause pain directly, pain is a symptom experienced by most people with als caused by reduced mobility. symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). progression although the initial symptoms and rate of progression vary from person to person, the disease usually spreads to unaffected regions, and the affected regions become more severely affected. most people eventually are not able to walk or use their hands and arms, lose the ability to speak and swallow food and their own saliva, and begin to lose the ability to cough and to breathe on their own. the rate of progression can be measured using the als functional rating scale - revised (alsfrs-r), a 12-item