<unk>  is a motor neuron disease,<unk> o spelled "motor neurone 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<unk><unk>  (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy, pseudobulbar palsy, and monomelic amyotrophy (MMA).<unk>  itself can be classified in a few different ways: by how fast the disease progresses which is related to the age of onset; by whether it is familial or sporadic, and by the region first affected. In about 25% of cases, muscles in the face, mouth, and throat are affected first because motor neurons in the part of the brainstem called the medulla oblongata (formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar-onset<unk> ". In about 5% of cases, muscles in the trunk of the body are affected first. In most cases the disease spreads and affects other spinal cord regions. A few people with<unk>  have symptoms that are limited to one spinal cord region for at least 12 to 24 months before spreading to a second region; these regional variants of<unk>  are associated with a better prognosis. Classical<unk> , PLS, and PMA Typical or "classical"<unk>  involves neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons).<unk>  can be classified by the types of motor neurons that are affected. Typical or "classical"<unk>  involves upper motor neurons in the brain and lower motor neurons in the spinal cord. Primary<unk><unk>  (PLS) involves only upper motor neurons, and progressive muscular atrophy (PMA) involves only lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of<unk> . Classic<unk>  accounts for about 70% of all cases of<unk>  and can be subdivided into limb-onset<unk>  <unk> o known as spinal-onset) and bulbar-onset<unk> . Limb-onset<unk>  begins with weakness in the arms and legs and accounts for about two-thirds of all classic<unk>  cases. Bulbar-onset<unk>  begins with weakness in the muscles of speech, chewing, and swallowing and accounts for the other one-third of cases. Bulbar onset is associated with a worse prognosis than limb-onset<unk> ; a population-based study found that bulbar-onset<unk>  has a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset<unk>  has a median survival of 2.6 years and a 10-year survival rate of 13%. A rare variant is respiratory-onset<unk>  that accounts for about 3% of all cases of<unk> , in which the initial symptoms are difficulty breathing (dyspnea) with exertion, at rest, or while lying down (orthopnea). Spinal and bulbar symptoms tend to be mild or absent at the beginning. It is more common in males. Respiratory-onset<unk>  has the worst prognosis of any<unk>  variant; in a population-based study, those with respiratory-onset had a median survival of 1.4 years and 0% survival at 10 years. Primary<unk><unk>  (PLS) accounts for about 5% of all cases of<unk>  and affects upper motor neurons in the arms and legs. However, more than 75% of people with apparent PLS develop lower motor neuron signs within four years of symptom onset, meaning that a definite diagnosis of PLS cannot be made until then. PLS has a better prognosis than classic<unk> , as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss. Progressive muscular atrophy (PMA) accounts for about 5% of all cases of<unk>  and affects lower motor neurons in the arms and legs. While PMA is associated with longer survival on average than classic<unk> , it still progresses to other spinal cord regions over time, eventually leading to respiratory failure and death. Upper motor neuron signs can develop late in the course of PMA, in which case the diagnosis might be changed to classic<unk> . Regional variants Regional variants of<unk>  have symptoms that are limited to a single spinal cord region for at least a year; they progress more slowly than classic<unk>  and are associated with longer survival. Examples include flail arm syndrome, flail leg syndrome, and isolated bulbar<unk> . Flail arm syndrome and flail leg syndrome are often considered to be regional variants of PMA because they only involve lower motor neurons. Isolated bulbar<unk>  can involve upper or lower motor neurons. These regional variants of<unk>  cannot be diagnosed at the onset of symptoms; a failure of the disease to spread to other spinal cord regions for an extended period of time (at least 12 months) must be observed. Flail arm syndrome,<unk> o called brachial<unk>  diplegia, is characterized by lower motor neuron damage in the cervical spinal cord only, leading to gradual onset of weakness in the proximal arm muscles and decreased or absent reflexes. Flail leg syndrome,<unk> o called leg<unk>  diplegia, is characterized by lower motor neuron damage in the lumbosacral spinal cord only, leading to gradual onset of weakness in the legs and decreased or absent reflexes. Isolated bulbar<unk>  is characterized by upper or lower motor neuron damage in the bulbar region only, leading to gradual onset of difficulty with speech (dysarthria) and swallowing (dysphagia); breathing (respiration) is generally preserved, at least initially. Two small studies have shown that people with isolated bulbar<unk>  may live longer than people with bulbar-onset<unk> . Age of onset<unk>  can<unk> o be classified based on the age of onset. While the peak age of onset is 58 to 63 for sporadic<unk>  and 47 to 52 for familial<unk> , about 10% of all cases of<unk>  begin before age 45 ("young-onset"<unk> , and about 1% of all cases begin before age 25 (juvenile<unk> . People who develop young-onset<unk>  are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of disease. Juvenile<unk>  is more likely to be familial than adult-onset<unk> ; genes known to be associated with juvenile<unk>  include<unk> 2, SETX, SPG11, FUS, and SIGMAR1. Although most people with juvenile<unk>  live longer than those with adult-onset<unk> , 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.
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