FALS

• 家族性筋萎縮性側索硬化症

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familial amyotrophic lateral sclerosis

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/12/18 01:19:14」(JST)

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"ALS" redirects here. For other uses, see ALS (disambiguation).

"Motor neurone disease" redirects here. For a broader group of diseases that affect motor neurons, see Motor neuron disease.

Amyotrophic lateral sclerosis (ALS)
Classification and external resources
This MRI (parasagittal FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule and can be tracked to the subcortical white matter of the motor cortex, outlining the corticospinal tract, consistent with the clinical diagnosis of ALS. However, typically MRI is unremarkable in a person with ALS.
ICD-10	G12.2
ICD-9	335.20
OMIM	105400
DiseasesDB	29148
MedlinePlus	000688
eMedicine	neuro/14 emerg/24 pmr/10
NCI	Amyotrophic lateral sclerosis
Patient UK	Amyotrophic lateral sclerosis
MeSH	D000690

Amyotrophic lateral sclerosis (ALS)— Lou Gehrig's disease, and rarely Charcot disease—is a neurodegenerative disorder with various causes. The term motor neurone disease (MND) is sometimes used interchangeably with ALS, while others use it to refer to a group of similar conditions that include ALS. ALS is characterised by muscle spasticity and rapidly progressive weakness due to muscle wasting. This results in difficulty speaking, swallowing, and breathing. The disease usually starts around the age of 60, except in cases that are directly inherited when the usual age of onset is around 50.

About 5-10% of cases are directly inherited from a person's parents. ALS is the most common of the five types of motor neuron disease.

The average survival from onset to death is three to four years. Only 4% survive longer than 10 years, although rare cases survive 50 years or more. Most die from respiratory failure. In much of the world, rates of ALS are unknown. In Europe, the disease affects about 2.2 people per 100,000 per year. In the United States, more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.

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 were first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis. It became well known in the United States when it affected famous baseball player Lou Gehrig, and later when the ice bucket challenge became popular in 2014.

Signs and symptoms

The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disorder.

Cognitive function is generally spared for most people, although some (about 5%) also develop frontotemporal dementia. A higher proportion of people (30–50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing. Infrequently, ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy. 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, the symptoms are overlooked. The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include trouble swallowing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/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. About 75% of people contracting the disorder experience "limb-onset" ALS, i.e., first symptoms in the arms or legs. People with the leg-onset form may experience awkwardness when walking or running or notice they are tripping or stumbling, often with a "dropped foot" which drags gently along the ground. Arm-onset people may experience difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock. Occasionally, the symptoms remain confined to one limb for a long period of time or for the whole length of the illness; this is known as monomelic amyotrophy.

About 25% of cases are "bulbar-onset" ALS. These people first notice difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. Other symptoms include difficulty 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. A small proportion of people may also present with what appears to be frontotemporal dementia, but later progresses to include more typical ALS symptoms.

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. An abnormal reflex commonly called Babinski's sign also indicates upper motor neuron damage. 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). Around 15–45% of people experience pseudobulbar affect, a neurological disorder also known as "emotional lability", which consists of uncontrollable laughter, crying, or smiling, attributable to degeneration of bulbar upper motor neurons, resulting in exaggeration of motor expressions of emotion. To be diagnosed with ALS, people must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

Progression

Although the order and rate of symptoms varies from person to person, most people eventually are not able to walk or use their hands and arms. They also lose the ability to speak and swallow food, while most end up on a portable ventilator, called a BiPAP. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale Revised (ALSFRS-R)", a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, patients lose about 0.9 FRS point per month. A survey-based study amongst clinicians showed they rated a 20% change in the slope of the ALSFRS-R would be clinically meaningful. Regardless of the part of the body first affected by the disorder, muscle weakness and atrophy spread to other parts of the body as the disorder progresses. In limb-onset ALS, symptoms usually spread from the affected limb to the opposite limb before affecting a new body region, whereas in bulbar-onset ALS, symptoms typically spread to the arms before the legs.

Disorder progression tends to be slower in patients who are younger than 40 at onset, are mildly obese, have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms. Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.

The CX3CR1 allelic variants have also been shown to have an effect on the disorder's progression and life expectancy.

Late stages

Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die from respiratory failure, usually within three to five years from the onset of symptoms. The median survival time from onset to death is around 39 months, and only 4% survive longer than 10 years. Guitarist Jason Becker has lived since 1989 with the disorder, while physicist Stephen Hawking has survived for more than 50 years, but they are considered unusual cases.

Difficulty in chewing and swallowing makes eating very difficult and increases the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Most people with ALS die of respiratory failure or pneumonia.

In late stages, the oculomotor nerve that controls the movements of the eye can be affected as can the extraocular muscles. The eye movements remain unaffected largely until the later stages due to differences in the extraocular muscles compared to the skeletal muscles that are initially and readily affected. In the disease's final stages, a person's condition may resemble locked-in syndrome.

Eye movement

People with ALS may have difficulty in generating voluntary fast movements of the eye. The speed of eye movement is slower in people with ALS. Problems in generating smooth pursuit and convergence movements have also been noted. Testing the vestibulo-ocular reflex should help in identifying these problems. The electrooculography (EOG) technique measures the resting potential of the retina. EOG findings in people with ALS show progressive changes that correlate with disorder progression, and provide a measurement for clinically evaluating the effects of disorder progression on oculomotor activity. Additionally, EOG may allow earlier detection of problems with the eyes.

The embryonic lineage of EOMs differs from that of somite-derived muscles. EOMs are unique because they continuously remodel through life and maintain a population of active satellite cells during aging. EOMs have significantly more myogenic precursor cells than limb skeletal muscles.

Causes

Genetics

About 5–10% of cases are directly inherited from a person's parents. A defect on chromosome 21, which codes for superoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall. This mutation is believed to be transmitted in an autosomal dominant manner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutant SOD1 gene, seen in North America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.

In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS combined with frontotemporal dementia ALS-FTD, and accounts for some 6% of cases of ALS among white Europeans. The gene is also found in people of Filipino descent.

The UBQLN2 gene encodes production in the cell of ubiquilin 2, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. Mutations in UBQLN2 interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia.

To date, a number of genetic mutations have been associated with various types of ALS. The currently known associations are:

Type	OMIM	Gene	Locus	Remarks
ALS1	105400	SOD1	21q22.1	The most common form of familial ALS
ALS2	205100	ALS2	2q33.1
ALS3	606640	?	18q21
ALS4	602433	SETX	9q34.13
ALS5	602099	?	15q15.1–q21.1	Juvenile onset
ALS6	608030	FUS	16p11.2
ALS7	608031	?	20p13
ALS8	608627	VAPB	20q13.3
ALS9	611895	ANG	14q11.2
ALS10	612069	TARDBP	1p36.2
ALS11	612577	FIG4	6q21
ALS12	613435	OPTN	10p13
ALS13	183090	ATXN2	12q24.12
ALS14	613954	VCP	9p13.3	Recent new study shows strong link in ALS mechanism
ALS15	300857	UBQLN2	Xp11.23–p11.1	Described in one family
ALS16	614373	SIGMAR1	9p13.3	Juvenile onset, very rare, described only in one family
ALS17	614696	CHMP2B	3p11	Very rare, reported only in a handful of people
ALS18	614808	PFN1	17p13.3	Very rare, described only in a handful of Chinese families
ALS19	615515	ERBB4	2q34	Very rare, as of late 2013 described only in four people
ALS20	615426	HNRNPA1	12q13	Very rare, as of late 2013 described only in two people
ALS-FTD	105550	C9orf72	9p21.2	Accounts for around 6% of ALS cases among white Europeans

SOD1

In 1993, scientists discovered that mutations in the gene (SOD1) that produces the Cu/Zn superoxide dismutase (SOD1) enzyme were associated with around 20% of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disorder, some of which (such as H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated.

A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of free radicals. A gain of SOD1 function could be toxic in other ways.

Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan. This indicates the toxic properties of the mutant SOD1 are a result of a gain in function rather than a loss of normal function. In addition, aggregation of proteins has been found to be a common pathological feature of both familial and sporadic ALS (proteopathy). Interestingly, in mutant SOD1 mice (most commonly, the G93A mutant), aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration. Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins. Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations cause only 2% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies, but it is hoped that more useful models will be developed.

An online database is available which was designed to provide both the scientific community and the wider public with up-to-date information on ALS genetics. This is known as ALSOD - website originally designed for the SOD1 gene in 1999, but since upgraded to include over 40 ALS-related genes.

Other factors

Where no family history of the disease is present – i.e., in around 90% of cases – no cause is known for ALS. Potential causes for which evidence is inconclusive include head trauma, military service, frequent drug use, and participation in contact sports. More recently, some research has suggested a link may exist between ALS and food contaminated by blue-green algae.

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the neurotransmitters in the brain. Scientists have found, compared with healthy people, people with ALS have higher levels of glutamate in their serum and spinal fluid. Riluzole is currently the only FDA-approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.

Certain studies suggested a link between sporadic ALS, specifically in athletes, and a diet enriched with branched-chain amino acids, a common dietary supplement among athletes, which cause cell hyperexcitability resembling that usually observed in people with ALS. The proposed underlying mechanism is that cell hyperexcitability results in increased calcium absorption by the cell, and thus brings about cell death of neuronal cells, which have particularly low calcium buffering capabilities.

Some evidence supports superoxide dismutase 1 (SOD1) protein misfolding propagates between molecules in a similar fashion to prions.

Another very common cause of ALS is a lesion to the motor system in areas such as the frontotemporal lobes. Lesions in these areas often show signs of early deficit, which can be used to predict the loss of motor function, and result in the spread of ALS. The mechanisms of ALS are present long before any signs or symptoms become apparent. Before any muscular atrophy becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.

Many other potential causes, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated, but are without consistent findings.

Pathophysiology

The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-rich inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation. These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS.

Extraocular and skeletal motor units

Despite sharing fixed sequences of recruitment, extraocular muscles (EOMs) and skeletal muscles exhibit different characteristics. The following are characteristics of EOMs that differ from skeletal motor units.

• One neural fiber connects with only one or two muscle fibers
• No ocular stretch reflexes, despite being rich in muscle spindles
• No recurrent inhibition
• No special fast-twitch or slow-twitch muscles
• All eye motor neurons participate equally in all types of eye movements—not specialized for saccades or smooth pursuit

Differences are also noted between healthy and affected EOMs. EOMs from postmortem donors preserved their cytoarchitecture, as compared to limb muscles. Healthy EOMs consist of a central global layer (GL) facing the globe and a thin orbital layer (OL) facing the walls of the orbit. EOMs affected by ALS preserve the GL and OL organization. EOMs possess the neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and these neuroprotective factors are also preserved in EOMs affected by ALS. Laminin is a structural protein typically found in the neuromuscular junction (NMJ). Lnα4 is a laminin isoform that is a hallmark of skeletal muscle NMJs. People with ALS showed preserved Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same people. Preservation of laminin expression may play a role in preserving EOM integrity in people with ALS. People with sporadic ALS (sALS) have increased levels of intracelluar calcium, causing increased neurotransmitter release. Passive transfer of sera from people with sALS increases spontaneous transmitter release in spinal, but not EOM terminals; therefore, EOMs are assumed to be resistant to changes in physiologic conditions typically found in ALS.

However, some effects of the disorder were noted. EOMs affected by ALS had a larger variation in fiber size compared to those in age-matched healthy controls. EOMs exhibited both clustered and scattered atrophic and hypertrophic fibers that are characteristic of disorder, but these muscles showed significantly less damage compared to limb muscles from the same donors. These EOMs also showed an increase in connective tissue and areas of fatty replacement in compensation of fiber loss and atrophy. Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients. Additionally, myosin heavy chain content of the EOM fibers was altered, with a loss of normal expression of MyHCslow tonic in the GL and the OL did not contain MyHCemb, which is normally expressed in this layer. This change may represent a change in innervation pattern that may include reinnervation by a different type of motor neuron or loss of multiple innervations. Changes in MyHCslow and MyHCemb are the only fiber changes seen in EOMs, leaving the EOM fiber composition relatively normal. Because EOMs are normally highly innervated, any denervation is compensated for by neighbouring axons which preserve function.

Lactate and cinnamate

Lactic acid is an end product of glycolysis and is known to cause muscle fatigue. Lactate dehydrogenase (LDH) enzyme exerts its effects bidirectionally and is able to oxidize lactate into pyruvate so it can be used in the Krebs cycle. In EOM, lactate sustains muscle contraction during increased activity levels. EOMs that have high LDH activity are thought to be resistant to ALS.

Cinnamate is a blocker of lactate transport and exogenous lactate on fatigue resistance. Cinnamate is able to cause fatigue in EOM, while decreasing EOM endurance and residual force; however, cinnamate has no effect on the extensor digitorum longus muscle in the leg. In contrast, replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOMs. Fatiguability in EOMs was only found when a combination of exogenous lactacte plus cinnamate replaced glucose.

Diagnosis

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.

MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the clinical diagnosis of ALS.

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. The physician may order magnetic resonance imaging (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Based on the patient's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.

Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia virus (HTLV), Lyme disease, syphilis and tick-borne encephalitis viruses can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients should always obtain a specialist neurological opinion, so alternative diagnoses are clinically ruled out.

However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%. In one study, 190 patients who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these patients (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three patients had a false negative diagnosis, myasthenia gravis (MG), an autoimmune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not. Myasthenic syndrome, also known as Lambert-Eaton syndrome, can mimic ALS and its initial presentation can be similar to that of MG.

Current research focuses on abnormalities of neuronal cell metabolism involving glutamate and the role of potential neurotoxins and neurotrophic factors.

Management

Riluzole (Rilutek) is the only treatment found to improve survival, but only to a modest extent. It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. People taking it must be monitored for liver damage (occurring in about 10% of people taking the drug). It is approved by Food and Drug Administration and recommended by the National Institute for Clinical Excellence. Riluzole is an antiglutaminergic, which reduces damage to motor neurons by decreasing the release of glutamate, which reduces glutamate receptor stimulation and helps to regulate intracellular calcium concentrations in the neuron. This prevents the initiation of apoptosis by mitochondria sensitive to high calcium levels. Riluzole does not reverse damage already done to motor neurons. Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals working with patients and caregivers to keep patients as mobile and comfortable as possible.

Medications

Medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, dysphagia, and constipation. Baclofen and diazepam are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl or amitriptyline may be prescribed when ALS patients begin having trouble swallowing their saliva.

Therapy

Physical therapists and occupational therapists play a large role in rehabilitation for individuals with ALS. Specifically, physical and occupational therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, preventing complications, and promoting functional independence.

Occupational therapy and special equipment such as assistive technology can also enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help patients remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable people to retain as much safety and independence in activities of daily living as possible.

ALS patients who have difficulty speaking may benefit from working with a speech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals.

Nutrition

Patients and caregivers can learn from dieticians how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. Occupational therapists can assist with recommendations for adaptive equipment to ease the physical task of self-feeding. Speech-language pathologists make food choice recommendations that are more conducive to their unique deficits and abilities. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.

Researchers have stated, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake" and have a severe loss of appetite. Both animal and human research suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their caloric intake. As of 2012, "a lack of robust evidence for interventions" remained for the management of weight loss.

Breathing support

When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation, bilevel positive airway pressure (BiPAP), or biphasic cuirass ventilation (BCV) may be used to aid breathing. Such devices artificially inflate the person's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths. People may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the person's windpipe through an opening in the neck.

Persons and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the person's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support and have deep discussions on quality of life. Some persons under long-term tracheotomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheotomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough, though in all cases speech will be lost as the disease progresses. This technique preserves speech in some persons with long-term mechanical ventilation. Other persons may be able to use a speaking valve such as a Passey-Muir speaking valve with the assistance and guidance of a speech-language pathologist.

External ventilation machines that use the ventilation mode of BiPAP are frequently used to support breathing, initially at night, and later during the daytime, as well. The use of BPAP (more often referred to as noninvasive ventilation, NIV) is only a temporary remedy, however, and long before BPAP stops being effective, persons should decide whether to have a tracheotomy and long-term mechanical ventilation. At this point, some persons choose palliative hospice care.

Palliative care

Social workers and home care and hospice nurses help people with ALS, their families, and caregivers with the medical, emotional, and financial challenges of coping, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Home nurses are available not only to provide medical care, but also to teach caregivers about tasks such as maintaining respirators, giving feedings, and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.

Epidemiology

ALS is classified as a rare disease, but is the most common motor neuron disease. People of all races and ethnic backgrounds are affected. One or two of 100,000 people develop ALS each year. Amyotrophic lateral sclerosis affects around 30,000 Americans. ALS cases are estimated at 1.2–4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations. Filipinos are second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000 individuals.

Although the incidence of ALS is thought to be regionally uniform, three regions in the West Pacific in the past have had an elevated occurrence of ALS. This seems to be declining in recent decades. The largest is the area of Guam inhabited by the Chamorro people, who have historically had a high incidence (as many as 143 cases per 100,000 people per year) of a condition called Lytico-Bodig disease which is a combination of symptoms similar to ALS, parkinsonism, and dementia. Lytico-Bodig disease has been linked to the consumption and topical use of cycad seeds and in particular, the chemical found in cycad seeds, β-methylamino-L-alanine (BMAA). Two more areas of increased incidence are West Papua and the Kii Peninsula of Japan, both with topical cycad seed use.

Reports have been made of several "clusters" including three American football players from the San Francisco 49ers, more than 50 association football players in Italy, three association football-playing friends in the south of England, and conjugal (husband and wife) cases in the south of France. Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.

History

English scientist Augustus Waller described the appearance of shriveled nerve fibers in 1850, and French doctor Jean-Martin Charcot first described ALS symptoms in autopsy patients in 1869. He published a paper in 1874 describing the disease whose title is the first formal use of the term ALS (De la sclérose latérale amyotrophique - "Amyotrophic Lateral Sclerosis"). In 1881, it is translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System.

ALS became a cause célèbre in the United States in 1939 when baseball legend Lou Gehrig's career, and two years later, his life, was ended by the disease. He gave his farewell speech on July 4, 1939.

In the 1950s, an ALS epidemic occurred among the Chamorro people on Guam.

By 1991, researchers had linked chromosome 21 to familial ALS (FALS). In 1993, the SOD1 gene on chromosome 21 was found to play a role in some cases of FALS. In 1996, riluzole became the first FDA-approved drug for ALS.

In 1998, the El Escorial criteria were developed as the standard for classifying ALS patient in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for rating the declines in ALS patient in clinical research. Noncoding repeat expansions in C9ORF72 were found to be a major cause of ALS and frontotemporal dementia in 2011.

Various videos across the web spread awareness of ALS and raised funds for research with the "ALS Ice Bucket Challenge".

Etymology

Amyotrophic comes from the Greek word amyotrophia: a- means "no", myo refers to "muscle", and trophia means "nourishment"; amyotrophia therefore means "no muscle nourishment," which describes the characteristic atrophy of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where affected portions of the nerve cells are located. Degeneration in this area leads to scarring or hardening ("sclerosis").

Clinical research

A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at ClinicalTrials.gov. The world's largest genetic study, called project MinE, initiated by two people with ALS is going on currently. It is a crowdfunded research project with many countries involved to discover more genes.

A phase-II trial on tirasemtiv has been completed with a follow-on phase-IIb study in progress under the name "BENEFIT-ALS". Results of the first study are available here. The current trial is an international, placebo-controlled, multiple-center study on 680 participants. This makes it one of the largest studies to date. A phase-II trial on ozanezumab is in progress. It is a large multiple-site international research project sponsored by GlaxoSmithKline.

A phase-II clinical trial is being conducted by BrainStorm Cell Therapeutics at the Hadassah Medical Center in Israel and interim results "demonstrated a tendency toward stabilization in some parameters in the ALS Functional Rating Scale." People in the trial have bone marrow stem cells removed and differentiated in a clean room into cells that express neurotropic factors. The cells are injected back into the same person by intrathecal and intramuscular injections. A second phase-II trial is expected to open in the United States at several institutions including the Mayo Clinic.

Charity fundraising

Further information: Ice Bucket Challenge

In August 2014, a challenge went viral online which was commonly known as the "ALS Ice Bucket Challenge". Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US $10 (or a similar amount in their local currency) to ALS research at the ALS Association, or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of August 25, the Ice Bucket Challenge raised $79.7 million for the ALS Association, compared to $2.5 million raised over the same period in 2013. Many celebrities have taken part in the challenge.

See also

• Category:People with motor neurone disease

References

External links

• Amyotrophic lateral sclerosis at DMOZ
• Amyotrophic lateral sclerosis. Lancet. 2011 Mar 12;377(9769):942-55. Comprehensive review article.
• ALS Fact Sheet

UpToDate Contents

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• 1. 家族性筋萎縮性側索硬化症 familial amyotrophic lateral sclerosis
• 2. 筋萎縮性側索硬化症およびその他の運動ニューロン疾患の診断 diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease
• 3. 筋萎縮性側索硬化症の疫学および病因 epidemiology and pathogenesis of amyotrophic lateral sclerosis
• 4. 前頭側頭型認知症：疫学、病理学、および病因 frontotemporal dementia epidemiology pathology and pathogenesis
• 5. 前頭側頭型認知症：臨床的特徴および診断 frontotemporal dementia clinical features and diagnosis

English Journal

• Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral sclerosis disease phenotype.

• Nizzardo M1, Simone C1, Rizzo F1, Ulzi G1, Ramirez A1, Rizzuti M1, Bordoni A1, Bucchia M1, Gatti S2, Bresolin N1, Comi GP1, Corti S1.
• Scientific reports.Sci Rep.2016 Feb 16;6:21301. doi: 10.1038/srep21301.
• Neurotoxicity due to the accumulation of mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS); these mutations result in progressive motor neuron death through one or mor
• PMID 26878886

• Heterogeneity of Matrin 3 in the developing and aging murine central nervous system.

• Rayaprolu S1,2, D'Alton S1,2, Crosby K1,2, Moloney C1,2, Howard J1,2, Duffy C1,2, Cabrera M1,2, Siemienski Z1,2, Hernandez AR1,2, Gallego-Iradi C1,2, Borchelt DR1,2,3, Lewis J1,2,3.
• The Journal of comparative neurology.J Comp Neurol.2016 Feb 15. doi: 10.1002/cne.23986. [Epub ahead of print]
• Mutations in the MATR3 gene encoding the nucleotide binding protein Matrin 3 have recently been identified as causing a subset of familial amyotrophic lateral sclerosis (fALS) and more rarely causing distal myopathy. Translating the identification of MATR3 mutations into an understanding of disease
• PMID 26878116

• Structural basis of Cu, Zn-superoxide dismutase amyloid fibril formation involves interaction of multiple peptide core regions.

• Ida M1, Ando M1, Adachi M1, Tanaka A2, Machida K2, Hongo K3, Mizobata T3, Yamakawa MY4, Watanabe Y4, Nakashima K4, Kawata Y5.
• Journal of biochemistry.J Biochem.2016 Feb;159(2):247-60. doi: 10.1093/jb/mvv091. Epub 2015 Aug 29.
• Cu, Zn-superoxide dismutase (SOD1), an enzyme implicated in the progression of familial amyotrophic lateral sclerosis (fALS), forms amyloid fibrils under certain experimental conditions. As part of our efforts to understand ALS pathogenesis, in this study we found that reduction of the intramolecula
• PMID 26319711

Japanese Journal

• 沖縄型神経原性筋萎縮症（HMSN-P）の疾患概念の確立と歴史

• 髙嶋 博
• 臨床神経学 53(11), 1196-1198, 2013
• 沖縄地方に多発する感覚障害をともなう遺伝性神経原性筋萎縮症は，沖縄型神経原性筋萎縮症（Hereditary motor and sensory neuropathy with proximal dominant involvement; HMSN-P）と命名されている，成人発症，常染色体優性遺伝の筋萎縮症である．本症は，1983年（昭和58年）の厚生省の筋ジストロフィー班で報告された．1989年， …
• NAID 130004505384

• iPS細胞をもちいたALSの病態解析

• 江川 斉宏,井上 治久
• 臨床神経学 53(11), 1020-1022, 2013
• … FALS）患者由来の人工多能性幹細胞（induced pluripotent stem cell; …
• NAID 130004505323

• VD-012-4 食道癌に対する腹腔鏡下腹部操作 : 4cmの小切開(FALS法)(VD-012 ビデオセッション(12)食道 鏡視下-1,第112回日本外科学会定期学術集会)

• 市原 隆夫,相馬 逸郎,林 伸泰,中野 克俊,桧垣 直純,村上 雅一,林田 博人,岡 義雄,左近 賢人
• 日本外科学会雑誌 113(臨時増刊号_2), 466, 2012-03-05
• NAID 110009548605

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★リンクテーブル★

リンク元	「家族性筋萎縮性側索硬化症」「familial amyotrophic lateral sclerosis」
関連記事	「FA」

「家族性筋萎縮性側索硬化症」

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英

familial amyotrophic lateral sclerosis、FALS

「familial amyotrophic lateral sclerosis」

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家族性筋萎縮性側索硬化症

関

FALS

「FA」

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• ファンコーニ貧血 Fanconi anemia
• フシジン フシジン酸 fusidic acid
• 線維腺腫 fibroadenoma