Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a
neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
that results in the progressive loss of
motor neuron
A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...
s that control
voluntary muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
.
ALS is the most common type of
motor neuron diseases.
Early symptoms of ALS include
stiff muscles,
muscle twitches, and gradual increasing weakness and
muscle wasting
Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness ...
.
''Limb-onset ALS'' begins with weakness in the arms or legs, while ''bulbar-onset ALS'' begins with difficulty
speaking
Speech is a human vocal communication using language. Each language uses phonetic combinations of vowel and consonant sounds that form the sound of its words (that is, all English words sound different from all French words, even if they are th ...
or
swallowing
Swallowing, sometimes called deglutition in scientific contexts, is the process in the human or animal body that allows for a substance to pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. Swallowing i ...
.
Half of the people with ALS develop at least mild difficulties with
thinking
In their most common sense, the terms thought and thinking refer to conscious cognitive processes that can happen independently of sensory stimulation. Their most paradigmatic forms are judging, reasoning, concept formation, problem solving, an ...
and behavior, and about 15% develop
frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
.
Most people experience pain.
The affected muscles are responsible for chewing food, speaking, and walking.
Motor neuron loss continues until the ability to eat, speak, move, and finally the ability to breathe is lost.
ALS eventually causes
paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
and early death, usually from
respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
.
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 linked to a
history of the disease in the family, and these are known as ''familial ALS''.
About half of these genetic cases are due to one of two specific
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s.
ALS and frontotemporal dementia (FTD) are considered to be part of a common disease continuum (ALS-FTD) because of genetic, clinical, and pathological similarities.
The underlying mechanism involves damage to both
upper and
lower motor neuron
Lower motor neurons (LMNs) are motor neurons located in either the anterior grey column, anterior nerve roots (spinal lower motor neurons) or the cranial nerve nuclei of the brainstem and cranial nerves with motor function (cranial nerve lower mo ...
s;
in ALS-FTD, neurons in the frontal and temporal lobes of the brain die as well.
The
diagnosis
Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". In systems engin ...
is based on a person's
signs and symptoms
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
, with testing done to rule out other potential causes.
There is no known cure for ALS.
The goal of treatment is to improve symptoms.
[ A medication called riluzole may extend life by about two to three months.] Non-invasive ventilation
Non-invasive ventilation (NIV) is the use of breathing support administered through a face mask, nasal mask, or a helmet. Air, usually with added oxygen, is given through the mask under positive pressure; generally the amount of pressure is alter ...
may result in both improved quality and length of life. Mechanical ventilation
Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move air ...
can prolong survival but does not stop disease progression. A feeding tube
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, her ...
may help. The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50.[ The average survival from onset to death is two to four years, though this can vary, and about 10% survive longer than 10 years,] and death is usually due to respiratory failure.[ In Europe, the disease affects about two to three people per 100,000 per year.] Rates in much of the world are unclear.[ In the United States, it most commonly occurs in whites.]
Descriptions of the disease date back to at least 1824 by Charles Bell
Sir Charles Bell (12 November 177428 April 1842) was a Scotland, Scottish surgeon, anatomist, physiologist, neurologist, artist, and philosophical theologian. He is noted for discovering the difference between sensory nerves and motor nerves in ...
.[ In 1869, the connection between the symptoms and the underlying neurological problems was first described by French neurologist ]Jean-Martin Charcot
Jean-Martin Charcot (; 29 November 1825 – 16 August 1893) was a French neurology, neurologist and professor of anatomical pathology. He worked on hypnosis and hysteria, in particular with his hysteria patient Louise Augustine Gleizes. Charcot ...
, who in 1874 began using the term ''amyotrophic lateral sclerosis''. It became well known in the United States in the 20th century when in 1939 it affected baseball player Lou Gehrig
Henry Louis Gehrig (born Heinrich Ludwig Gehrig ; June 19, 1903June 2, 1941) was an American professional baseball first baseman who played 17 seasons in Major League Baseball (MLB) for the New York Yankees (1923–1939). Gehrig was renowned f ...
(leading to his death two years later), and later worldwide, following the 1963 diagnosis of then 21-year-old cosmologist
Cosmology () is a branch of physics and metaphysics dealing with the nature of the universe. The term ''cosmology'' was first used in English in 1656 in Thomas Blount's ''Glossographia'', and in 1731 taken up in Latin by German philosopher ...
Stephen Hawking. However, unlike most individuals with ALS, Hawking managed to survive his illness for another 55 years. The first ALS gene was discovered in 1993 while the first animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
was developed in 1994. In 2014, videos of the Ice Bucket Challenge
The Ice Bucket Challenge, sometimes called the ALS Ice Bucket Challenge, is an activity involving the pouring of a bucket of ice water over a person's head, either by another person or self-administered, to promote awareness of the disease amyo ...
went viral on the Internet and increased public awareness of the condition.
Classification
ALS is a motor neuron disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron 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 comm ...
, also spelled "motor neurone disease", which is a group of neurological disorder
A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakn ...
s that selectively affect motor neuron
A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...
s, the cells that control voluntary muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
of the body. Other motor neuron diseases include primary lateral sclerosis
Primary lateral sclerosis (PLS) is a very rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases. Motor neuron diseases develop when the n ...
(PLS), progressive muscular atrophy
Progressive muscular atrophy (PMA), also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a disorder characterised by the degeneration of lower motor neurons, resulting in generalised, progressive loss of muscle function.
P ...
(PMA), progressive bulbar palsy
Progressive bulbar palsy (PBP) is a medical condition. It belongs to a group of disorders known as motor neuron diseases. Lapiedra 2002 PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the ...
, pseudobulbar palsy
Pseudobulbar palsy is a medical condition characterized by the inability to control facial movements (such as chewing and speaking) and caused by a variety of neurological disorders. Patients experience difficulty chewing and swallowing, have in ...
, and monomelic amyotrophy
Monomelic amyotrophy (MMA) is a rare motor neuron disease first described in 1959 in Japan. Its symptoms usually appear about two years after adolescent growth spurt and is significantly more common in males, with an average age of onset between 1 ...
(MMA).
ALS 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
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
called the medulla oblongata
The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...
(formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar
The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (invol ...
-onset ALS". 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 ALS 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 ALS are associated with a better prognosis.]
Classical ALS, PLS, and PMA
ALS can be classified by the types of motor neurons that are affected. Typical or "classical" ALS involves upper motor neuron
Upper motor neurons (UMNs) is a term introduced by William Gowers in 1886. They are found in the cerebral cortex and brainstem and carry information down to activate interneurons and lower motor neurons, which in turn directly signal muscles t ...
s in the brain and lower motor neuron
Lower motor neurons (LMNs) are motor neurons located in either the anterior grey column, anterior nerve roots (spinal lower motor neurons) or the cranial nerve nuclei of the brainstem and cranial nerves with motor function (cranial nerve lower mo ...
s in the spinal cord. Primary lateral sclerosis
Primary lateral sclerosis (PLS) is a very rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases. Motor neuron diseases develop when the n ...
(PLS) involves only upper motor neurons, and progressive muscular atrophy
Progressive muscular atrophy (PMA), also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a disorder characterised by the degeneration of lower motor neurons, resulting in generalised, progressive loss of muscle function.
P ...
(PMA) involves only lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of ALS.[
Classic 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 arms and legs][ and accounts for about two-thirds of all classic ALS cases.][ Bulbar-onset ALS 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 ALS; a population-based study found that bulbar-onset ALS has a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS has a median survival of 2.6 years and a 10-year survival rate of 13%.] A rare variant is respiratory-onset ALS that accounts for about 3% of all cases of ALS,[ in which the initial symptoms are difficulty breathing (]dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...
) with exertion, at rest, or while lying down (orthopnea
Orthopnea or orthopnoea is shortness of breath (dyspnea) that occurs when lying flat, causing the person to have to sleep propped up in bed or sitting in a chair. It is commonly seen as a late manifestation of heart failure, resulting from fluid ...
). Spinal and bulbar symptoms tend to be mild or absent at the beginning. It is more common in males.[ Respiratory-onset ALS has the worst prognosis of any ALS 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 lateral sclerosis (PLS) accounts for about 5% of all cases of ALS 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 ALS, 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 ALS and affects lower motor neurons in the arms and legs.][ While PMA is associated with longer survival on average than classic ALS, 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 ALS.][
]
Regional variants
Regional variants of ALS have symptoms that are limited to a single spinal cord region for at least a year; they progress more slowly than classic ALS and are associated with longer survival. Examples include flail arm syndrome, flail leg syndrome, and isolated bulbar ALS. 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 ALS can involve upper or lower motor neurons. These regional variants of ALS 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, also called brachial amyotrophic 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, also called leg amyotrophic 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 ALS is characterized by upper or lower motor neuron damage in the bulbar region only, leading to gradual onset of difficulty with speech (dysarthria
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...
) and swallowing (dysphagia
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
); breathing
Breathing (or ventilation) is the process of moving air into and from the lungs to facilitate gas exchange with the internal environment, mostly to flush out carbon dioxide and bring in oxygen.
All aerobic creatures need oxygen for cellular ...
(respiration) is generally preserved, at least initially. Two small studies have shown that people with isolated bulbar ALS may live longer than people with bulbar-onset ALS.
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 disease.[ Juvenile ALS is more likely to be familial than adult-onset ALS; genes known to be associated with juvenile ALS include '']ALS2
Alsin is a protein that in humans is encoded by the ''ALS2'' gene. ''ALS2'' orthologs have been identified in all mammals for which complete genome data are available.
See also
* Juvenile primary lateral sclerosis
* Amyotrophic lateral sclerosi ...
'', ''SETX
Probable helicase senataxin is an enzyme that in humans is encoded by the ''SETX'' gene.
This gene encodes a protein named senataxin, a 302kDa protein
Sequence and structure
There is high homology between human SETX and yeast Sen1. Sen1 in ye ...
'', ''SPG11
Spatacsin is a protein that in humans is encoded by the ''SPG11'' gene.
Function
Spatacsin, in combination with the SPG15 protein, attaches the AP5 adaptor complex to the outside of late Endosomes or Lysosomes when the protein via which it bind ...
'', '' 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
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
, and muscle spasms
A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder.
A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle c ...
throughout the body due to the degeneration of the upper motor 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 ]extraocular muscles
The extraocular muscles (extrinsic ocular muscles), are the seven extrinsic muscles of the human eye. Six of the extraocular muscles, the four recti muscles, and the superior and inferior oblique muscles, control movement of the eye and the ot ...
(the muscles responsible for eye movement) are usually spared until the final stages of the disease.
Cognitive
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
or behavioral dysfunction is present in 30–50% of individuals with ALS.[ Around half of people with ALS will experience mild changes in cognition and behavior, and 10–15% will show signs of ]frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
(FTD).[ Most people with ALS who have normal cognition at the time of diagnosis have preserved cognition throughout the course of their disease; the development of cognitive impairment in those with normal cognition at baseline is associated with a worse prognosis. Repeating phrases or gestures, apathy, and loss of inhibition are frequently reported behavioral features of ALS. Language dysfunction, ]executive dysfunction
In psychology and neuroscience, executive dysfunction, or executive function deficit, is a disruption to the efficacy of the executive functions, which is a group of cognitive processes that regulate, control, and manage other cognitive processes ...
, and troubles with social cognition
Social cognition is a sub-topic of various branches of psychology that focuses on how people process, store, and apply information about other people and social situations. It focuses on the role that cognitive processes play in social interactio ...
and verbal memory
Verbal memory is a term used in cognitive psychology which refers to memory of words and other abstractions involving language.
Verbal encoding
Verbal encoding refers to the interpretation of verbal stimuli. Verbal encoding appears to be strongly ...
are the most commonly reported cognitive symptoms in ALS; a meta-analysis found no relationship between dysfunction and disease severity. However, cognitive and behavioral dysfunctions have been found to correlate with reduced survival in people with ALS and increased caregiver burden; this may be due in part to deficits in social cognition.[ About half the people who have ALS experience ]emotional lability
In medicine and psychology, emotional lability is a sign or symptom typified by exaggerated changes in mood or affect in quick succession. Sometimes the emotions expressed outwardly are very different from how the person feels on the inside. Thes ...
, in which they cry or laugh for no reason; it is more common in those with bulbar-onset ALS.[
Pain is a symptom experienced by most people with ALS and can take the form of ]neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...
(pain caused by nerve damage), spasticity, muscle cramps, and nociceptive pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
caused by reduced mobility and muscle weakness; examples of nociceptive pain in ALS include contracture
In pathology, a contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...
s (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, and pressure ulcers.[
Sensory nerves and the ]autonomic nervous system
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
are generally unaffected, meaning the majority of people with ALS maintain hearing
Hearing, or auditory perception, is the ability to perceive sounds
In physics, sound is a vibration that propagates as an acoustic wave, through a transmission medium such as a gas, liquid or solid.
In human physiology and psycholog ...
, sight
Visual perception is the ability to interpret the surrounding Biophysical environment, environment through photopic vision (daytime vision), color vision, scotopic vision (night vision), and mesopic vision (twilight vision), using light in the ...
, touch
In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...
, smell, and taste
The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...
.
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. 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 muscle
Intercostal muscles are many different groups of muscles that run between the ribs, and help form and move the chest wall. The intercostal muscles are mainly involved in the mechanical aspect of breathing by helping expand and shrink the size of ...
s that support breathing are affected first.[
Over time, people experience increasing difficulty moving, swallowing (]dysphagia
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
), and speaking or forming words (dysarthria
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...
). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.
...
) and exaggerated reflexes (hyperreflexia
Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate upper disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by highe ...
), including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign
The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In healthy adults, the plantar reflex causes a downward response of the hallux (flexion). An upward r ...
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 (fasciculation
A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serio ...
s). However, twitching is more of a side effect than a diagnostic symptom; it either occurs after or accompanies weakness and atrophy.
Progression
Although the initial symptoms and rate of progression vary from person to person, the disease eventually spreads to unaffected regions and the affected regions become more 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 Amyotrophic Lateral Sclerosis (ALS), is a neurodegenerative disease that typically affects adults around 54-67 years of age, although anyone can be diagnosed with the disease. People diagnosed with ALS live on average 2–4 years after diagnosis d ...
(ALSFRS-R), a 12-item instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability); it is the most commonly used outcome measure in clinical trials and is used by doctors to track disease progression. Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with ALS lose about 0.9 FRS points per month. A survey-based study among clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.
Disease progression tends to be slower in people who are younger than 40 at onset, are mildly obese, have symptoms 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 ALS, respiratory-onset ALS and frontotemporal dementia.
Late stages
Difficulties with chewing and swallowing make eating very difficult and increase the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia
Aspiration pneumonia is a type of lung infection that is due to a relatively large amount of material from the stomach or mouth entering the lungs. Signs and symptoms often include fever and cough of relatively rapid onset. Complications may inclu ...
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 muscle
Intercostal muscles are many different groups of muscles that run between the ribs, and help form and move the chest wall. The intercostal muscles are mainly involved in the mechanical aspect of breathing by helping expand and shrink the size of ...
s of the rib cage
The rib cage, as an enclosure that comprises the ribs, vertebral column and sternum in the thorax of most vertebrates, protects vital organs such as the heart, lungs and great vessels.
The sternum, together known as the thoracic cage, is a semi- ...
that support breathing weaken, measures of lung function
The lungs are the primary Organ (anatomy), organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the vertebral co ...
such as vital capacity
Vital capacity (VC) is the maximum amount of air a person can inhale after a maximum exhalation. It is equal to the sum of inspiratory reserve volume, tidal volume, and expiratory reserve volume. It is approximately equal to Forced Vital Capacity ( ...
and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. The most common cause of death among people with ALS are respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
or pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...
and most people with ALS die in their own home from the former cause, with their breath stopping while they sleep.
Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die between two and four years after the diagnosis.[ Around half of people with ALS die within 30 months of their symptoms beginning, and about 20% of people with ALS live between five and ten years after symptoms begin.][ Guitarist ]Jason Becker
Jason ( ; ) was an ancient Greek mythological hero and leader of the Argonauts, whose quest for the Golden Fleece featured in Greek literature. He was the son of Aeson, the rightful king of Iolcos. He was married to the sorceress Medea. He was ...
has lived since 1989 with the disorder, while cosmologist
Cosmology () is a branch of physics and metaphysics dealing with the nature of the universe. The term ''cosmology'' was first used in English in 1656 in Thomas Blount's ''Glossographia'', and in 1731 taken up in Latin by German philosopher ...
Stephen Hawking lived for 55 more years following his diagnosis, but they are considered unusual cases.
Cause
Though the exact cause of ALS 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 liability threshold model In mathematical or statistical modeling a threshold model is any model where a threshold value, or set of threshold values, is used to distinguish ranges of values where the behaviour predicted by the model varies in some important way. A particula ...
for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life.
Genetics
ALS can be classified as familial or sporadic, depending on whether or not there is a family history of the disease. There is no consensus among neurologists on the exact definition of familial ALS. The strictest definition is that a person with ALS must have two or more first-degree relatives (children, siblings, or parents) who also have ALS. A less strict definition is that a person with ALS must have at least one first-degree or second-degree relative
A second-degree relative (SDR) is someone who shares 25% of a person's genes. It includes uncles, aunts, nephews, nieces, grandparents, grandchildren, half-siblings, and double cousins.
See also
*Family
*First-degree relative
*Third-degree rela ...
(grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who also has ALS. Familial ALS is usually said to account for 10% of all cases of ALS, though estimates range from 5% to 20%. Higher estimates use a broader definition of familial ALS and examine the family history of people with ALS more thoroughly.
In sporadic ALS, there is no family history of the disease. Sporadic ALS and familial ALS appear identical clinically and pathologically and are similar genetically; about 10% of people with sporadic ALS have mutations in genes that are known to cause familial ALS.[ In light of these parallels, the term "sporadic ALS" has been criticized as misleading because it implies that cases of sporadic ALS are only caused by environmental factors; the term "isolated ALS" has been suggested as a more accurate alternative.]
More than 20 genes have been associated with familial ALS, of which four account for the majority of familial cases: ''C9orf72
C9orf72 (chromosome 9 open reading frame 72) is a protein which in humans is encoded by the gene ''C9orf72''.
The human ''C9orf72'' gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,546 to base pai ...
'' (40%), ''SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
'' (20%), '' FUS'' (1–5%), and ''TARDBP
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
'' (1–5%).[ The genetics of familial ALS are better understood than the genetics of sporadic ALS;][ , the known ALS genes explained 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.] ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.[
ALS and ]frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
(FTD) are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities. Genetically, ''C9orf72'' repeat expansions account for about 40% of familial ALS and 25% of familial FTD.[ Clinically, 50% of people with ALS have some cognitive or behavioral impairments and 5–15% have FTD, while 40% of people with FTD have some motor neuron symptoms and 12.5% have ALS.][ Pathologically, abnormal aggregations of ''TDP-43'' protein are seen in up to 97% of ALS patients and up to 50% of FTD patients.] In December 2021 a paper found the ''TDP-43'' proteinopathy is in turn caused by defective cyclophilin A
Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the ''PPIA'' gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein ca ...
which regulates ''TARDBP'' gene expression. Other genes known to cause FTD-ALS include ''CHCHD10
Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial, also known as Protein N27C7-4 is a protein that in humans is encoded by the ''CHCHD10'' gene.
Structure
The ''CHCHD10'' gene is located on the q arm of chro ...
'', ''SQSTM1
Sequestosome-1 is a protein that in humans is encoded by the ''SQSTM1'' gene. Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacti ...
'', and '' TBK1''.
Environmental factors
Where no family history of the disease is present – around 90% of cases – no cause is known. Possible associations for which evidence is inconclusive include military service and smoking. Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation
In statistics, correlation or dependence is any statistical relationship, whether causal or not, between two random variables or bivariate data. Although in the broadest sense, "correlation" may indicate any type of association, in statistics ...
. Various proposed factors include exposure to environmental toxins
A toxin is a naturally occurring organic matter, organic poison produced by metabolic activities of Life, living Cell (biology), cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by orga ...
(inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.[
A 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to ]lead
Lead is a chemical element with the symbol Pb (from the Latin ) and atomic number 82. It is a heavy metal that is denser than most common materials. Lead is soft and malleable, and also has a relatively low melting point. When freshly cu ...
; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-3 fatty acid
Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
intake, exposure to extremely low frequency
Extremely low frequency (ELF) is the ITU designation for electromagnetic radiation ( radio waves) with frequencies from 3 to 30 Hz, and corresponding wavelengths of 100,000 to 10,000 kilometers, respectively. In atmospheric sc ...
electromagnetic fields, pesticides, and serum uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
.
In a 2017 study by the United States Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
analyzing U.S. deaths from 1985 to 2011, occupations correlated with ALS deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs. Other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock. There is a tentative association with exposure to various pesticide
Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lampri ...
s, including the organochlorine insecticides aldrin
Aldrin is an organochlorine insecticide that was widely used until the 1990s, when it was banned in most countries. Aldrin is a member of the so-called "classic organochlorines" (COC) group of pesticides. COCs enjoyed a very sharp rise in popular ...
, dieldrin
Dieldrin is an organochloride originally produced in 1948 by J. Hyman & Co, Denver, as an insecticide. Dieldrin is closely related to aldrin, which reacts further to form dieldrin. Aldrin is not toxic to insects; it is oxidized in the insect to fo ...
, DDT
Dichlorodiphenyltrichloroethane, commonly known as DDT, is a colorless, tasteless, and almost odorless crystalline chemical compound, an organochloride. Originally developed as an insecticide, it became infamous for its environmental impacts. ...
, and toxaphene
Toxaphene was an insecticide used primarily for cotton in the southern United States during the late 1960s and the 1970s. Toxaphene is a mixture of over 670 different chemicals and is produced by reacting chlorine gas with camphene. It can be mo ...
.
Head injury
A 2015 review found that moderate to severe traumatic brain injury
A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...
is a risk factor for ALS, but whether mild traumatic brain injury increases rates was unclear. A 2017 meta-analysis found an association between head injuries and ALS; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed ALS, rather than the cause of ALS.
Physical activity
A number of reviews prior to 2021 found no relationship between the amount of physical activity and the risk of developing ALS. A 2009 review found that the evidence for physical activity as a risk factor for ALS was limited, conflicting, and of insufficient quality to come to a firm conclusion. A 2014 review concluded that physical activity in general is not a risk factor for ALS, that soccer and American football are possibly associated with ALS, and that there was not enough evidence to say whether or not physically demanding occupations are associated with ALS. A 2016 review found the evidence inconclusive and noted that differences in study design make it difficult to compare studies, as they do not use the same measures of physical activity or the same diagnostic criteria for ALS.
However, research published in 2021 suggested that there was a positive causal relationship between ALS and intense physical exercise in those with a risk genotype.
Sports
Both football and American football have been identified as risk factors for ALS in several studies, although this association is based on small numbers of ALS cases. A 2012 retrospective cohort study of 3,439 former NFL players found that their risk of dying from neurodegenerative causes was three times higher than the general US population, and their risk of dying from ALS or Alzheimer's disease was four times higher. However, this increased risk was calculated on the basis of two deaths from Alzheimer's disease and six deaths from ALS out of 334 deaths total in this cohort, meaning that this study does not definitively prove that playing American football is a risk factor for ALS. Some NFL players thought to have died from ALS may have actually had chronic traumatic encephalopathy
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets worse o ...
(CTE), a neurodegenerative disorder associated with multiple head injuries that can present with symptoms that are very similar to ALS.[
Football was identified as a possible risk factor for ALS in a retrospective cohort study of 24,000 Italian footballers who played between 1960 and 1996. There were 375 deaths in this group, including eight from ALS. Based on this information and the incidence of ALS, it was calculated that the soccer players were 11 times more likely to die from ALS than the general Italian population.][ However, this calculation has been criticized for relying on an inappropriately low number of expected cases of ALS in the cohort.] When the lifetime risk of developing ALS was used to predict the number of expected cases, soccer players were no more likely to die of ALS than the general population.[
]
Smoking
Smoking is possibly associated with ALS. A 2009 review concluded that smoking was an established risk factor for ALS. A 2010 systematic review and meta-analysis concluded that there was not a strong association between smoking and ALS, but that smoking might be associated with a higher risk of ALS in women. A 2011 meta-analysis concluded that smoking increases the risk of ALS versus never smoking. Among smokers, the younger they started smoking, the more likely they were to get ALS; however, neither the number of years smoked nor the number of cigarettes smoked per day affected their risk of developing ALS.
Risk factor
ALS can strike at any age, but it 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 the difference will disappear after age 70. It has also been suggested that military veterans are about 1.5 to 2 times more likely to develop ALS, though the reason is unclear.
Pathophysiology
Neuropathology
The defining feature of ALS is the death of both upper motor neurons (located in the motor cortex
The motor cortex is the region of the cerebral cortex believed to be involved in the planning, control, and execution of voluntary movements.
The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately a ...
of the brain) and lower motor neurons (located in the brainstem and spinal cord). In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of ALS is the presence of inclusion bodies
Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells ...
(abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is TDP-43
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
protein;[ however, in those with ''SOD1'' or ''FUS'' mutations, the main component of the inclusion bodies] is SOD1 protein or FUS protein, respectively. The gross pathology
Gross pathology refers to macroscopic manifestations of disease in organs, tissues, and body cavities. The term is commonly used by anatomical pathologists to refer to diagnostically useful findings made during the gross examination portion of ...
of ALS, which are features of the disease that can be seen with the naked eye, include skeletal muscle atrophy, motor cortex atrophy, sclerosis of the corticospinal
The pyramidal tracts include both the corticobulbar tract and the corticospinal tract. These are aggregations of efferent nerve fibers from the upper motor neurons that travel from the cerebral cortex and terminate either in the brainstem (''co ...
and corticobulbar tract
In neuroanatomy, the corticobulbar (or corticonuclear) tract is a two-neuron white matter motor pathway connecting the motor cortex in the cerebral cortex to the medullary pyramids, which are part of the brainstem's medulla oblongata (also called ...
s, thinning of the hypoglossal nerve
The hypoglossal nerve, also known as the twelfth cranial nerve, cranial nerve XII, or simply CN XII, is a cranial nerve that innervates all the extrinsic and intrinsic muscles of the tongue except for the palatoglossus, which is innervated by ...
s (which control the tongue), and thinning of the anterior roots
In anatomy and neurology, the ventral root of spinal nerve, anterior root, or motor root is the efferent motor root of a spinal nerve.
At its distal end, the ventral root joins with the dorsal root
The dorsal root of spinal nerve (or posterior ...
of the spinal cord.[ Aside from the death of motor neurons, two other characteristics common to most ALS variants are focal initial pathology, meaning that symptoms start in a single spinal cord region, and progressive continuous spread, meaning that symptoms spread to additional regions over time. ]Prion
Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...
-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others. The glymphatic system
The glymphatic system (or glymphatic clearance pathway, or paravascular system) was described and named in 2013 as a system for waste clearance in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF) ...
may also be involved in the pathogenesis
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
of ALS.
Biochemistry
It is still not fully understood why neurons die in ALS, but this neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
is thought to involve many different cellular and molecular processes.[ The genes known to be involved in ALS can be grouped into three general categories based on their normal function: protein degradation, the ]cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
, and RNA processing. Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of wild-type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
(normal) SOD1 protein are common in sporadic ALS. It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner.[ Other protein degradation genes that can cause ALS when mutated include '' VCP'', '' OPTN'', ''TBK1'', and ''SQSTM1''. Three genes implicated in ALS that are important for maintaining the cytoskeleton] and for axonal transport[ include '']DCTN1
Dynactin subunit 1 is a protein that in humans is encoded by the ''DCTN1'' gene.
Function
This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 23 subunits (11 individual proteins ranging in size from 22 to ...
'', ''PFN1
Profilin-1 is a protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactio ...
'', and ''TUBA4A
Tubulin alpha-4A chain is a protein that in humans is encoded by the ''TUBA4A'' gene.
Function
Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The ...
''.
There are a number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in ''TARDBP'', the gene that codes for TDP-43, are a rare cause of ALS.[ ''FUS'' codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated.][ It is thought that mutations in ''TARDBP'' and ''FUS'' increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm. Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal protein both within and between cells in a prion-like manner.] This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with ALS include '' ANG'', ''SETX
Probable helicase senataxin is an enzyme that in humans is encoded by the ''SETX'' gene.
This gene encodes a protein named senataxin, a 302kDa protein
Sequence and structure
There is high homology between human SETX and yeast Sen1. Sen1 in ye ...
'', and ''MATR3
Matrin-3 is a protein that in humans is encoded by the ''MATR3'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or '' ...
''.[
''C9orf72'' is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms.] The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these ''C9orf72'' repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in ''C9orf72''-ALS using human induced pluripotent stem cell
Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in ...
(iPSC) technologies coupled with CRISPR/Cas9
Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic e ...
gene-editing, and human post-mortem spinal cord tissue examination.
Excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 (EAAT2
Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the ''SLC1A2'' gene. Alternatively spliced transcript variants of thi ...
), which is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. Riluzole, a drug that modestly prolongs survival in ALS, inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect.[
]
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
A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...
observes in the person and a series of tests to rule out other diseases. Physicians obtain the person's full medical history
The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is information gained by a physician by asking specific questions, either to the patient or to other peo ...
and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia
Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate upper disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by highe ...
, and spasticity are worsening. A number of biomarkers are being studied for the condition, but so far are not in general medical use.
Diagnostic criteria
The diagnosis of ALS is based on the El Escorial Revised criteria and the Awaji criteria.[ The original El Escorial criteria had four levels of diagnostic certainty, based on how many of the four spinal cord regions were involved: bulbar, cervical, thoracic, and lumbar. Definite ALS was defined as upper motor neuron (UMN) and lower motor neuron (LMN) signs in three spinal cord regions, probable ALS as UMN and LMN signs in two regions, possible ALS as UMN and LMN signs in only one region, and suspected ALS as LMN signs only. The El Escorial Revised criteria, also known as the Airlie House criteria, dropped the "suspected ALS" category and added a "laboratory-supported probable ALS" category. The Awaji criteria give abnormal EMG tests the same weight as clinical signs of LMN dysfunction in making the diagnosis of ALS,][ thus making the "laboratory-supported probable ALS" category unnecessary. The only three categories in the Awaji criteria are definite ALS, probable ALS, and possible ALS.]
The El Escorial Revised criteria are specific for ALS, which means that someone who meets the criteria is very likely to have ALS; however, they are not especially sensitive for ALS, which means that someone who does not meet the criteria can still have ALS. Their sensitivity is particularly poor in the early stages of ALS. The Awaji criteria have better sensitivity than the El Escorial Revised criteria, especially for bulbar-onset ALS.[ A 2012 meta-analysis found that the El Escorial Revised criteria had a sensitivity of 62.2%, while the Awaji criteria had a sensitivity of 81.1%; both sets of criteria had a specificity of about 98%. The El Escorial criteria were designed to standardize patient groups for clinical trials but are not as useful in clinical practice; possible ALS as described by the El Escorial criteria is almost always clinically ALS.][
]
Differential diagnosis
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
Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyog ...
(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
In neuroscience, nerve conduction velocity (CV) is an important aspect of nerve conduction studies. It is the speed at which an electrochemical impulse propagates down a neural pathway. Conduction velocities are affected by a wide array of factors ...
(NCV). Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
(damage to peripheral nerves) or myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...
(muscle disease) rather than ALS. While a magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
(MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, a herniated disc
Spinal disc herniation is an injury to the cushioning and connective tissue between vertebrae, usually caused by excessive strain or trauma to the spine. It may result in back pain, pain or sensation in different parts of the body, and physical ...
in the neck, syringomyelia
Syringomyelia is a generic term referring to a disorder in which a cyst or cavity forms within the spinal cord. Often, syringomyelia is used as a generic term before an etiology is determined. This cyst, called a syrinx, can expand and elongate ...
, or cervical spondylosis
Spondylosis is the degeneration of the vertebral column from any cause. In the more narrow sense it refers to spinal osteoarthritis, the age-related wear and tear of the spinal column, which is the most common cause of spondylosis. The degenera ...
.
Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.
A number of infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus (HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
), human T-lymphotropic virus
The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and ...
(HTLV), Lyme disease
Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia'' bacterium, which is spread by ticks in the genus ''Ixodes''. The most common sign of infection is an expanding red rash, known as erythema migran ...
, and syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, an ...
.[ Neurological disorders such as multiple sclerosis, ]post-polio syndrome
Post-polio syndrome (PPS, poliomyelitis sequelae) is a group of latent symptoms of poliomyelitis (polio), occurring at about a 25–40% rate (latest data greater than 80%). These symptoms are caused by the damaging effects of the viral infection ...
, multifocal motor neuropathy
Multifocal motor neuropathy (MMN) is a progressively worsening condition where muscles in the extremities gradually weaken. The disorder, a pure motor neuropathy syndrome, is sometimes mistaken for amyotrophic lateral sclerosis (ALS) because of t ...
, CIDP
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called c ...
, spinal muscular atrophy
Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...
, and spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cor ...
can also mimic certain aspects of the disease and should be considered.
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 the prognosis of ALS and closely related subtypes of motor neurone disease are generally poor, neurologists may carry out investigations to evaluate and exclude other diagnostic possibilities. Disorders of the neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
, such as myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...
(MG) and Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.
Around 60% of those with LEMS have an underlying malignancy, most commonly small-cell lung cancer; it is therefore regarded ...
, may also mimic ALS, although this rarely presents diagnostic difficulty over time. Benign fasciculation syndrome
Benign fasciculation syndrome (BFS) is characterized by fasciculation (twitching) of voluntary muscles in the body. The twitching can occur in any voluntary muscle group but is most common in the eyelids, arms, hands, fingers, legs, and feet. The ...
and cramp fasciculation syndrome Cramp fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability disorder. It is more severe than the related (and common) disorder known as benign fasciculation syndrome; it causes fasciculations, cramps, pain, fatigue, and muscle s ...
may also, occasionally, mimic some of the early symptoms of ALS. Nonetheless, the absence of other neurological features that develop inexorably with ALS means that, over time, the distinction will not present any difficulty to the experienced neurologist; where doubt remains, EMG may be helpful.
Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics being less than 10%. One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.
Management
There is no cure for ALS.[ Management focuses on treating symptoms and providing supportive care, with the goal of improving quality of life and prolonging survival.][ This care is best provided by multidisciplinary teams of healthcare professionals; attending a multidisciplinary ALS clinic is associated with longer survival, fewer hospitalizations, and improved quality of life.][ Riluzole prolongs survival by about 2–3 months.] Edaravone
Edaravone, sold under the brand name Radicava among others, is a medication used to treat stroke and amyotrophic lateral sclerosis (ALS). It is given by intravenous infusion and Oral administration, by mouth.
The most common side effects includ ...
slows functional decline slightly in a small number of people with ALS; it is expensive and must be administered by daily IV infusions that may decrease quality of life. Other medications may be used to manage other symptoms.
Non-invasive ventilation
Non-invasive ventilation (NIV) is the use of breathing support administered through a face mask, nasal mask, or a helmet. Air, usually with added oxygen, is given through the mask under positive pressure; generally the amount of pressure is alter ...
(NIV) is the main treatment for respiratory failure in ALS.[ In people with normal bulbar function, it prolongs survival by about seven months and improves quality of life. One study found that NIV is ineffective for people with poor bulbar function] while another suggested that it may provide a modest survival benefit.[ Many people with ALS have difficulty tolerating NIV.] Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage their symptoms.[ While invasive ventilation prolongs survival, disease progression and functional decline continue.][ It may decrease the quality of life of people with ALS or their caregivers.][ Invasive ventilation is more commonly used in Japan than North America or Europe.]
Physical therapy can promote functional independence through aerobic, range of motion, and stretching exercises. Occupational therapy can assist with activities of daily living through adaptive equipment. Speech therapy can assist people with ALS who have difficulty speaking. Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.[ Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques. A ]feeding tube
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, her ...
should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water.[ The feeding tube is usually inserted by ]percutaneous endoscopic gastrostomy
Percutaneous endoscopic gastrostomy (PEG) is an endoscopic medical procedure in which a tube (PEG tube) is passed into a patient's stomach through the abdominal wall, most commonly to provide a means of feeding when oral intake is not adequate (fo ...
(PEG). There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life.[
]Palliative care
Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...
should begin shortly after someone is diagnosed with ALS. Discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Hospice care can improve symptom management at the end of life and increases the likelihood of a peaceful death.[ In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.][
]
Medications
Riluzole has been found to modestly prolong survival by about 2–3 months. It may have a greater survival benefit for those with bulbar-onset ALS
Amyotrophic lateral sclerosis (ALS), also known as motor neuron 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 commo ...
. It may work by decreasing release of the excitatory neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
from pre-synaptic neurons.[ The most common side effects are nausea and a lack of energy (]asthenia
Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...
). People with ALS should begin treatment with riluzole as soon as possible following their diagnosis.
Edaravone
Edaravone, sold under the brand name Radicava among others, is a medication used to treat stroke and amyotrophic lateral sclerosis (ALS). It is given by intravenous infusion and Oral administration, by mouth.
The most common side effects includ ...
has been shown to modestly slow the decline in function in a small group of people with early-stage ALS. It may work by protecting motor neurons from oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. The most common side effects are bruising and gait disturbance. Treatment with edaravone is expensive and requires daily hour-long IV infusions for 10 days in a two-week period.[
Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and ]phlegm
Phlegm (; , ''phlégma'', "inflammation", "humour caused by heat") is mucus produced by the respiratory system, excluding that produced by the nasal passages. It often refers to respiratory mucus expelled by coughing, otherwise known as sputum ...
. Gabapentin
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabet ...
, pregabalin
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety disord ...
, and tricyclic antidepressants
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
(e.g., amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
) can be used for neuropathic pain, while nonsteroidal anti-inflammatory drugs ( NSAIDs), acetaminophen
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
, and opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
s can be used for nociceptive pain.[
Depression can be treated with ]selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracell ...
s (SSRIs) or tricyclic antidepressants, while benzodiazepines can be used for anxiety. There are no medications to treat cognitive impairment/frontotemporal dementia (FTD); however, SSRIs and antipsychotics can help treat some of the symptoms of FTD. Baclofen
Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life. It is ta ...
and tizanidine
Tizanidine, sold under the brand name Zanaflex among others, is a medication that is used to treat muscle spasticity due to spinal cord injury or multiple sclerosis as well as spastic cerebral palsy. Effectiveness appears similar to baclofen ...
are the most commonly used oral drugs for treating spasticity; an intrathecal
Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain ma ...
baclofen pump can be used for severe spasticity. Atropine
Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...
, scopolamine, amitriptyline or glycopyrrolate
Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has few to no central effects. It is available in oral, intravenous, topical, and inhaled forms. It is a ...
may be prescribed when people with ALS begin having trouble swallowing their saliva (sialorrhea
Hypersalivation, or ptyalism, also known as sialorrhea or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape ...
).
A 2017 review concluded that mexiletine
Mexiletine (INN) (sold under the brand names Mexitil and Namuscla) is a medication used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness. Common side effects include abdominal pain, chest discomfort, drowsiness, ...
was safe and effective for treating cramps in ALS based on a randomized controlled trial from 2016. In a study from 2020, AMX0035, a combination of sodium phenylbutyrate
Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an ...
and taurursodiol, was shown to prolong the survival of patients by several months. In March 2022, an independent advisory panel to the FDA voted 6–4 that data was insufficient to show the drug slowed progression of ALS.
Breathing support
Non-invasive ventilation
Non-invasive ventilation
Non-invasive ventilation (NIV) is the use of breathing support administered through a face mask, nasal mask, or a helmet. Air, usually with added oxygen, is given through the mask under positive pressure; generally the amount of pressure is alter ...
(NIV) is the primary treatment for respiratory failure in ALS[ and was the first treatment shown to improve both survival and quality of life.][ NIV uses a face or nasal mask connected to a ventilator that provides intermittent positive pressure to support breathing. Continuous positive pressure is not recommended for people with ALS because it makes breathing more difficult.][ Initially, NIV is used only at night][ because the first sign of respiratory failure is decreased gas exchange (]hypoventilation
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
) during sleep; symptoms associated with this nocturnal hypoventilation include interrupted sleep, anxiety, morning headaches, and daytime fatigue. As the disease progresses, people with ALS develop shortness of breath when lying down, during physical activity or talking, and eventually at rest. Other symptoms include poor concentration, poor memory, confusion, respiratory tract infections, and a weak cough. Respiratory failure is the most common cause of death in ALS.[
It is important to monitor the respiratory function of people with ALS every three months, because beginning NIV soon after the start of respiratory symptoms is associated with increased survival. This involves asking the person with ALS if they have any respiratory symptoms and measuring their respiratory function.][ The most commonly used measurement is upright ]forced vital capacity
Spirometry (meaning ''the measuring of breath'') is the most common of the pulmonary function tests (PFTs). It measures lung function, specifically the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is he ...
(FVC), but it is a poor detector of early respiratory failure and is not a good choice for those with bulbar symptoms, as they have difficulty maintaining a tight seal around the mouthpiece. Measuring FVC while the person is lying on their back (supine FVC) is a more accurate measure of diaphragm weakness than upright FVC. Sniff nasal inspiratory pressure (SNIP) is a rapid, convenient test of diaphragm strength that is not affected by bulbar muscle weakness.[ If someone with ALS has signs and symptoms of respiratory failure, they should undergo daytime ]blood gas analysis
A blood gas test or blood gas analysis tests blood to measure blood gas tension values, it also measures blood pH, and the level and base excess of bicarbonate. The source of the blood is reflected in the name of each test; arterial blood ga ...
[ to look for ]hypoxemia
Hypoxemia is an abnormally low level of oxygen in the blood. More specifically, it is oxygen deficiency in arterial blood. Hypoxemia has many causes, and often causes hypoxia as the blood is not supplying enough oxygen to the tissues of the body ...
(low oxygen in the blood) and hypercapnia
Hypercapnia (from the Greek ''hyper'' = "above" or "too much" and ''kapnos'' = "smoke"), also known as hypercarbia and CO2 retention, is a condition of abnormally elevated carbon dioxide (CO2) levels in the blood. Carbon dioxide is a gaseous pro ...
(too much carbon dioxide in the blood).[ If their daytime blood gas analysis is normal, they should then have nocturnal ]pulse oximetry
Pulse oximetry is a noninvasive method for monitoring a person's oxygen saturation. Peripheral oxygen saturation (SpO2) readings are typically within 2% accuracy (within 4% accuracy in 95% of cases) of the more accurate (and invasive) reading of ...
to look for hypoxemia during sleep.[
Non-invasive ventilation prolongs survival longer than riluzole. A 2006 randomized controlled trial found that NIV prolongs survival by about 48 days and improves quality of life; however, it also found that some people with ALS benefit more from this intervention than others. For those with normal or only moderately impaired bulbar function, NIV prolongs survival by about seven months and significantly improves quality of life. For those with poor bulbar function, NIV neither prolongs survival nor improves quality of life, though it does improve some sleep-related symptoms.] Despite the clear benefits of NIV, about 25–30% of all people with ALS are unable to tolerate it, especially those with cognitive impairment or bulbar dysfunction. Results from a large 2015 cohort study suggest that NIV may prolong survival in those with bulbar weakness, and so NIV should be offered to all people with ALS, even if it is likely that they will have difficulty tolerating it.[
]
Invasive ventilation
Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea (tracheostomy
Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision (cut) on the anterior aspect (front) of the neck and opening a direct airway through an incision in the Vertebrate trachea, trache ...
) and inserting a tube
Tube or tubes may refer to:
* ''Tube'' (2003 film), a 2003 Korean film
* ''The Tube'' (TV series), a music related TV series by Channel 4 in the United Kingdom
* "Tubes" (Peter Dale), performer on the Soccer AM television show
* Tube (band), a ...
connected to a ventilator.[ It is an option for people with advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use.][ While invasive ventilation prolongs survival, especially for those younger than 60, it does not treat the underlying neurodegenerative process. The person with ALS will continue to lose motor function, making communication increasingly difficult and sometimes leading to ]locked-in syndrome
Locked-in syndrome (LIS), also known as pseudocoma, is a condition in which a patient is aware but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for vertical eye movements and bli ...
, in which they are completely paralyzed except for their eye muscles.[ About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life][ but most still consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and may decrease their quality of life.][ Attitudes toward invasive ventilation vary from country to country; about 30% of people with ALS in Japan choose invasive ventilation, versus less than 5% in North America and Europe.]
Therapy
Physical therapy
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
plays a large role in rehabilitation for individuals with ALS. Specifically, physical, occupational, and speech therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.
Occupational therapy and special equipment such as assistive technology
Assistive technology (AT) is a term for assistive, adaptive, and rehabilitative devices for people with disabilities and the elderly. Disabled people often have difficulty performing activities of daily living (ADLs) independently, or even with ...
can also enhance people's independence and safety throughout the course of ALS.[ Gentle, low-impact ]aerobic exercise
Aerobic exercise (also known as endurance activities, cardio or cardio-respiratory exercise) is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, inv ...
such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.
...
and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles, because muscle exhaustion can lead to worsening of symptoms associated with ALS, rather than providing help to people with ALS. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible. Since respiratory insufficiency is the primary cause of mortality, physical therapists can help improve respiratory outcomes in people with ALS by implementing pulmonary physical therapy. This includes inspiratory muscle training, lung volume recruitment training, and manual assisted cough therapy aimed at increasing respiratory muscle strength as well as increasing survival rates.
People with ALS who have difficulty speaking or swallowing may benefit from working with a speech-language pathologist.[ These health professionals can teach people 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
Augmentative and alternative communication (AAC) encompasses the communication methods used to supplement or replace speech or writing for those with impairments in the production or comprehension of spoken or written language. AAC is used by t ...
such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.[
In a study published in 2022, a completely locked-in ALS patient was fitted with two 64-bit brain implant microarrays in his motor cortex in 2020. Using audible feedback from his own intentional neural firing rates, he was able to communicate letters to form phrases. This is the first example of communication at length with a fully locked-in ALS patient.]
Nutrition
Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.[ Weight loss in ALS is caused by muscle wasting due to motor neuron death, increased resting energy expenditure, and decreased food intake. Difficulty swallowing (]dysphagia
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
) develops in about 85% of people with ALS at some point over the course of their disease and is a major cause of decreased food intake, leading to malnutrition and weight loss.[ It is important to regularly assess the weight and swallowing ability of people with ALS.][ Initially, dysphagia may be managed by dietary changes and modified swallowing techniques.][ Difficulty swallowing liquids usually develops first and can be managed by switching to thicker liquids like fruit nectar or smoothies, or by adding fluid thickeners to thin fluids like water and coffee. People with ALS should eat soft, moist foods, which tend to be easier to swallow than dry, crumbly, or chewy foods.] They should also be instructed on proper head posture during swallowing, which can make swallowing easier.[ There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival.]
A feeding tube
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, her ...
should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water.[ This can take the form of a ]gastrostomy
Gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression.
Typically this would include an incision in the patient's epigastrium as part of a formal operation. It can be perfor ...
tube, in which a tube is placed through the wall of the abdomen into the stomach, or a nasogastric tube
Nasogastric intubation is a medical process involving the insertion of a plastic tube (nasogastric tube or NG tube) through the nose, down the oesophagus, and down into the stomach. Orogastric intubation is a similar process involving the inserti ...
, in which a tube is placed through the nose and down the esophagus into the stomach.[ A gastrostomy tube is more appropriate for long-term use][ than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers.][ The feeding tube is usually inserted by ]percutaneous endoscopic gastrostomy
Percutaneous endoscopic gastrostomy (PEG) is an endoscopic medical procedure in which a tube (PEG tube) is passed into a patient's stomach through the abdominal wall, most commonly to provide a means of feeding when oral intake is not adequate (fo ...
(PEG). There is some evidence that a PEG tube should be inserted before vital capacity drops below 50% of expected, as a low vital capacity may be associated with a higher risk of complications. However, a large 2015 study showed that PEG insertion is safe in people with advanced ALS and low vital capacities, as long as they are on NIV during the procedure.
There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life[ by sustaining nutrition and medication intake.][ This reduces the risk of weight loss and dehydration, and can decrease anxiety from extended mealtimes][ and decreased oral food intake.][
]
End-of-life care
Palliative care
Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...
, which relieves symptoms and improves quality of life without treating the underlying disease, should begin shortly after someone is diagnosed with ALS. Early discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures.[ Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out ]advance directive
An advance healthcare directive, also known as living will, personal directive, advance directive, medical directive or advance decision, is a legal document in which a person specifies what actions should be taken for their health if they are no ...
s indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes. Late in the disease course, difficulty speaking due to muscle weakness (dysarthria
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...
) and cognitive dysfunction may impair their ability to communicate their wishes regarding care.[ Continued failure to solicit the preferences of the person with ALS may lead to unplanned and potentially unwanted emergency interventions, such as invasive ventilation. If people with ALS or their family members are reluctant to discuss end-of-life issues, it may be useful to use the introduction of gastrostomy or noninvasive ventilation as an opportunity to bring up the subject.][
]Hospice care
Hospice care is a type of health care that focuses on the palliation of a terminally ill patient's pain and symptoms and attending to their emotional and spiritual needs at the end of life. Hospice care prioritizes comfort and quality of life by ...
, or palliative care at the end of life, is especially important in ALS because it helps to optimize the management of symptoms and increases the likelihood of a peaceful death.[ It is unclear exactly when the end-of-life phase begins in ALS, but it is associated with significant difficulty moving, communicating, and, in some cases, thinking.][ Although many people with ALS fear choking to death (suffocating),][ they can be reassured that this occurs rarely, about 0–3% of the time. About 90% of people with ALS die peacefully. In the final days of life, opioids can be used to treat pain and ]dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...
, while benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s can be used to treat anxiety.[
]
Epidemiology
ALS is the most common motor neuron disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron 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 comm ...
in adults and the third most common neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
[ after ]Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. Worldwide the number of people who develop ALS yearly is estimated to be 1.9 people per 100,000 per year, while the number of people who have ALS at any given time is estimated to be about 4.5 people per 100,000. In Europe, the number of new cases a year is about 2.6 people per 100,000, while the number affected is 7–9 people per 100,000.[ The lifetime risk of developing ALS is 1:350 for European men and 1:400 for European women. Men have a higher risk mainly because spinal-onset ALS is more common in men than women.][ The number of those with ALS in the United States in 2015 was 5.2 people per 100,000, and was higher in whites, males, and people over 60 years old.] The number of new cases is about 0.8 people per 100,000 per year in east Asia and about 0.7 people per 100,000 per year in south Asia. About 80% of ALS epidemiology studies have been conducted in Europe and the United States, mostly in people of northern European descent.[ There is not enough information to determine the rates of ALS in much of the world, including Africa, parts of Asia, India, Russia, and South America.][ There are several geographic clusters in the Western Pacific where the prevalence of ALS was reported to be 50–100 times higher than the rest of the world, including Guam, the ]Kii Peninsula
The is the largest peninsula on the island of Honshū in Japan. It is named after the ancient Kii Province.
Overview
The area south of the “ Central Tectonic Line” is called , and is home to reef-like coral communities which are among ...
of Japan, and Western New Guinea
Western New Guinea, also known as Papua, Indonesian New Guinea, or Indonesian Papua, is the western half of the Melanesian island of New Guinea which is administered by Indonesia. Since the island is alternatively named as Papua, the region ...
. The incidence in these areas has decreased since the 1960s; the cause remains unknown.[
People of all races and ethnic backgrounds may be affected by ALS,] but it is more common in whites than in Africans, Asians, or Hispanics. In the United States in 2015, the prevalence of ALS in whites was 5.4 people per 100,000, while the prevalence in blacks was 2.3 people per 100,000. The Midwest had the highest prevalence of the four US Census regions with 5.5 people per 100,000, followed by the Northeast (5.1), the South (4.7), and the West (4.4). The Midwest and Northeast likely had a higher prevalence of ALS because they have a higher proportion of whites than the South and West. Ethnically mixed populations may be at a lower risk of developing ALS; a study in Cuba found that people of mixed ancestry were less likely to die from ALS than whites or blacks. There are also differences in the genetics of ALS between different ethnic groups; the most common ALS gene in Europe is ''C9orf72'', followed by ''SOD1'', ''TARDBP'', and ''FUS'', while the most common ALS gene in Asia is ''SOD1'', followed by ''FUS'', ''C9orf72'', and ''TARDBP''.
ALS can affect people at any age, but the peak incidence is between 50 and 75 years[ and decreases dramatically after 80 years.] The reason for the decreased incidence in the elderly is unclear. One thought is that people who survive into their 80s may not be genetically susceptible to developing ALS; alternatively, ALS in the elderly might go undiagnosed because of comorbidities
In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
(other diseases they have), difficulty seeing a neurologist, or dying quickly from an aggressive form of ALS. In the United States in 2015, the lowest prevalence was in the 18–39 age group, while the highest prevalence was in the 70–79 age group. Sporadic ALS usually starts around the ages of 58 to 63 years, while familial ALS starts earlier, usually around 47 to 52 years.[ The number of ALS cases worldwide is projected to increase from 222,801 in 2015 to 376,674 in 2040, an increase of 69%. This will largely be due to the aging of the world's population, especially in developing countries.][
]
History
Descriptions of the disease date back to at least 1824 by Charles Bell
Sir Charles Bell (12 November 177428 April 1842) was a Scotland, Scottish surgeon, anatomist, physiologist, neurologist, artist, and philosophical theologian. He is noted for discovering the difference between sensory nerves and motor nerves in ...
. In 1850, François-Amilcar Aran
François-Amilcar Aran (12 July 1817, in Bordeaux – 22 February 1861, in Paris) was a French physician.
He studied medicine in Bordeaux and received his doctorate in Paris with a thesis on heart palpitations. In Paris he subsequently becam ...
was the first to describe a disorder he named "progressive muscular atrophy", a form of ALS in which only the lower motor neurons are affected. In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot
Jean-Martin Charcot (; 29 November 1825 – 16 August 1893) was a French neurology, neurologist and professor of anatomical pathology. He worked on hypnosis and hysteria, in particular with his hysteria patient Louise Augustine Gleizes. Charcot ...
, who initially introduced the term ''amyotrophic lateral sclerosis'' in his 1874 paper. Flail arm syndrome, a regional variant of ALS, was first described by Alfred Vulpian
Edmé Félix Alfred Vulpian (5 January 1826 – 18 May 1887) was a French physician and neurologist. He was the co-discoverer of Vulpian-Bernhardt spinal muscular atrophy and the Vulpian-Heidenhain-Sherrington phenomenon.
Vulpian was born in Par ...
in 1886. Flail leg syndrome, another regional variant of ALS, was first described by Pierre Marie
Pierre Marie (9 September 1853 – 13 April 1940) was a French neurology, neurologist and political journalist close to the French Section of the Workers' International, SFIO.
Medical Career
After finishing medical school, he served as an int ...
and his student Patrikios in 1918.
In 1945, American naval doctors reported that ALS was 100 times more prevalent among the Chamorro people
The Chamorro people (; also CHamoru) are the indigenous people of the Mariana Islands, politically divided between the United States territory of Guam and the encompassing Commonwealth of the Northern Mariana Islands in Micronesia. Today, signif ...
of Guam
Guam (; ch, Guåhan ) is an organized, unincorporated territory of the United States in the Micronesia subregion of the western Pacific Ocean. It is the westernmost point and territory of the United States (reckoned from the geographic cent ...
than in the rest of the world. In 1956 the variant of ALS endemic to Guam was named "amyotrophic lateral sclerosis/parkinsonism dementia complex" (ALS/PDC), as it had the typical symptoms of ALS accompanied by parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
-like symptoms; the name in the local language is lytico-bodig disease
Lytico-bodig (also Lytigo-bodig) disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC) is a neurodegenerative disease of uncertain etiology endemic to the Chamorro people of the island of Guam in Micronesia. ''Ly ...
. Despite a number of genetic and environmental studies, the cause of ALS/PDC remains unknown. Rates peaked in the early 1950s and steadily declined thereafter, and by 1985 the incidence of ALS/PDC in Guam was about the same as the rest of the world.
The first gene to be associated with ALS was ''SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
'', which was identified in 1993.[ This led to the development of the first ]animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
of ALS, the transgenic
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
''SOD1'' mouse, in 1994.[ In December 1995, riluzole became the first FDA-approved drug for ALS. It was then approved in Europe in 1996 and in Japan in 1998.][ In 1996, the ALS Functional Rating Scale (ALSFRS) was first published; it was a 10-item questionnaire that measured the ability of people with ALS to perform ]activities of daily living
Activity may refer to:
* Action (philosophy), in general
* Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may st ...
. In 1999, the scale was changed to give more weight to respiratory symptoms. The resulting ALS Functional Rating Scale - Revised Amyotrophic Lateral Sclerosis (ALS), is a neurodegenerative disease that typically affects adults around 54-67 years of age, although anyone can be diagnosed with the disease. People diagnosed with ALS live on average 2–4 years after diagnosis d ...
(ALSFRS-R) is a 12-item questionnaire that replaces the single question about breathing with a question each about dyspnea, orthopnea, and respiratory insufficiency.
In 2006, it was discovered that the protein TDP-43 is a major component of the inclusion bodies seen in both ALS and frontotemporal dementia (FTD), which provided evidence that ALS and FTD are part of a common disease spectrum. This led to the discovery in 2008 that mutations in ''TARDBP'', the gene that codes for TDP-43, are a cause of familial ALS.[ In 2011, noncoding repeat expansions in ''C9orf72'' were found to be a major cause of ALS and FTD.][ Edaravone was approved to treat ALS in Japan and South Korea in 2015 and in the United States in 2017.] , it has not been approved to treat ALS in Europe.
Diagnostic criteria
In the 1950s, electrodiagnostic testing (EMG and NCV) began to be used to evaluate clinically suspected ALS. In 1969 Edward H. Lambert published the first EMG/NCS diagnostic criteria for ALS, consisting of four findings he considered to strongly support the diagnosis. In 1990, the World Federation of Neurology
World Federation of Neurology (WFN) was formed in Brussels, Belgium, in 1957, as an association of national neurological societies. It is a UK registered charity with a mission to foster quality neurology and brain health worldwide through promo ...
(WFN) held a meeting at El Escorial
El Escorial, or the Royal Site of San Lorenzo de El Escorial ( es, Monasterio y Sitio de El Escorial en Madrid), or Monasterio del Escorial (), is a historical residence of the King of Spain located in the town of San Lorenzo de El Escorial, u ...
, Spain, to come up with precise diagnostic criteria for ALS to help standardize clinical trials; the resulting "El Escorial" criteria were published in 1994. In 1998, the WFN held another meeting to revise the criteria at Airlie House in Warrenton, Virginia
Warrenton is a town in Fauquier County, Virginia, of which it is the seat of government. The population was 9,611 at the 2010 census, up from 6,670 at the 2000 census. The estimated population in 2019 was 10,027. It is at the junction of U.S. R ...
; the resulting "Airlie House" or "El Escorial Revised" criteria were published in 2000. In 2006, a meeting was held on Awaji Island in Japan to discuss how to use EMG and NCV tests to help diagnose ALS earlier; the resulting "Awaji" criteria were published in 2008.
Name
''Amyotrophic'' comes from Greek
Greek may refer to:
Greece
Anything of, from, or related to Greece, a country in Southern Europe:
*Greeks, an ethnic group.
*Greek language, a branch of the Indo-European language family.
**Proto-Greek language, the assumed last common ancestor ...
: ''a-'' means "no", ''myo-'' (from ''mûs'') refers to "muscle", and ''trophḗ'' means "nourishment". Therefore, ''amyotrophy
Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle-aged males with type 2 diabetes. It also occurs with motor neuron disease.
Differential diagnosis
The following are considered differenti ...
'' means "muscle malnourishment" or the wasting of muscle tissue. ''Lateral'' identifies the areas in a person's spinal cord where the affected motor neurons that control muscle are located. '' Sclerosis'' means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.
ALS is sometimes referred to as ''Charcot's disease'' (not to be confused with Charcot–Marie–Tooth disease
Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most ...
and Charcot joint disease
Neuropathic arthropathy (or neuropathic osteoarthropathy), also known as Charcot joint (often Charcot foot) after the first to describe it, Jean-Martin Charcot, refers to progressive degeneration of a weight-bearing joint, a process marked by ...
), because Jean-Martin Charcot
Jean-Martin Charcot (; 29 November 1825 – 16 August 1893) was a French neurology, neurologist and professor of anatomical pathology. He worked on hypnosis and hysteria, in particular with his hysteria patient Louise Augustine Gleizes. Charcot ...
was the first to connect the clinical symptoms with the pathology seen at autopsy. The British neurologist Russell Brain
Walter Russell Brain, 1st Baron Brain (23 October 1895 – 29 December 1966) was a British neurologist. He was principal author of the standard work of neurology, ''Brain's Diseases of the Nervous System'', and longtime editor of the homonymo ...
coined the term ''motor neurone disease'' in 1933 to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease, ''neurone'' being a historically incorrect form of ''neuron''. In some countries, especially the United States, ALS is called ''Lou Gehrig's disease'' after the American baseball
Baseball is a bat-and-ball sport played between two teams of nine players each, taking turns batting and fielding. The game occurs over the course of several plays, with each play generally beginning when a player on the fielding tea ...
player Lou Gehrig
Henry Louis Gehrig (born Heinrich Ludwig Gehrig ; June 19, 1903June 2, 1941) was an American professional baseball first baseman who played 17 seasons in Major League Baseball (MLB) for the New York Yankees (1923–1939). Gehrig was renowned f ...
who developed ALS in 1938.
In the United States and continental Europe, the term ''ALS'' (as well as ''Lou Gehrig's disease'' in the US) refers to all forms of the disease, including "classical" ALS, progressive bulbar palsy
Progressive bulbar palsy (PBP) is a medical condition. It belongs to a group of disorders known as motor neuron diseases. Lapiedra 2002 PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the ...
, progressive muscular atrophy
Progressive muscular atrophy (PMA), also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a disorder characterised by the degeneration of lower motor neurons, resulting in generalised, progressive loss of muscle function.
P ...
, and primary lateral sclerosis
Primary lateral sclerosis (PLS) is a very rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases. Motor neuron diseases develop when the n ...
. In the United Kingdom and Australia, the term ''motor neurone disease'' refers to all forms of the disease while ''ALS'' only refers to "classical" ALS, meaning the form with both upper and lower motor neuron involvement.
Society and culture
In August 2014, a challenge went viral online, commonly known as the "ALS Ice Bucket Challenge
The Ice Bucket Challenge, sometimes called the ALS Ice Bucket Challenge, is an activity involving the pouring of a bucket of ice water over a person's head, either by another person or self-administered, to promote awareness of the disease amy ...
". 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$
The United States dollar (symbol: $; code: USD; also abbreviated US$ or U.S. Dollar, to distinguish it from other dollar-denominated currencies; referred to as the dollar, U.S. dollar, American dollar, or colloquially buck) is the official ...
10 (or a similar amount in their local currency) to ALS research at the ALS Association
The ALS Association is an American nonprofit organization that funds global amyotrophic lateral sclerosis (ALS) research, provides care services and programs to people affected by ALS through its nationwide network of chapters, and works with ALS ...
, the ALS Therapy Development Institute, ALS Society of Canada
The ALS Society of Canada is a registered, not-for-profit Canadian organization. ALS Canada, founded in 1977, is a national voluntary health organization dedicated to the fight against amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig' ...
or Motor Neurone Disease Association
The Motor Neurone Disease Association (MND Association) focuses on improving access to care, research and campaigning for those people living with or affected by motor neurone disease (MND) in England, Wales and Northern Ireland. MND is also know ...
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. , the Ice Bucket Challenge had raised $115 million for the ALS Association. Many celebrities have taken part in the challenge. The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene '' NEK1'' may potentially contribute to the development for ALS.
Research
Model organisms
Many different organisms are used as models for studying ALS, including ''Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' (a species of yeast), ''Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'' (a roundworm), ''Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' (the common fruit fly), ''Danio rerio
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
'' (the zebrafish), ''Mus musculus
Mus or MUS may refer to:
Abbreviations
* MUS, the NATO country code for Mauritius
* MUS, the IATA airport code for Minami Torishima Airport
* MUS, abbreviation for the Centre for Modern Urban Studies on Campus The Hague, Leiden University, Neth ...
'' (the house mouse), and ''Rattus norvegicus
''Rattus'' is a genus of muroid rodents, all typically called rats. However, the term rat can also be applied to rodent species outside of this genus.
Species and description
The best-known ''Rattus'' species are the black rat (''R. rattus'') ...
'' (the common rat).[ None of these models perfectly represents ALS in humans, partly because most animal models are based on gene overexpression, meaning that multiple copies of the mutant human gene are inserted into the transgenic model, and partly because the human nervous system is very different from that of other animals.][
The first animal model for ALS was the ''SOD1''G93A transgenic mouse, which was developed in 1994. It expresses about 20–24 copies of the mutant human ''SOD1'' gene] and reproduces most of the clinical and pathological findings seen in ALS. Although there are now over 20 different ''SOD1'' mouse models, the ''SOD1''G93A model remains both the most widely used ''SOD1'' mouse model and the most widely used ALS mouse model overall.[ Much of the present understanding of ALS pathophysiology came from studying mouse models that overexpress mutant ''SOD1'',] especially ''SOD1''G93A mice.[ However, many drug targets that were shown to be effective in the ''SOD1''G93A transgenic mouse failed in clinical trials in humans; other ''SOD1'' models have had similar problems.] Most of these drugs were identified as potentially effective based on a single study in a rodent ''SOD1'' model and then failed in clinical trials in patients who primarily had sporadic ALS. It is thought that these clinical trials failed because ''SOD1'' mutations account for only 2% of all ALS cases and because the pathology of ''SOD1'' ALS is thought to be distinct from all other types of ALS; it lacks the abnormal aggregations of TDP-43 protein or FUS protein seen in nearly all other cases of ALS.[
, there are about 20 ''TARDBP'' mouse models, a dozen ''FUS'' mouse models, and a number of ''C9orf72'', ''PFN1'', and ''UBQLN2'' mouse models. There are also new methods of developing animal models, including viral ]transgenesis
Gene delivery is the process of introducing foreign genetic material, such as DNA or RNA, into host cells. Gene delivery must reach the genome of the host cell to induce gene expression. Successful gene delivery requires the foreign gene deli ...
, in which viruses are used to deliver mutant genes to an animal model, and CRISPR/Cas9
Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic e ...
, which can be used to give an animal model multiple mutated genes. Both of these methods are faster and cheaper than traditional methods of genetically engineering mice; they also allow scientists to study the effects of a mutation in mice of different genetic backgrounds, which better represents the genetic diversity seen in humans.[
Cellular models used to study ALS include the yeast ''Saccharomyces cerevisiae'' and rat or mouse motor neurons in culture. Small-animal models include the fruit fly, the roundworm ''C. elegans'', and the zebrafish. Of the three, the fruit fly is the most widely used; it has a rapid life-cycle, short lifespan, a sophisticated nervous system, and many genetic tools available. ''C. elegans'' has a short life-cycle, is easy to manipulate genetically, and has a simple but well-understood nervous system. The zebrafish has transparent embryos that can be injected with DNA or RNA and has a lifespan of up to two years.] Induced pluripotent stem cells
Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in ...
(iPSCs) can be used to convert skin fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
into motor neurons.[ It is now possible to generate iPSCs from people with ALS, which can then be converted into spinal motor neurons, which are useful for studying disease mechanisms and for testing potential drugs for ALS.] iPSCs allow sporadic ALS to be modelled, which cannot be done with animal models.
Treatments
From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs); of these, riluzole was the only one that showed a slight benefit in improving survival. Drugs tested and not shown to be effective in clinical trials in humans include antiviral drugs, anti-excitotoxic drugs, growth factors, neurotrophic factors, anti-inflammatory drugs, antioxidants, anti-apoptotic drugs, and drugs to improve mitochondria function.
An analysis of 23 large phase II and phase III RCTs that failed between 2004 and 2014 concluded that there were many potential reasons for their lack of success. These trials in humans went ahead on the basis of positive results in ''SOD1'' transgenic mice, which are not a good animal model for sporadic ALS. In most preclinical studies the ''SOD1'' mice were given the drug during the presymptomatic stage, which makes the results less likely to apply to people with ALS, who begin treatment well after their symptoms begin. Positive results in small phase II studies in humans could also be misleading and lead to failure in phase III trials. Other potential issues included the drug not reaching its intended site of action in the central nervous system and drug interactions
Drug interactions occur when a drug's mechanism of action is disturbed by the concomitant administration of substances such as foods, beverages, or other drugs. The cause is often the inhibition of the specific receptors available to the drug, ...
between the study drug and riluzole.
Repetitive transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation in which a changing magnetic field is used to induce an electric current at a specific area of the brain through electromagnetic induction. An electric pulse gener ...
had been studied in ALS in small and poorly designed clinical trials; , evidence was insufficient to know whether rTMS is safe or effective for ALS. One 2016 review of stem-cell therapy
Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. , the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but ...
trials found tentative evidence that intraspinal stem cell implantation was relatively safe and possibly effective. A 2019 Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
of cell-based therapies found that there was insufficient evidence to speculate about efficacy. Masitinib
Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumours in animals, specifically dogs.Information abouMasivetat the European pharmacy agency website Since its introduction in November 2008 it has been distributed und ...
has been approved as an orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
in Europe and the United States, with studies ongoing . Beta-adrenergic agonist
Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. I ...
drugs have been proposed as a treatment for their effects on muscle growth and neuroprotection, but research in humans is insufficient to determine their efficacy.
Cause
With the discovery that ''TDP-43
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
'', '' FUS'', and ''C9orf72
C9orf72 (chromosome 9 open reading frame 72) is a protein which in humans is encoded by the gene ''C9orf72''.
The human ''C9orf72'' gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,546 to base pai ...
'' can cause ALS as well as related forms of frontotemporal dementia (FTD/ALS) there has been intense effort to understand how these mutations cause disease, and whether other protein dysfunction may be important. , it appeared that differences in the methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of arginine residues in FUS protein may be relevant, and methylation status may be a way to distinguish some forms of FTD from ALS.
See also
* Transportin 1
Notes
References
External links
ALS Association Official Website
*
{{Authority control
Motor neuron diseases
Rare diseases
Unsolved problems in neuroscience
Systemic atrophies primarily affecting the central nervous system
Cytoskeletal defects
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Neuromuscular disorders
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