Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis

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Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is a form of motor neuron disease (called motor neurone disease
Motor neurone disease
The motor neurone diseases are a group of neurological disorders that selectively affect motor neurones, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. They are generally progressive in nature, and can cause...

 in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...

) caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

 and the cortical neurons
Motor cortex
Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...

 that provide their efferent input. The condition is often called Lou Gehrig
Lou Gehrig
Henry Louis "Lou" Gehrig , nicknamed "The Iron Horse" for his durability, was an American Major League Baseball first baseman. He played his entire 17-year baseball career for the New York Yankees . Gehrig set several major league records. He holds the record for most career grand slams...

's disease in North America, after the New York Yankees
New York Yankees
The New York Yankees are a professional baseball team based in the The Bronx, New York. They compete in Major League Baseball in the American League's East Division...

 baseball player who was diagnosed with the disease in 1939. The disorder is characterized by rapidly progressive weakness
Weakness
Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. 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...

, muscle atrophy
Muscle atrophy
Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...

 and fasciculations, spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

, dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...

, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

, and respiratory compromise. Sensory function generally is spared, as is autonomic, and oculomotor activity. ALS is a progressive
Progressive disease
Progressive disease is a physical ailment whose natural course in most cases is the worsening, growth, or spread of the disease. This may happen until death, serious debility, or organ failure occurs. Though the time distinctions are imprecise, diseases can be rapidly progressive or slowly...

, fatal, neurodegenerative disease with most affected patients dying of respiratory compromise and pneumonia after 2 to 3 years; although some perish within a year from the onset of symptoms, and occasional individuals have a more indolent course and survive for many years.

Signs and symptoms


The disorder causes muscle weakness and atrophy throughout the body caused by degeneration of the upper
Upper motor neuron
Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle...

 and lower motor neuron
Lower motor neuron
Lower motor neurons are the motor neurons connecting the brainstem and spinal cord to muscle fibers, bringing the nerve impulses from the upper motor neurons out to the muscles...

s. Unable to function, the muscles weaken and atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...

. Affected individuals may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually, but not always, spared.

Cognitive function is generally spared for most patients although some (~5%) also have frontotemporal dementia
Frontotemporal dementia
Frontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe...

. A higher proportion of patients (~30-50%) also have more subtle cognitive changes which may go unnoticed but are revealed by detailed neuropsychological testing. Sensory nerves and the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

, which controls functions like sweating, are generally unaffected but may be involved for some patients.

Initial symptoms


The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include muscle fasciculation (twitching), cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first. About 75% of people contracting the disease experience "limb onset" ALS i.e. first symptoms in the arms ("upper limb", not to be confused with "upper motor neuron") or legs ("lower limb", not to be confused with "lower motor neuron"). Patients with the leg onset form may experience awkwardness when walking or running or notice that they are tripping or stumbling, often with a "dropped foot" which drags gently along the ground. Arm-onset patients may experience difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock. Occasionally, the symptoms remain confined to one limb for a long period of time or for the whole length of the illness; this is known as monomelic amyotrophy
Monomelic amyotrophy
Monomelic amyotrophy is an untreatable, focal, motor neuron disease that primarily affects young males in India and Japan...

.

About 25% of cases are "bulbar onset" ALS. These patients first notice difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. Other symptoms include difficulty swallowing, and loss of tongue mobility. A smaller proportion of patients experience "respiratory onset" ALS where the intercostal
Intercostal
Intercostal means "between the ribs". It can refer to:* Intercostal muscle* Highest intercostal vein* Intercostal arteries* Intercostal space...

 muscles that support breathing are affected first.

Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease progresses. Patients experience increasing difficulty moving, swallowing (dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

), and speaking or forming words (dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...

). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

) and exaggerated reflexes (hyperreflexia
Hyperreflexia
Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...

) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign
Plantar reflex
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 normal adults the plantar reflex causes a downward response of the hallux...

 (the big toe extends upward and other toes spread out) also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). Around 15–45% of patients experience pseudobulbar affect
Pseudobulbar affect
Pseudobulbar affect , emotional lability, labile affect or emotional incontinence refers to a neurologic disorder characterized by involuntary crying or uncontrollable episodes of crying and/or laughing, or other emotional displays. PBA occurs secondary to neurologic disease or brain injury...

, also known as "emotional lability", which consists of uncontrollable laughter, crying or smiling, attributable to degeneration of bulbar upper motor neurons resulting in exaggeration of motor expressions of emotion.

To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

Disease progression


Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually most patients are not able to stand or walk, get in or out of bed on their own, or use their hands and arms. Difficulty swallowing and chewing impair the patient's ability to eat normally and increase the risk of choking or aspirating food/liquids into the lungs. Aspiration pneumonia and weight maintenance can then become a problem. Because the disease usually does not affect cognitive abilities, patients are aware of their progressive loss of function and may become anxious and depressed. A small percentage of patients go on to develop frontotemporal dementia
Frontotemporal dementia
Frontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe...

 characterized by profound personality changes; this is more common among those with a family history of dementia. A larger proportion of patients experience mild problems with word-generation, attention, or decision-making. Cognitive function may be affected as part of the disease process or could be related to poor breathing at night (nocturnal hypoventilation). Health care professionals need to explain the course of the disease and describe available treatment options so that patients can make informed decisions in advance.

As the diaphragm and intercostal muscle
Intercostal muscle
Intercostal muscles are several 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...

s (rib cage) weaken, forced vital capacity and inspiratory pressure diminish. In bulbar onset ALS, this may occur before significant limb weakness is apparent. Bilevel positive pressure ventilation (frequently referred to by the tradename BiPAP) is frequently used to support breathing, first at night, and later during the daytime as well. It is recommended that long before BiPAP becomes insufficient, patients must decide whether to have a tracheostomy and long term mechanical ventilation. At this point, some patients choose palliative hospice care
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...

. Most people with ALS die of respiratory failure or pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

. Death usually occurs within two to five years of diagnosis. Although the disease can strike at any age, most people are between forty and seventy years of age when the disease strikes and men are affected slightly more frequently than women. An estimated 5,000 people in the United States are diagnosed with the disease each year. ALS, a progressive disease, leads to death in half of the people diagnosed within three years and ninety percent within six years. In a population based study in Minnesota, USA, looking back over 85 years, 14 percent of people with ALS survived more than 5 years. Those who survived 5 years or longer were clinically similar to the total population ALS population in terms of gender, age, gender, and site of onset, but they had a longer time from symptomatic onset to time of diagnosis

ALS predominantly affects the motor neurons, and in the majority of cases the disease does not impair a patient's mind, personality, intelligence, or memory. Nor does it affect a person's ability to see, smell, taste, hear, or feel touch. Control of eye muscles is the most preserved function, although some patients with an extremely long duration of disease (20+ years) may lose eye control too. Unlike multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, bladder and bowel control are usually preserved in ALS, although as a result of immobility and diet changes, intestinal problems such as constipation can require intensive management.

Cause


For patients without a family history of the disease, which includes ~95% of cases, there is no known cause for ALS.

There is a known hereditary factor in familial ALS (FALS), where the condition is known to run in families, although this accounts for only around 5% of all cases. An inherited genetic defect on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS. This mutation is believed to be autosomal dominant. The most common ALS causing SOD1 mutation in North America is A4V, characterized by an exceptionally rapid progression from onset to death. The children of those diagnosed with familial ALS have a higher risk factor for developing the disease; however, those who have close family members who have been diagnosed with sporadic ALS have no greater a risk factor than the general population, suggesting again an environmental or other non-genetic cause.

Some environmental causative factors have been suggested for the increased incidence in the western Pacific. Prolonged exposure to a dietary neurotoxin called BMAA is one suspected risk factor in Guam
Guam
Guam is an organized, unincorporated territory of the United States located in the western Pacific Ocean. It is one of five U.S. territories with an established civilian government. Guam is listed as one of 16 Non-Self-Governing Territories by the Special Committee on Decolonization of the United...

; this neurotoxin produced by cyanobacteria is one of several possible neurotoxic compounds found in the seed of the cycad
Cycad
Cycads are seed plants typically characterized by a stout and woody trunk with a crown of large, hard and stiff, evergreen leaves. They usually have pinnate leaves. The individual plants are either all male or all female . Cycads vary in size from having a trunk that is only a few centimeters...

 Cycas circinalis
Cycas circinalis
Cycas circinalis, also known as the Queen Sago, is a type of cycad that was thought to be linked with the degenerative disease Lytico-Bodig disease on the island of Guam; however, the species native to Guam has since been recognised as a separate species, Cycas micronesica, by K.D...

, a tropical plant found in Guam, which was used in the human food supply during the 1950s and early 1960s.

The very high incidence of the disease among Italian soccer
Football (soccer)
Association football, more commonly known as football or soccer, is a sport played between two teams of eleven players with a spherical ball...

 players (more than five times higher than normally expected) has raised the concern of a possible link between the disease and the use of pesticides on the soccer fields (several of which have been linked to neuronal toxicity). A 2004 Italian study trying to link a high incidence of ALS in soccer players to performance-enhancing drugs
Performance-enhancing drugs
Performance-enhancing drugs are substances used by athletes to improve their performances in the sports in which they engage.- Types of performance-enhancing drugs :...

 failed when the group was compared to cyclists that also used performance-enhancing drugs but without contracting ALS. A possible conclusion was that soccer players experience frequent head trauma (heading the ball, falls and collisions sustained during games) compared to cyclists who wear head protection and rarely have falls.

According to the ALS Association
ALS Association
The ALS Association is an American non profit organization that raises money for research and patient services, promotes awareness about and advocates in state and federal government on issues related to amyotrophic lateral sclerosis , also known as Lou Gehrig's disease...

, veterans of the United States military are at an increased risk of contracting ALS (again, possibly implying a link to neurotoxic chemical exposure). In its report ALS in the Military, the group pointed to an almost 60% greater chance of the disease in military veterans than the general population. For Gulf War veterans, the chance is seen as twice that of veterans not deployed to the Persian Gulf in a joint study by the Veterans Affairs Administration
United States Department of Veterans Affairs
The United States Department of Veterans Affairs is a government-run military veteran benefit system with Cabinet-level status. It is the United States government’s second largest department, after the United States Department of Defense...

 and the DOD, another epidemiologic association suggesting a link to toxic exposure.

A 2010 study has raised questions about the diagnosis of ALS in some veterans and athletes, suggesting that repeated concussions may cause a chronic traumatic encephalopathy
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy is a progressive degenerative disease found in individuals who have been subjected to multiple concussions and other forms of head injury. A variant of the condition, dementia pugilistica, is primarily associated with boxing...

 that mimics ALS; this might explain the higher rate of ALS diagnoses in those populations.

Pathophysiology

Genetic associations include
Type OMIM Gene Locus
ALS1 SOD1
SOD1
Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases.- Function :...

21q22.1
ALS2 ALS2
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.-External Links:** *...

2q33.1
ALS3 ? 18q21
ALS4 SETX
SETX
Probable helicase senataxin is an enzyme that in humans is encoded by the SETX gene.-External links:** -Further reading:http://ghr.nlm.nih.gov/gene/SETX...

9q34.13
ALS5 ? 15q15.1-q21.1
ALS6 FUS
FUS
RNA-binding protein FUS is a protein that in humans is encoded by the FUS gene.- Function :The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding...

16p11.2
ALS7 ? 20p13
ALS8 VAPB
VAPB
Vesicle-associated membrane protein-associated protein B/C is a protein that in humans is encoded by the VAPB gene.-Further reading:...

20q13.3
ALS9 ANG
ANG
ANG is the ISO 639-3 code for Old English. It may also refer to:* Air National Guard, part of the United States National Guard* Anga, Ang Desh or Ang Mahajanapada, one of the 16 Mahajanapada of Ancient India...

14q11.2
ALS10 TARDBP
TARDBP
TAR DNA-binding protein 43 , is a cellular protein which in humans is encoded by the TARDBP gene.- Discovery :TARDBP was originally identified as a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. It was also reported to regulate alternate...

1p36.2
ALS11 FIG4
Fig4
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 is an enzyme that in humans is encoded by the FIG4 gene.- Function :...

6q21
ALS12 OPTN 10p15-p14
ALS13 ATXN2
ATXN2
Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene.-Further reading:-External Links:*...

12q24.12
ALS14 VCP
Valosin-containing protein
Transitional endoplasmic reticulum ATPase also known as valosin-containing protein is an enzyme that in humans is encoded by the VCP gene.- Function :...

9p13.3


The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop proteinaceous inclusions
Inclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...

 in their cell bodies and axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

s. This may be partly due to defects in protein degradation. These inclusions often contain ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

, and generally incorporate one of the ALS-associated proteins: SOD1
SOD1
Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases.- Function :...

, TAR DNA binding protein (TDP-43, or TARDBP), or FUS
FUS
RNA-binding protein FUS is a protein that in humans is encoded by the FUS gene.- Function :The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding...

. Interestingly, these inclusions do not stain with the dyes Congo Red
Congo red
Congo red is the sodium salt of 3,3'-bis. It is a secondary diazo dye...

 or Thioflavin S, and are therefore non-amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...

 aggregates. This is in contrast to the aggregates and plaques seen in many other neurodegenerative diseases of protein aggregation, including Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

, Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...

, and prion diseases
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...

.

SOD1


The cause of ALS is not known, though an important step toward determining the cause came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

 that protects the body from damage caused by superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 again largely by the mitochondria. Free radicals can accumulate and cause damage to both mitochondrial and nuclear DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disease, some of which have a very long clinical course (e.g. H46R), while others, such as A4V, being exceptionally aggressive. Evidence suggests that failure of defenses against oxidative stress up-regulates programmed cell death (apoptosis), among many other possible consequences. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a gain of function).

Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia
Sarcopenia
Sarcopenia is the degenerative loss of skeletal muscle mass and strength associated with aging...

) and a shortened lifespan (see article on superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

). This indicates that the toxic properties of the mutant SOD1 are a result of a gain in function rather than a loss of normal function. In addition, aggregation of proteins has been found to be a common pathological feature of both familial and sporadic ALS (see article on proteopathy
Proteopathy
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body...

). Interestingly, in mutant SOD1 mice (most commonly, the G93A mutant), aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration. It is speculated that aggregate accumulation of mutant SOD1 plays a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins. Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations cause only 2% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies but it is hoped that more useful models will be developed.

Lactate Dyscrasia Hypothesis


Researchers specializing in the neurobiology of aging have proposed a novel molecular model for the pathogenesis of ALS called the lactate dyscrasia hypothesis that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...

 (NMJ) to regulate the flow of lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...

 from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell.

Other factors


Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 and spinal fluid. Riluzole
Riluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....

 is currently the only FDA approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.

Diagnosis


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

 (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
Nerve conduction velocity
Nerve conduction velocity is the speed at which an electrochemical signal propagates down a neural pathway. Many things can affect this, including axon diameter, myelination, the internal resistance of the axon, and temperature. Nerve conduction velocity differs from species to species, and to a...

 (NCV). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....

 (damage to peripheral nerves) or myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...

 (muscle disease) rather than ALS. The physician may order magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, a hernia
Hernia
A hernia is the protrusion of an organ or the fascia of an organ through the wall of the cavity that normally contains it. A hiatal hernia occurs when the stomach protrudes into the mediastinum through the esophageal opening in the diaphragm....

ted disk in the neck, syringomyelia
Syringomyelia
Syringomyelia is a generic term referring to a disorder in which a cyst or cavity forms within the spinal cord. This cyst, called a syrinx, can expand and elongate over time, destroying the spinal cord. The damage may result in pain, paralysis, weakness, and stiffness in the back, shoulders, and...

, or cervical spondylosis
Spondylosis
Spondylosis is a term referring to degenerative osteoarthritis of the joints between the centra of the spinal vertebrae and/or neural foraminae. If this condition occurs in the zygapophysial joints, it can be considered facet syndrome...

.

Based on the patient's symptoms and findings from the examination and from these tests, the physician may order tests on blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 and urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 samples to eliminate the possibility of other diseases as well as routine laboratory tests. In some cases, for example, if a physician suspects that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.

Infectious diseases such as human immunodeficiency virus (HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

), human T-cell leukaemia virus (HTLV), Lyme disease
Lyme disease
Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...

, syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

 and tick-borne encephalitis viruses can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, post-polio syndrome
Post-polio syndrome
Post-polio syndrome is a condition that affects approximately 25–50% of people who have previously contracted poliomyelitis—a viral infection of the nervous system—after the initial infection. Typically the symptoms appear 15–30 years after recovery from the original paralytic attack, at an age of...

, multifocal motor neuropathy
Multifocal motor neuropathy
Multifocal motor neuropathy 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 because of the similarity in the clinical picture, especially if muscle...

, CIDP, and spinal muscular atrophy
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...

 can also mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.

Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients should always obtain a second neurological opinion.

Slowing progression


Riluzole
Riluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....

 (Rilutek) as of 2011 is the only treatment that has been found to improve survival but only to a modest extent. It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damage (occurring in ~10% of people taking the drug). It is approved by Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) and recommended by the National Institute for Clinical Excellence (NICE).

Symptomatic


Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; and home care and hospice nurses. Working with patients and caregivers, these teams can design an individualized plan of medical and physical therapy and provide special equipment aimed at keeping patients as mobile and comfortable as possible.

Medical professionals can prescribe medications to help reduce fatigue, ease muscle cramps, control spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

, and reduce excess saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...

 and phlegm
Phlegm
Phlegm is a liquid secreted by the mucous membranes of mammalians. Its definition is limited to the mucus produced by the respiratory system, excluding that from the nasal passages, and particularly that which is expelled by coughing . Phlegm is in essence a water-based gel consisting of...

. Drugs also are available to help patients with pain, depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

, sleep disturbances, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

, and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

.

Physical therapists and occupational therapists play a large role in rehabilitation for individuals with ALS. Specifically, physical and occupational therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, preventing complications, and promoting functional independence. There is also a strong emphasis on the importance of patient and caregiver education that can be reinforced by physical therapists or occupational therapists. Research is controversial as to whether implementing a specific exercise program for these individuals may be beneficial; moreover, it is important for a physical therapist to address and understand the risks associated with implementing these types of programs for each and every person with ALS and the severity of their condition. The controversy lies in the fact that because ALS is characteristic of the degeneration of upper and lower motor neurons, that these neurons may react differently to specific exercise programs. Because spasticity is a common characteristic for individuals with ALS, physical therapists aim to reduce this by implementing range of motion activities with minimal resistance. In addition to range of motion activities, positioning techniques and splinting have also been shown to reduce spasticity; moreover, these techniques can also play an integral role in the reduction of pain for people with ALS. Overall, physical therapists have been proven to have positive effects on individuals with ALS by prescribing techniques and equipment to assist with conserving energy, emphasizing the importance of education, limiting pain, and help to maintain a level of function appropriate for each of their clients with ALS.

Occupational therapy and special equipment such as assistive technology
Assistive technology
Assistive technology or adaptive technology is an umbrella term that includes assistive, adaptive, and rehabilitative devices for people with disabilities and also includes the process used in selecting, locating, and using them...

 can also enhance patients' independence and safety throughout the course of ALS. But physical therapists must be mindful when prescribing assistive devices, keeping in mind the patients and their attitudes. Devices should make the patient feel hopeful, not helpless. Gentle, low-impact aerobic exercise
Aerobic exercise
Aerobic exercise is physical exercise of relatively low intensity that depends primarily on the aerobic energy-generating process. Aerobic literally means "living in air", and refers to the use of oxygen to adequately meet energy demands during exercise via aerobic metabolism...

 such as walking, swimming, and stationary bicycling
Exercise bicycle
An exercise bicycle or bike, or stationary bicycle, or Exercycle is a device with saddle, pedals, and some form of handlebars arranged as on a bicycle, but used as exercise equipment rather than transportation...

 can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical therapists can recommend exercises that provide these benefits without overworking muscles. They can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients remain mobile. Examples of devices prescribed can include cervical collar
Cervical collar
A cervical collar is an orthopedic medical device used to support a patient's neck and head. It is also used by emergency personnel for victims of traumatic head or neck injuries, and can be used to treat chronic medical conditions....

s. In ALS, there will be a progression of cervical extensor weakness. Weakness of the muscles will cause the patient's head to fall forward, leading to acute neck pain, potential for chronic cervical conditions to develop and tightness of anterior neck muscles. A forward head posture will interfere in patients ADLs, making them more dependent on caretakers. A cervical collar can help restore their independence and comfort. When there is mild to moderate weakness of the cervical extensor, the therapist may provide a soft foam collar. When more severe weakness is observed, a more rigid collar will be beneficial. Occupational therapists can provide or recommend equipment and adaptations to enable people to retain as much independence in activities of daily living as possible.

ALS patients who have difficulty speaking may benefit from working with a speech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication
Augmentative and alternative communication
Augmentative and alternative communication is an umbrella term that 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...

 such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals. These methods and devices help patients communicate when they can no longer speak or produce vocal sounds. With the help of occupational therapists, speech-generating devices can be activated by switches or mouse emulation techniques controlled by small physical movements of, for example, the head, finger or eyes. In every case, the appropriate therapist should be mindful of the patients' preferences, attitudes, and likely progression over time.

Patients and caregivers can learn from speech-language pathologists and nutritionists how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.

When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation (IPPV), bilevel positive airway pressure
Bilevel positive airway pressure
Bilevel positive airway pressure is a continuous positive airway pressure mode used during noninvasive positive pressure ventilation. It delivers a preset inspiratory positive airway pressure and expiratory positive airway pressure . BPAP can be described as a Continuous Positive Airway...

 (BIPAP), or biphasic cuirass ventilation
Biphasic Cuirass Ventilation
Biphasic cuirass ventilation is a method of ventilation which requires the patient to wear an upper body shell or cuirass, so named after the body armor worn by medieval soldiers. The ventilation is biphasic because the cuirass is attached to a pump which actively controls both the inspiratory and...

 (BCV)) may be used to aid breathing. Such devices artificially inflate the patient's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths. Patients may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea
Vertebrate trachea
In tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...

) and for long-term use, an operation such as a tracheostomy, in which a plastic breathing tube
Tracheal tube
A tracheal tube is a catheter that is inserted into the trachea in order for the primary purpose of establishing and maintaining a patent airway and to ensure the adequate exchange of oxygen and carbon dioxide. Many different types of tracheal tubes are available, suited for different specific...

 is inserted directly in the patient's windpipe through an opening in the neck.

Patients and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the patient's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support. Some patients under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough. This technique preserves speech in some patients with long-term mechanical ventilation.

Social workers and home care and hospice nurses help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney
Power of attorney
A power of attorney or letter of attorney is a written authorization to represent or act on another's behalf in private affairs, business, or some other legal matter...

, preparing a living will
Living will
An advance health care directive, also known as living will, personal directive, advance directive, or advance decision, are instructions given by individuals specifying what actions should be taken for their health in the event that they are no longer able to make decisions due to illness or...

, and finding support groups for patients and caregivers. Home nurses are available not only to provide medical care but also to teach caregivers about tasks such as maintaining respirators, giving feedings, and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.

Researchers have stated that "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake." Both animal and human research suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their calorie intake.

Many ALS patients use complementary and alternative medicines in an attempt to slow their disease. This may include popular vitamin supplements such as Vitamin C, high doses of vitamins and nutrients ("mega-dosing"), traditional Chinese medicine, or other forms of therapy such as acupuncture, reiki, or massage. To date there have been no studies demonstrating that such treatment approaches have an effect on the progression of the disease. Given the lack of therapeutic options, people with ALS can be vulnerable to snake oil
Snake oil
Snake oil is a topical preparation made from the Chinese Water Snake , which is used to treat joint pain. However, the most common usage of the phrase is as a derogatory term for quack medicine...

 scams involving complicated medical terminology or potentially exciting technologies such as stem cell transplantation. Practitioners of these scams promise amazing results but carry out little or no real follow up or study of the patients they have treated in order to prove their assertions. The risks of false hope, financial harm, and potentially medically harm, are a threat to the wellbeing of ALS patients and their families.

Prognosis


Eventually most people with ALS are not able to stand or walk, get in or out of bed on their own, use their hands and arms, or communicate. In later stages of the disease, individuals have difficulty breathing as the muscles of the respiratory system weaken. Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die from respiratory failure, usually within three to five years from the onset of symptoms. The median survival time from onset to death ranges from 20 to 48 months, but 10 to 20% of ALS patients have a survival longer than 10 years. The world's most widely recognized person with ALS, Stephen Hawking
Stephen Hawking
Stephen William Hawking, CH, CBE, FRS, FRSA is an English theoretical physicist and cosmologist, whose scientific books and public appearances have made him an academic celebrity...

, has lived with the disease for more than 40 years, though his is an unusual case.

Epidemiology


ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. One or two out of 100,000 people develop ALS each year. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected slightly more often than women.

"Familial ALS" accounts for approximately 5%–10% of all ALS cases and is caused by genetic factors. Of these, approximately 1 in 10 is linked to a mutation in copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

/zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

 superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 (SOD1), an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 responsible for scavenging free radicals. A recent study has identified a gene called FUS
FUS
RNA-binding protein FUS is a protein that in humans is encoded by the FUS gene.- Function :The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding...

 ("Fused in Sarcoma", ALS6) as being responsible for 1 in 20 cases of fALS.

Although the incidence of ALS is thought to be regionally uniform, there are three regions in the West Pacific where there has in the past been an elevated occurrence of ALS. This seems to be declining in recent decades. The largest is the area of Guam
Guam
Guam is an organized, unincorporated territory of the United States located in the western Pacific Ocean. It is one of five U.S. territories with an established civilian government. Guam is listed as one of 16 Non-Self-Governing Territories by the Special Committee on Decolonization of the United...

 inhabited by the Chamorro people, who have historically had a high incidence (as much as 143 cases per 100,000 people per year) of a condition called Lytico-Bodig disease
Lytico-Bodig disease
Lytico-Bodig disease, sometimes spelled Lytigo-bodig is a neurological disease of uncertain aetiology that exists in the United States territory of Guam....

 which is a combination of ALS, Parkinsonism, and dementia. Two more areas of increased incidence are West Papua and the Kii Peninsula
Kii Peninsula
The is the largest peninsula on the island of Honshū in Japan. The area south of the “Central Tectonic Line” is called Nankii , and includes the most poleward living coral reefs in the world due to the presence of the warm Kuroshio Current, though these are threatened by global warming and human...

 of Japan.

Although there have been reports of several "clusters" including three American football
American football
American football is a sport played between two teams of eleven with the objective of scoring points by advancing the ball into the opposing team's end zone. Known in the United States simply as football, it may also be referred to informally as gridiron football. The ball can be advanced by...

 players from the San Francisco 49ers
San Francisco 49ers
The San Francisco 49ers are a professional American football team based in San Francisco, California, playing in the West Division of the National Football Conference in the National Football League . The team was founded in 1946 as a charter member of the All-America Football Conference and...

, more than fifty football players in Italy, three football-playing friends in the south of England, and reports of conjugal (husband and wife) cases in the south of France, these are statistically plausible chance events. Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.

In 2010, a VA study found that head trauma
Head injury
Head injury refers to trauma of the head. This may or may not include injury to the brain. However, the terms traumatic brain injury and head injury are often used interchangeably in medical literature....

 can produce symptoms that resemble ALS but that are actually chronic traumatic encephalopathy
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy is a progressive degenerative disease found in individuals who have been subjected to multiple concussions and other forms of head injury. A variant of the condition, dementia pugilistica, is primarily associated with boxing...

 (CTE). Postmortem brain studies conducted on two American football
American football
American football is a sport played between two teams of eleven with the objective of scoring points by advancing the ball into the opposing team's end zone. Known in the United States simply as football, it may also be referred to informally as gridiron football. The ball can be advanced by...

 players showed evidence of CTE, rather than ALS.

Etymology


Amyotrophic comes from the Greek language
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...

: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophication
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...

 of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("sclerosis
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...

") in the region.

History

Timeline
Year Event
1850 English scientist Augustus Waller
Augustus Volney Waller
Augustus Volney Waller FRS was a British neurophysiologist. He was the first to describe the degeneration of severed nerve fibers, now known as Wallerian degeneration.-Life:...

 describes the appearance of shriveled nerve fibers
1869 French doctor Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

 first describes ALS in scientific literature
1881 "On Amyotrophic Lateral Sclerosis" is translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System
1939 ALS becomes a cause célèbre
Cause célèbre
A is an issue or incident arousing widespread controversy, outside campaigning and heated public debate. The term is particularly used in connection with celebrated legal cases. It is a French phrase in common English use...

in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 when baseball legend Lou Gehrig
Lou Gehrig
Henry Louis "Lou" Gehrig , nicknamed "The Iron Horse" for his durability, was an American Major League Baseball first baseman. He played his entire 17-year baseball career for the New York Yankees . Gehrig set several major league records. He holds the record for most career grand slams...

's career—and, two years later, his life—is ended by the disease. He gives his farewell speech on July 4.
1950s ALS epidemic occurs among the Chamorro people on Guam
1991 Researchers link chromosome 21 to FALS (Familial ALS)
1993 SOD1
SOD1
Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases.- Function :...

 gene on chromosome 21 found to play a role in some cases of FALS
1996 Rilutek becomes the first FDA-approved drug for ALS
1998 The El Escorial criteria is developed as the standard for classifying ALS patient in clinical research

Clinical Research


A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at ClinicalTrials.gov
ClinicalTrials.gov
ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...

.

KNS-760704 is under clinical investigation in ALS patients. It is hoped that the drug will have a neuroprotective effect. It is one enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

 of pramipexole
Pramipexole
Pramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease and restless legs syndrome...

, which is approved for the treatment of Parkinson's disease and restless legs syndrome. The single-enantiomer preparation is essentially inactive at dopamine receptors, is not dose limited by the potent dopaminergic properties of pramipexole. Results of a Phase II clinical trial conducted by Knopp Neurosciences and involving 102 patients were reported in 2010; the trial found a dose-dependent slowing in loss of function.

Olesoxime
Olesoxime
Olesoxime is the lead compound of Trophos' proprietary cholesterol-oxime compound family of mitochondrial pore modulators. It is a molecule that has a cholesterol-like structure and displays strong neuroprotective properties...

 (TRO19622) is being tested in a phase 3 clinical study by Trophos
Trophos
Trophos is a biopharmaceutical company specialising in the discovery and development of novel therapeutics to treat both orphan neurodegenerative diseases and more prevalent disorders....

, French biotechnology company, as part of the MitoTarget Project. The molecule has a cholesterol-like structure and displays strong neuroprotective properties, and it should be as effective as a cocktail of three neurotrophic factors in keeping motor neurons alive in culture.
The ongoing clinical study aims to test efficacy, safety, tolerability and plasma levels in patients with ALS, to see whether a single daily dose of two capsules – under certain circumstances – can improve survival and symptoms of ALS patients.
The trial started in May 2009, all the patients are recruited and results are expected in the last quarter of 2011. The study is taking place in France, Belgium, Germany, the UK and Spain.

Talampanel
Talampanel
Talampanel is a drug which is being investigated for the treatment of epilepsy, malignant gliomas and amyotrophic lateral sclerosis ..As of May 2010, results from the trial for ALS have been found negative....

 is being tested in ALS by Teva Pharmaceutical Industries
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...

; a Phase II trial was completed in April 2010.

The new discovery of RNAi
RNAI
RNAI is a non-coding RNA that is an antisense repressor of the replication of some E. coli plasmids, including ColE1. Plasmid replication is usually initiated by RNAII, which acts as a primer by binding to its template DNA. The complementary RNAI binds RNAII prohibiting it from its initiation role...

 has some promise in treating ALS. In recent studies, RNAi has been used in lab rats to shut off specific genes that lead to ALS. Cytrx
Cytrx
CytRx Corp. is a biopharmaceutical research and development oncology company in Los Angeles, California.The CytRx oncology pipeline includes three programs in clinical development: bafetinib, tamibarotene and INNO-206...

 Corporation has sponsored ALS research using RNAi gene silencing technology targeted at the mutant SOD1 gene. Cytrx's orally-administered drug Arimoclomol
Arimoclomol
Arimoclomol is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California...

 is currently in clinical evaluation as a therapeutic treatment for ALS.

See also

  • ALS Association
    ALS Association
    The ALS Association is an American non profit organization that raises money for research and patient services, promotes awareness about and advocates in state and federal government on issues related to amyotrophic lateral sclerosis , also known as Lou Gehrig's disease...

  • ALS Society of Canada
    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 , also known as Lou Gehrig’s disease, and to providing support for those living with...

  • NEALS Consortium - The Northeast ALS Consortium
  • ALS Therapy Alliance
  • ALS Therapy Development Institute
    ALS Therapy Development Institute
    The ALS Therapy Development Institute is a non-profit biotechnology company seeking effective treatments for amyotrophic lateral sclerosis . It is a registered 501 non-profit organization in the United States...

  • Multifocal motor neuropathy
    Multifocal motor neuropathy
    Multifocal motor neuropathy 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 because of the similarity in the clinical picture, especially if muscle...

    , a condition often mistaken for ALS
  • Muscular Dystrophy Association
    Muscular Dystrophy Association
    The Muscular Dystrophy Association is an American organization which combats muscular dystrophy and diseases of the nervous system and muscular system in general by funding research, providing medical and community services, and educating health professionals and the general public...

  • The Aging Brain
    Aging brain
    Age is a major risk factor for most common neurodegenerative diseases, including Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Other risk factors, including genetic mutations, low educational attainments and head injury contribute much less to the risk...


External links