Amyotrophic lateral sclerosis (ALS) is a progressive and generally fatal neurological disorder of upper and lower motor neurons, causing weakness, muscle wasting, abnormal muscle contractions (fasciculations) and altered muscle tone and reflexes. Emotional or cognitive disturbances rarely occur. The cause is not yet known, although a few potential causative factors have been identified and a small percentage of cases appear to have a genetic basis.
The diagnosis is customarily made clinically and by exclusion of some other conditions, but some abnormalities of the electromyogram (EMG) are also characteristic. Treatment is largely ineffective, and attention is mainly directed toward management of the various symptoms; most patients die of respiratory complications within 5 years and almost all within 10 years. There have been many high-profile ALS cases, including baseball great Lou Gehrig, whose name is often given to the disease, and there are a few noted examples of long survival, chiefly theoretical physicist Stephen Hawking [1].
Quote:
- The disease has also been named after Jean-Martin Charcot, who first described it comprehensively as with many other neurological disorders.
- The first clinical observation of probable ALS, emphasizing weakness and wasting, was made by Charles Bell in 1836, and Augustus Waller described the degeneration of motor nerve fibers that came to bear his name in 1850.
- The condition was at first called progressive muscular atrophy, a term also applied to various muscle and peripheral nerve disorders, and a similar condition but with upper motor neuron features like spasticity and increased reflexes was identified in the 1860s.
- Charcot differentiated a disease of motor neurons from other neuromuscular disorders in 1874, and introduced the name the disease now carries.
- The first comprehensive neurological textbooks, by Gowers in English and Oppenheim in German, suggested that ALS cases could involve upper or lower motor neurons, or both, with different symptom profiles, and the term “motor neuron disease” that is now used interchangeably with ALS was suggested for this complex of symptoms by Sir Russell (later Lord) Brain in 1933 [2].
CLINICAL FEATURES
- The cardinal manifestations of ALS are muscular weakness and atrophy, beginning with clumsiness, impaired fine motor skills, stiffness or aching of an arm or leg in about 75 per cent of patients (limb-onset).
- Bulbar (brainstem) onset occurs in 25 per cent of cases, with slurred and nasal speech, impaired articulation and difficulty swallowing.
- About 3 per cent of patients have early involvement of the intercostal muscles and experience early breathing difficulties along with other symptoms (respiratory onset).
- Cognitive changes can be found with careful interview or neuropsychological testing in 30 to 50 per cent, although only about 5 per cent of patients develop frontotemporal dementia (formerly called Pick’s disease) with cognitive impairment, difficulty with expressive and receptive language, apathy and blunted emotions and sometimes irascible or inappropriate behavior. Sensation and autonomic nervous system function are almost always spared [3].
Quote:Fasciculations are localized contraction and relaxation of muscles that can be seen under the skin and that represent the discharge of individual motor neurons and the muscle fibers they activate; there are many causes for fasciculations, most of them benign, but widespread fasciculations and in particular involvement of the tongue are indicative of motor neuron disease.
Fasciculations in the EMG are especially ominous, and the EMG is also commonly obtained to exclude muscle disease, while nerve conduction velocities are also measured and are normal in ALS but slowed in peripheral nerve disorders. MRI and other imaging studies are likewise normal, but may be obtained to exclude lesions of the brain stem or cervical spinal cord that can mimic these symptoms [4].
- The disease is progressive but the symptoms are variable, and patients who have bulbar symptoms, lower motor neuron features such as decreased muscle tone and reflexes, respiratory involvement and frontotemporal dementia at onset progress more rapidly.
- Spasticity, hyperactive reflexes and other upper motor neuron features may predict slower progression, as may symptom onset before age 40, symptoms confined to one limb or being slightly overweight.
- The extraocular muscles, which have motor units which are much smaller and more numerous than the other skeletal muscles, are not involved until late in the disease course, probably because of the greater supply of motor neurons; as a result, eye movements may be preserved when other motor function is lost.
- Most patients lose the function of arms and legs and generally speech as well, and will eventually require a feeding tube to avoid aspiration of food and a ventilator on account of respiratory muscle failure [5].
Functional state is usually measured by the 12-point ALS Functional Rating Scale (Revised) or ALSFRS-R, and patients lose on average 0.9 points per month [6]. The median survival from onset to death is 39 months, and 96 per cent of patients are dead after 10 years [7].
Quote:In addition to Lou Gehrig, a number of athletes have developed ALS, including American football player Steve Gleason and British footballer Don Revie, fitness expert Augie Nieto and a later New York Yankee, “Catfish” Hunter.
Actor Sir David Niven was also a highly fit competitive sailor, and many musicians noted for dexterity died of ALS, including composer Dmitri Shostakovich, rock guitarists Dan Toler and Mike Porcaro and jazz bassist Charles Mingus.
These and other cases have suggested a relationship between physical fitness or agility and ALS risk. Noted political figures with ALS have included New York senator Jacob Javits and Chinese leader Mao Zedong.
The most prominent celebrity case of ALS, however, is physicist Stephen Hawking, who became one of the world’s best-known scientists despite inexorably progressive ALS of very atypically long duration, and who has pioneered the use of multiple adaptive technologies to continue working despite profound neurological deficit. Hawking’s advocacy and widely-noted example has contributed to the popularity of the “ice bucket challenge” as a fund-raising device for ALS research [8].
EPIDEMIOLOGY
ALS is estimated to affect 1 to 3 individuals per 100,000 in the United States Caucasian population, with approximately 5,500 new cases diagnosed annually and about 30,000 active cases. In Europe the disease affects approximately 2.2 individuals per 100,000 per year, predominating among Caucasians. The disease is infrequent among non-Caucasians. Occasional clusters of ALS have been encountered, in the United States in New Hampshire, Vermont, Northeastern Ohio, and Texas among other places, and in several former San Francisco 49er football players. Several proximate cases were also found among Italian and British footballers, and there have been several reports of conjugal ALS affecting husbands and wives in France and Italy, in addition to the small percentage of ALS cases that are hereditary [1].
GENETICS
Between 5 and 10 per cent of ALS cases are apparently familial, and first-degree relatives of ALS patients have a risk of about 1 per cent for developing the disease [9]. The most common familial forms of ALS are associated with a series of autosomal dominant mutations of a gene on chromosome 21 coding for the enzyme superoxide dismutase that is prominently involved in antioxidant protection of tissues from toxic free radicals. These comprise about 20 per cent of familial ALS cases, and represent about 2 per cent of all ALS patients. The SOD1 mutation is associated with rapidly progressive ALS and has been described in North American cases; Scandinavian patients have been described with a slightly different mutation called D90A-SOD1, and have a more indolent disease lasting on average 11 years from onset to death. These mutations may result in an ineffective antioxidant enzyme and accumulation of free radicals with resultant motor neuron damage [10].
Another mutation associated with ALS is a C9orf72, a hexanucleotide repeat on chromosome 9 that has been found in about 6 per cent of European ALS cases, almost all of them with frontotemporal dementia. The mutation has also been found in ALS cases in the Phillipines, and Filipinos are third behind white Americans and Europeans in ALS incidence. The mutation consists of hundreds or repetitions of the nucleotide sequence GGGGCC, which is normally repeated only a few times, and which when excessively repeated may interfere with the normal expression of some protein involved in nerve function [11].
There are many other mutations associated with familial ALS, particularly ALS plus dementia. These cases are often dominantly inherited and linked to the X-chromosome, and are sometimes juvenile in onset, whereas the vast majority of ALS otherwise occurs in middle age and after. The UBQLN2 gene on the X-chromosome ordinarily codes for ubiquilin 2, a protein involved in the breakdown of proteins in motor neurons, and mutation there is thought to result in a nonfunctional gene product that allows the accumulation of harmful damaged proteins [12]. The several other mutations have to date been described only in single families or individuals with ALS, and in all of these cases it is not yet clear what gene product or products are being interfered with to incite the motor neuron degeneration.
CAUSES OF ALS (Amyotropic Lateral Sclerosis)
The cause of amyotrophic lateral sclerosis is unknown, but the etymology of its name, meaning in Greek no muscle nourishment, reflects the traditional belief that some trophic or nourishing factor for motor neurons is absent or becomes deficient. More recent suggestions have involved the accumulation of toxic factors or cell breakdown products, as is becoming apparent in some of the dementias that sometimes coexist with ALS. The chief anatomical feature is death of upper and lower motor neurons in the spinal cord, brain stem and cerebral cortex, preceded by the accumulation in the cell bodies and axons of inclusions, aggregates of proteins that are normally removed or destroyed. Several proteins have been shown to accumulate in ALS: superoxide dismutase, TAR (transactive response) DNA binding protein (TARDBP) and FUS, which is short for RNA binding protein FUSed in sarcoma/translocated in sarcoma. Superoxide dismutase is a protective antioxidant enzyme, while TARDBP and FUS normally stabilize RNA and regulate its transcription in cells but have been shown to accumulate in neurons in frontotemporal dementia and the dementia associated with parkinsonism. These accumulated proteins generally have ubiquitin attached to them; ubiquitin, discovered in 1975 and found almost everywhere in the nervous system (i.e., ubiquitously, hence its name) is a regulatory protein attached to other proteins that are earmarked to be broken down and cleared from the cell. It is likely that these proteins have been tagged for disposal but the protein breakdown system has failed to dispose of them. As a result they accumulate and eventually kill the motor neuron, and when one-third of the motor neurons have been destroyed the symptoms of ALS begin to appear [9].
It is not known why protein disposal fails, but the genetic findings described above could explain the coexistence of familial ALS and dementia. In the other 90 per cent of cases, there is evidence of an increase in blood and spinal fluid of the excitatory neurotransmitter glutamate, which may be toxic to motor neurons and which is reduced by riluzole, the only drug to date to have even minimal effect on the disease13. Branched-chain amino acids, present in the diet and also a common dietary supplement, have been suggested to cause motor neuron hyperexcitability and calcium absorption, which can lead to cell death14. Prions, small proteins that can be transmitted between people and animals as viruses are, can cause neurological disease by interfering with the folding of major cellular proteins and rendering them inactive, and have been implicated in bovine spongiform encephalopathy (“mad cow” disease), Jakob-Creutzfeldt disease and several other conditions; prion-induced protein misfolding has also been suggested as a cause of ALS [15].
TREATMENT OF ALS (Amyotropic Lateral Sclerosis)
The only medication approved for ALS in the United States and United Kingdom is riluzole, a glutamate antagonist which modestly but significantly lengthened survival time after diagnosis, particularly with the brainstem and lower motor neuron signs and symptoms that are prognostically negative. It does not improve the disability or restore damaged or dead motor neurons, however, and liver toxicity must be watched for [16]. The various medical treatments for spasticity and pain are appropriate, amantadine has been used for fatigue and anticholinergic drugs such as older antiparkinsonian agents and tricyclic antidepressants will reduce saliva and lessen the risk of aspiration [5].
Most therapeutic trials for ALS have been discontinued early on account of lack of efficacy or adverse effects. Recent trials of adult stem cells by Israeli investigators have shown not only prolongation of survival but also slowing of the rate of disease progression as measured by the ALSFRS-R and a strong effect on the rate at which lung function declined, which is the major determinant of ALS mortality. The stem cells are reprogrammed into astrocyte-like cells which secrete glial cell line-derived neurotrophic factor (GDNF), a widely-distributed protein that has been shown to prevent cell death in Parkinson’s disease and ALS. The reprogrammed cells originated in the patient’s own bone marrow, so can be reintroduced without triggering an immune response. The Food and Drug Administration has approved the stem cell regimen for “fast track” trials in ALS in the United States, and a library of pluripotent adult stem cells from ALS patients has been developed at Johns Hopkins University for further studies [17].
CONTRIBUTIONS OF BIOTECHNOLOGY
The extraction, redifferentiation and reinfusion of stem cells so as to deliver neuroproduction to diseased motor neurons is an illustration of the potential benefits that biotechnology can offer a serious neurological disorder historically resistant to medical therapy. The long career of Stephen Hawking is another illustration of the assistance that technology can give to continued high-level functioning in neurological disorders. A series of computer-based voice simulations have been developed for his use over the years, initially controlled by his functioning hand but later using a dwindling number of functioning facial muscles. As these have deteriorated, infrared glasses have been used to detect minimal cheek muscle contractions to activate the speech synthesizer. A backup system has been developed for switch activation by facial expression, making use of the extraocular muscle preservation that is characteristic of the disease, and he is currently working on direct brain activation of communication devices using a single-channel device for acquisition of the electroencephalogram (EEG) signal long used for neurologic diagnosis and subjecting his EEG to frequency analysis, the output of which can be used as a trigger for assistive equipment [18].
REFERENCES
1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011). Amyotrophic lateral sclerosis. Lancet, 377(9769): 42-55.
2. Turner MR, Swash M, Ebers GC (2010). Lockhart Clarke’s contribution to the description of amyotrophic lateral sclerosis. Brain, 133(11): 3470-3479.
3. Hardiman O, van den Berg LH, Kiernan MC (2011). Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol, 7(11): 639-649.
4. Brooks BR, Miller RG, Swash M, Munsat TL (2000). El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler, 1(5): 293-299.
5. Eisen A (2009). Amyotrophic lateral sclerosis: A 40-year personal perspective. J Clin Neurosci, 16(4): 505-512.
6. Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz M (2010). Clinical significance of the change of decline in ALSFRS-R. Amyotroph Lateral Scler, 11(1-2): 178-180.
7. Turner MR, Parton MJ, Shaw CE, Leigh PN, Al-Chalabi A (2003). Prolonged survival in motor neuron disease: a descriptive study of the King’s database, 1990-2002. J Neurol Neurosurg Psychiat, 74(7): 995-995.
8. Stephen Hawking serves as a role model for ALS patients. CNN, April 21, 2009.
9. Sontheimer H (2015). Diseases of the Nervous System. Waltham, MA, Academic Press, pp. 165-172.
10. Battistini S, Ricci C, Lotti EM, Benigni M, Gagliardi S, Zucco R, Bondavalli M, Marcello N, Ceroni M, Cereda C (2010). Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene. J Neurol Sci, 293(1): 112-115.
11. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9-linked FTD and ALS. Neuron, 72(2): 245-256.
12. Deng H-X, Chen W, Hong S-T, Boykott K, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Dankervoort S, Bigio H, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011). Mutations in UBQLN2 gene cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature, 477: 211-215.
13. Al-Chalabi A, Leigh PN ( 2000). Recent advances in amyotrophic lateral sclerosis. Current Opinion in Neurology, 13(4): 397–405.
14. Manuel M, Heckman CJ ( 2011). Stronger is not always better: could a bodybuilding dietary supplement lead to ALS? Exp Neurol, 228(1): 1-5.
15. Rodgers KJ ( 2014). Non-protein amino acids and neurodegeneration: The enemy within. Exp Neurol, 252(3): 192-196.
16. Miller RG, Mitchell JD, Lyon M, Moore DH (2007). Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database System Rev, 1: CD001447.
17. Li Y, Balasubramanian U, Cohen D, Zhang P-W, Mosmiller E, Sattler R, Maragakis NJ, Rothstein JD (2015). A Comprehensive Library of Familial Human Amyotrophic Lateral Sclerosis Induced Pluripotent Stem Cells. PLOS One, 10(3): e011826. doi 10.1371/journal.pone.0118266.
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