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TEXT Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that affects as many as 20,000 Americans. It was first described in scientific literature in 1869 by a French neurologist named Jean-Martin Charcot. ALS is often referred to as Lou Gehrig`s disease after the 1930s baseball hero who was diagnosed with ALS in 1939. This disease belongs to a group of disorders called motor neuron disease. Specific nerve cells in the brain and spinal cord that control voluntary movement gradually degenerate during ALS. As a result, the muscles under their control weaken and waste away, leading to paralysis. ALS can affect patients differently depending on which muscles are weakened first. Symptoms of ALS can include tripping and falling, loss of motor control in hands and arms, difficulty speaking, swallowing and breathing, persistent fatigue, and twitching. ALS strikes in midlife usually affecting men about twice as much as women. ALS is typically fatal within five years after diagnosis (Pharminfonet 1). There are three types of ALS called Guamian, sporadic, and familial. Guamian refers to the high incidence of ALS on the island nation of Guam. Sporadic ALS accounts for about 90% of all patient cases. The cause of this none hereditary form of ALS is still a mystery although many researchers believe that environmental factors play a large role. Familial ALS accounts for 10% of all cases and is hereditary. An autosomal dominant gene passes this form. Although offspring have a 50% chance of acquiring the defective gene, not everyone with the defective gene inherits the disorder. Researchers now believe that this form of ALS is caused by a genetic mutation, which slows axonal transport. These mutations have been linked to mutations in the gene codes for superoxide dismutase (SOD1). Twenty percent of familial ALS cases have a specific gene defect in SOD1 (Eshleman 4). Researchers are unsure of the cause of ALS, but they do know that an excess of a neurotransmitter called glutamate clogs the synapse of the nerve cell, which prevents transmission of neural impulses. Several theories attempt to explain this phenomenon, but none have been directly supported by data. Largely the process of elimination achieves the diagnosis of ALS. It may take several months to diagnose a patient with ALS because early symptoms are similar to a variety of other neuromuscular diseases. Magnetic Resonance Imaging (MRI), electromyogram (EMG), muscle biopsy, and blood tests are used as diagnostic test for determining whether or not a patient has ALS. The major factor in the diagnosis of ALS is if the patient exhibits damage in both upper and lower motor neurons. Missense mutations in the SOD-1 gene are the cause of familial ALS. SOD-1 is located in the long arm of chromosome 21. It is responsible for encoding the enzyme copper/zinc superoxide dismutase and is 560 base pairs long (see appendix 1). There are five exons associated with the SOD-1 gene. Mutations causing ALS have been located in all the exons except exon 3. This absence of mutation in exon 3 has been attributed to a critical function of this exon; its integrity is necessary for the toxic effect of mutant SOD-1. It has been suggested that such a mutation may be lethal rather than lead to an adult onset disease. In one such mutation, a leusine is substituted with a phenylalanine at position 84 in exon 4. Over fifty different point mutations have been described involving exons 1,2,4, and 5 (see appendix 2). Another mutation in exon 4 from GAC to GTC resulted in the replacement of Asperagine with valine at position 90. The function of the enzyme is to destroy radicals, which are normally produced within the cells and are toxic to biological systems. When free radicals are allowed to build up the result is death of the motor neurons, the nerve cells affected in ALS (Marx 1393).Superoxide dismutase was called indophenoloxidase in earlier research of the enzyme. To analyze this enzyme, starch gels were stained by the phenazine-tetrazolium technique. Blue bands appeared to mark the site of the isoenzymes that are being researched. Also, light or achromatic areas appeared on the gel. The bands show the effects of the protein that oxidizes tetrazolium dyes in the presence of phenazine and light (MEDLINE 1).In other research, it was found that susceptibility of ALS might be due to deletions or insertions in the gene that codes for the heavy neurofilament subunit. Most research done on ALS focuses on specific families. One family studied showed x-linked dominant inheritance due to the late onset in females and the lack of male to male transmission (Wilkins 1977).Glutamate, the primary excitatory neurotransmitter in the brain, can exert specific neurotoxic and induce neuronal degeneration in vivo and in vitro. It has been suggested that the metabolism of glutamate is abnormal in patients with ALS. Research from a study hypothesized that the high-affinity glutamate transporter is the site of the defect. Inactivating the primary mechanism of glutamate and aspartate requires their removal from the extracellular space by a sodium-dependent transport system in astrocytes and neurons. Associated with this mechanism are high-affinity and low-affinity carriers. The low-affinity carrier is used in general metabolic activities. The high-affinity carrier is a component of the glutamate neurotransmitter system and is responsible for clearance of neurotransmitter glutamate from the synaptic cleft. This carrier does not distinguish between glutamate and aspartate. It has been shown that inhibiting glutamate transport is toxic to neurons. This is probably because of elevated levels of extracellular glutamate. A suggested mechanism for the elevated cerebrospinal fluid concentration of glutamate and aspartate in ALS patients could be deficient transport into cells (Rothstein 1992).Another mutation called murine motor neuron degeneration (Mnd) causes late onset progressive degeneration of upper and lower neurons. The Mnd gene was mapped in the mouse to proximal chromosome 8 by using endogeneous retroviruses as markers. From this study it was suggested to study human chromosome 8 between family members related to ALS patients (Messer 1992).Researchers at John`s Hopkins University described a study of one glutamate transporter EAAT2. They examined tissues from twenty people who had died from ALS and found that ten had frequently harbored mutations in the genetic instructions used to construct that crucial transporter. In order to build the proteins, cells normally use gene`s exons to create mRNA molecules. Some lacked a copy of the gene`s exons. Other contained introns in place of the gene`s final exon. They found that these mRNAs do not produce functional glutamate transporters. The mutant mRNAs and resulting absence of EAAT2 may explain an earlier finding that ALS patients have problems clearing glutamate. They speculate that the EAAT2 gene may contain mutations in these patients, but have not identified any so far. This finding may lead to the development of a specific test enabling physicians to diagnose ALS early in the disease process and improve therapies for patients (Travis 1996).The detection of ALS is a slow process, which may take several months to accomplish. The process of elimination largely does the diagnosis. Many different tests such as MRI, EMG, and blood tests are used to help determine ALS, but there is no specific test designed to give definite results. A study has been done on sporadic ALS patients where the patients were given recombinant human insulinlike growth factor-I (rhIGF-I). Progression of functional impairment in patients receiving high doses was 26% slower than in patients receiving the placebo (Lai 1997). There is one FDA approved drug called Rilutek, which slows progression of the disease. There are also a number of other medications used to relieve the symptoms of ALS. Therapies, supplements, and proper nutrition can also be part of a treatment plan. There is promising research being done currently on the over-the-counter supplement called Creatine. It has been shown in rats to be effective in preventing ALS (Eshleman 5).ALS is a disorder that has prominently been mentioned as justification for assisted suicide. Research in the states of Oregon and Washington surveyed ALS patients who mostly said they would consider assisted suicide. Many would request a prescription for a lethal dose of medication well before they intended to use it. Many feel that they are a burden to their family because of the complete loss of function they will endure. On the other hand, some patients opt to live for a long as possible, requesting a tracheotomy and assisted ventilation (Ganzini 1998).ALS is a particularly depressing and disabling disease. The way in which each patient responds to their diagnosis is very dependent upon their view of life. Each patient deals with their illness in a way unique to their own experience. Hopefully with the advances in genetic and medical research, treatment and prevention of ALS can be achieved.