Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a disorder characterized by loss of nervous control of voluntary muscles, resulting in muscle weakness, wasting, spasticity, and cramping. Degeneration of motor neurons in the brain and spinal cord, leading to the loss of muscle control, is the cause of ALS. A multitude of research has been conducted to attempt to find the cause of ALS. Like so many of the diseases today, there is no single cause, but many contributing factors and cellular dysfunction. Only 20% of the ALS cases are autosomal dominant inherited, out of which only 10% of those cases are linked to a genetic mutation. Many of the genetic mutations found are only observed in a few people and in a small region. Therefore, while the research continues, treatment is done for the symptoms experienced in an attempt to prolong the patient‚s life and in a more comfortable state.

Definition

Amyotrophic Lateral Sclerosis (ALS) is a fatal neuromuscular disorder causing progressive loss of nervous control of voluntary muscles because of destruction of nerve cells in the brain and spinal cord. ^{(2), (3)} In 1869, Jean-Martin Charcot was the first person to describe ALS in scientific literature. He was a French neurologist, explaining why the French today refer to ALS as Maladie de Charcot. ⁽³⁾ ALS is also called Lou Gehrig‚s disease in the United States, due to the fact that Lou Gehrig was a famous New York Yankee baseball player who died of the disease in 1941. He was diagnosed in 1939 at the age of 38. ⁽³⁾ ALS is referred to as Motor Neurone Disease (MND) in England. ⁽³⁾

Epidemiology

ALS has an incidence of about 2 per 100,000 and a prevalence of about 8 per 100,000. Therefore, if one looks at a population of 100,000, one would expect for 2 people to develop ALS, while 8 are living with it. ^{(3), (7)} Approximately 30,000 people are living with ALS in the United States. Every year about 5,000 new cases are diagnosed. ⁽³⁾ ALS occurs in both sexes and all races. Overall, men are more likely to develop ALS; there is a 1.5 to 1.0 ratio until age 60, then the ratio drops to 1 to 1. ⁽³⁾ One study reported that there is a high incidence in western Pacific, including Guam, western New Guinea, and the Kii Peninsula in Japan. ⁽⁴⁾ Although, young people can get ALS, symptoms are normally not seen until adulthood (after age 50). Average age of onset is 55; 80% of cases begin between ages 40 to 70. ALS has been found in persons as young as 12 and as old as 98. ⁽³⁾ Death often occurs within 2 to 10 years. ⁽²⁾ Fifty percent of ALS patients die within 18 months of diagnosis. Only 20% live over 5 years after diagnosis and only 10% live over 10 years. Despite the fact that men are more likely to develop ALS, women seem to live a shorter time once diagnosed. ⁽³⁾ Although most patients die of respiratory problems, it is usually not a painful death. A majority of ALS patients die due to insufficient oxygen, which results in a build-up of blood carbon dioxide levels. High levels of CO₂ make the patient sleepy, similar to the effects of narcotics. Many patients experience breathing discomfort close to the end, so medications are given to ease the discomfort and anxiety, further relaxing the patients. ⁽³⁾

Types of ALS

While ALS appears to run in families, only 5-10% of all ALS cases is hereditary. Familial ALS (FALS) is an autosomal dominant inheritance pattern. ^{(3), (7)} Sporadic ALS accounts for the other 90-95% of ALS cases. This form of ALS is not hereditary and a definite cause has yet to be determined. ⁽³⁾ The high incidence of ALS found on the island nation of Guam prompted scientist to call it Guamian ALS. ⁽³⁾ A subgroup of ALS is Bulbar ALS. It affects 25 % of all types of ALS patients. ALS patients usually have symptoms in their lower or upper limbs for diagnosis of the disease; however, if a patient experiences difficulty swallowing and speaking, followed by limb difficulties, Bulbar ALS is the diagnosis. ⁽³⁾

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Signs, Symptoms and Diagnosis

ALS symptoms range from tripping, stumbling, clumsiness, muscle twitching or cramping, loss of upper limb muscle control to chronic fatigue and difficulty speaking, swallowing, or breathing. Normally upper and lower motor neuron damage characterizes and diagnoses ALS, but there are other areas involved. ⁽³⁾ Lower motor neuron (LMN) signs and symptoms are due to the degeneration of anterior horn cells and cranial motor neurons ⁽⁷⁾; they include muscle weakness, atrophy, fasciculation, hyporeflexia, hypotonicity or flaccidity, and muscle cramping. ^{(3), (7)} Upper Motor Neuron (UMN) signs and symptoms may disappear as weakness progresses; they include muscle weakness, spasticity, stiffness, fasciculation, muscle clonus, hyperreflexia, and pathologic reflexes.^{(3), (7)} Bulbar involvement is due to the effect on lower cranial nuclei in the medulla or the corticobulbar fibers. The signs and symptoms can be predominate in one or mixed UMN and LMN involvement; they include dysphagia, sialorrhea (due to loss of normal swallowing secretions, not excess production), xerostomia, tongue atrophy, hyperactive gag and jaw reflexes, pseudobulbar palsy, laryngospasms, and dysarthia (which is flaccid with LMN and spastic with UMN). ^{(3), (7)} Dementia is rarely a sign of ALS. At least 95% of ALS patients maintain normal cognitive function and sharp mental acuity. This normalcy allows patients to remain involved in their healthcare decision making. ⁽⁷⁾ The sensory and autonomic nervous systems are usually not effected by ALS. About 25% of ALS patients complain about numbness, which is sometimes mistaken as pain. The actual motor neuron damage is not painful, but the cramps, constipation, pressure sores, and swollen feet may cause pain. ^{(3), (7)}

Through the process of elimination, a diagnosis or ALS can be made clinically, but may take weeks to months. According to the El Escorial World Federation of Neurology criteria for ALS diagnosis requires both UMN and LMN findings in the bulbar region and at least 2 spinal regions, or UMN and LMN in 3 spinal regions (cervical, thoracic, and lumbosacral). ⁽⁷⁾ Sensory function impairment should be absent or minimal; there must show progression of the disease and have no other known causes to be diagnoses as ALS. An electromyogram (EMG) will indicate loss of muscle function caused by lack of nervous stimulation. Abnormal images may be seen on a MRI of an ALS patient. ^{(3), (7)}

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Causes and Contributing Factors

Contributing factors, such as environmental toxins, may have some relationship to ALS, but are not necessarily causative factors. These factors include exposure to agricultural chemicals, environmental lead and manganese, brain and spinal cord trauma, use of pneumatic tools, dietary deficiencies or excess, selenium in drinking water, damage to DNA, and exposure to electric shocks. Some people believe there is some significance because there seems to be a higher incidence of ALS among airline pilots, electric utility workers and those exposed to agricultural chemicals. ⁽³⁾ Beyond the environmental factors, reactive oxygen species, glutamate excitoxicity, neurofilament accumulation, autoimmunity, and genetics may indirectly cause ALS. ⁽⁷⁾

Genetic mutations have been found to cause about 20% of the FALS cases, which are only 2% of the total population. This little amount of information leaves 98% of ALS patients with no cause for their disease; therefore, many theories have been proposed to give some insight on the cause of the neuron degeneration and muscle damage. ⁽³⁾ Although discussed later, oxidative injury may be due to the free radicals, which will damage parts of the cell if not converted to a safer compound. There are several theories for the build up of free radicals, including glutamate excitoxicity and genetic variations. Many ALS patients try to neutralize the free radicals by taking over-the-counter Coenzyme Q₁₀ and vitamin E. ⁽³⁾

Glutamate is a nonessential amino acid, which functions as a major excitatory neurotransmitter in the brain. If glutamate is not removed after nerve cells signal, it will accumulate in excess. This phenomenon could be due to impaired astroglial GLT-1 transporter, reducing glutamate transport, leading to neurotoxicicty. ^{(3), (7)} Since glutamate over stimulates specific neuronal metabolic functions, an excess of it in the synaptic cleft triggers a cascade of events that encourages cell death. ⁽³⁾ One disturbed function that could cause ALS is an elevated intake of calcium by motor neurons, which disrupts cellular functions. Glutamate transporters bind to N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the anterior horn cells. When binding to the non-NMDA receptors occurs, there is a possibility of toxicity because these receptors permit the influx of sodium ions and calcium. Cytosolic calcium activates a number of enzymes including proteases, xanthine oxidase (XO), phospholipase A2 (PL-A2) and nitric oxide synthetase (NOS). Some of these (PL-A2 and NOS) form free radicals, superoxide anions, and nitric oxide, which are all toxic. These highly charged, destructive molecules will degrade the motor neurons, leading to ALS. ⁽⁷⁾

Neurofilament accumulation in large swellings in the proximal axon of motor neurons is a characteristic pathologic feature of ALS. Seen in motor nerve cell bodies and their proximal axons, high accumulations are thought to cause oxidative damage. ⁽⁶⁾ If the axon becomes tangled, it is no longer able to transport nutrients from the cell body to the end of the axon. It is believed that the motor nerve cell may die slowly of strangulation.⁽³⁾

Two different mutations in the heavy neurofilament subunit (NEFH) gene have been identified in sporadic ALS patients. One mutation thought to cause ALS was the deletion in the C-terminal KSP repeat region of the NEFH gene in 5 of 356 patients with sporadic ALS. However, the study was inconclusive, leading one to believe the mutation of the KSP repeat was not the cause of the disorder for FALS; however, the mutation could effect motor neuron degeneration. ⁽⁶⁾ The second mutation was also observed in transgenic mice that had the mutation or an over-expression of the normal gene, who later developed ALS. It is believed that the defective axonal transport found in mice that have the human NEFH gene, shows a mechanism for motor neuron cell death in ALS. ⁽⁶⁾

At least two studies found that a transgenic mouse with an aberrant neurofilament light subunit (NEFL) is found to undergo motor neuron degeneration, perhaps due to neurofilament accumulations, leading to paralysis and ALS. ^{(4), (6)} Despite the fact that there are a limited number of studies done on neurofilament mutations, there is adequate evidence that motor neuron degeneration, which can lead to ALS, is in part due to the abnormal accumulation of neurofilaments.

Some believe antibodies to voltage-gated calcium channels may lead to the increase of calcium influx by leaving the gates open longer in nerve cells. This increase in calcium can cause nerve cell damage and death by activating intracellular enzymes. ⁽³⁾ As discussed previously, glutamate release may be stimulated by this antibody mediated calcium increase, which leads to further increase of calcium release and nerve cell damage. ⁽³⁾ On the other hand, some trials have been done to show that immune-modulating therapies for ALS are ineffective, therefore leaving doubt that ALS is due to an autoimmune process. ⁽⁷⁾

Causative factors of ALS are a highly researched area, especially looking at genetic mutations and variations. One commonly researched genetic component is the Copper/Zinc Superoxide Dismutase (SOD 1) gene. A normal Cu/Zn SOD 1 protein acts as a cytosolic enzyme that converts toxic superoxide anions to hydrogen peroxide and oxygen. There are thought to be at least 46 different SOD1 mutations, but the precise mechanism for causing ALS is unknown. ⁽⁸⁾ Twenty percent of FALS cases have mutations in the Cu/Zn SOD1 gene, located on chromosome 21. The other 80% have unknown causes. ⁽⁸⁾ In some FALS patients, there is a reduced amount of Cu/Zn SOD activity. However, it is unknown if the cause of motor neuron injury is due to the increased amounts of superoxide that are not converted to hydrogen peroxide and oxygen, or if it is the actual mutant enzyme causing neuron injury. ⁽⁷⁾ Mutant SOD may increase superoxide free radicals, which in turn, increase the rate of reaction of nitric oxide and the free radical. This reaction forms a strong oxidant, peroxynitrite, which again, can interact with the superoxide to form nitronium ions. These ions will cause nitration of proteins and injury to motor neurons. ⁽⁷⁾

The most common SOD1 mutation is the ala4val mutation. It is also associated with the most rapid progression of disease. This missense mutation results from a substitution of cytosine (C) to thymine (T) at codon 4 (GCC to GTC). This causes a substitution of amino acid alanine to valine (ala4val). Comparing this mutation to glul10gly, it is found that ala4val mutation causes shorter life duration compared to all other mutations. ⁽⁴⁾ The second most common SOD1 identified is the mutation at codon 113 of T to C (ATT to ACT), causing an amino acid change from isoleucine to threonine (ile113thr). ⁽⁴⁾ A gly93ala mutation has been observed in mice displaying ALS symptoms of motor neurons degeneration, along with accumulation of phosphorylated neurofilaments. ⁽⁶⁾ As discussed earlier, this accumulation could lead to strangulation of the axons, or oxidative injury.

One study found that a patient with rapid progression of FALS had a point mutation in exon 2 of the SOD 1 gene at codon 48 (CAT), which changes T to G, therefore, changing a histidine to glutamine. ⁽⁸⁾ The mutation was found by extracting the patient‚s DNA. Then Polymerase Chain Reaction (PCR) amplification of the four exons that are normally transcribed (1,2,4,5) from the SOD1 gene was performed using a published primer sequence. The PCR fragments were then analyzed by single strand conformational polymorphism (SSCP). If an abnormal migration pattern was seen, the fragments were further subcloned using the pGEM vector system to compare the mutated versus the normal clone to find the mutation believed to cause FALS. ⁽⁸⁾

Research done on families in the UK found that there are 10 different heterozygote missense point mutations in 8 different SOD-1 codons, and a novel 2-base frameshift insertion (132insTT) which causes aspartate to be read at codon 132, instead of glutamate. Also, a premature stop codon (TAA) is read at 133, leading to early cutting of the protein. Although this is important, it is not accurate to use as prediction of a prognosis. ⁽⁵⁾ The mutation was found when DNA was extracted from lymphocytes and the five exons of SOD1 were amplified using PCR and biotinylated primers. The fragments were then denatured and separated into single strands. Another set of primers was used to identify the mutations on exon 5, and the strands were sequenced using deoxy chain termination method and a labeled ATP. This confirmed the mutation on both sense and antisense sequences. This study only looked at FALS, not sporadic ALS patients or normal people. ⁽⁵⁾

While Cu/Zn SOD-1 is researched heavily, there are other genetic mutations that are believed to cause motor neuron degeneration, including leukemia inhibitory factor and EAAT2 protein. Leukemia inhibitory factor (lif) is a glycoprotein expressed by Schwann cells after a nerve lesion; it plays an important role in regeneration and maintenance of nerve cells. ⁽¹⁾ A point mutation was found at position 3400 in the DNA sequence of lif showing G to A substitution, which causes an amino acid change at position 64 in the mature lif protein (valine to methionine). The experimental sequenced DNA was compared to the lif DNA sequence deposited in GenBank (accession number M63420). ⁽¹⁾ All patients were heterozygous for this mutation, with no correlation between the lif gene mutation and clinical onset, age, or disease progression. However, there is a significantly higher frequency of this mutation in ALS patients, perhaps due to an increase in function of the mutant protein. The mutation position is in the region of the lif protein (AB loop), which interacts with the lif receptor. ⁽¹⁾ Although the finding of this mutation may be helpful in some definitive cause, it cannot be ruled out that other genetic mutations are not contributing to the neuron degeneration at the same time.

EAAT2 is protein that normally deactivates and recycles glutamate. John Hopkins researchers found that many sporadic ALS patients (65%) have little or no EAAT2 in certain areas of the brain and spinal cord, which leads to an excess of glutamate that kills the nerve that control muscles. ⁽³⁾ It is believed that the problem is in the way the nerve cells are transcribing DNA code for EAAT2 into RNA. The cells are cutting out some useful exons and keeping some useless introns, which produces a defective RNA, in turn producing a defective EAAT2 protein or no protein at all. ⁽³⁾ The cells were found to be cutting and pasting randomly instead of at specific sites, which could be due to an acquired or inherited mutation in the intron of EAAT2 inititating the cell to edit at the wrong places. The exact mutation has yet to be determined. This mutation was not found in the brain tissue of 12 normal subjects or 16 patients with Huntington‚s disease, Alzheimer‚s or spinal muscular atrophy. ⁽³⁾

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Treatments

Since there is no known cure for ALS, treatment is used to control the symptoms. Baclofen or diazepam is sometimes used to control spasticity, which interferes with daily life. Trihexyphenidyl or amtriptyline is used often to help people with impaired ability to swallow saliva, hence decreasing drooling, and patient embarrassment. ⁽²⁾ Physical and speech therapy, rehabilitation, use of braces/wheelchairs, and orthopedic intervention are used commonly to allow a patient to prolong muscle use for daily activity. ^{(2), (3)} Since choking is a common symptom, ALS patients often need the placement of a feeding tube in stomach (gastrostomy) early in progression of ALS. ⁽²⁾ In hopes of keeping the chest muscles from tightening, daily exercise with a spirometer is recommended. Eventually during their progress, most ALS patients will require a ventilator to breathe. ⁽³⁾

Besides treating the symptoms, some patients are able to slow the progression of the disease, if diagnosed early enough. Rilutek® (riluzole) is thought to prevent nerve cell degeneration by decreasing glutamate production, inactivating sodium channels, or by interfering with transmitter binding of amino acid receptor; therefore, slowing the progression of the disease. ⁽³⁾ Rilutek® (riluzole) is a member of the benzothiazole class and the action of how this drug slows the progression of ALS is still unknown. ⁽³⁾ United States FDA granted riluzole status as an orphan drug in 1993, intended for the use of this rare disease (less than 200,000 diagnosed), when other treatments are not available. ⁽³⁾

Inosine is a protein that is thought to be a master switch to turn on genes involved in the growth of nerve cells, to regenerate injured cells. In rats it caused nerve cells to sprout new axons, by the way of inosine entering the cell and activating a protein kinase enzyme that in turn controls the cell‚s program for axon growth. Researchers are still working on this project. ⁽³⁾

Emotional support is vital in coping with the disorder, especially since mental functioning is not affected. Depression in ALS patients and their caregivers is common. Antidepressants are often given to reduce the depression. ALS patients also benefit from counseling and a strong network of supportive family and friends. There are ALS support groups, such as, PALS- person(s) with ALS and CALS- caregiver(s) of PALS. ⁽³⁾ These groups help patients and their families cope with ALS by educating them on what to expect from the disease and different treatment options for various symptoms. Many ALS patients must secure health insurance or government assistance (Medicare/Medicaid) early after diagnosis due to the fact that ALS is an extremely expensive disease. From medications and therapy to home health aids or skilled nursing care, costs can exceed $30,000 a year. Patients and their families are also educated about end of life decisions, such as, living wills, advanced directives, and patient final wishes. ALS patients need to discuss this sort of information with their families and caregivers early after diagnosis, before speech and communication skills have ceased.

References

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1. Giess R, Beck M, Goetz R, Nitsch M, Toyka KV, Sendtner M. Potential role of LIF as a modifier gene in the pathogenesis of amyotrophic lateral sclerosis. Neurology 2000; 54 (4) http://www.mdconsult.com/

2. http://health.yahoo.com/health/diseases_·myotrophic_lateral_sclerosis/index2.html

3. http://www.lougehrigsdisease.net.html

4. Juneja T, Pericak-Vance MA, Laing NG, Dave S, Siddique T. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase. Neurology 1997; 48 (1): 55-57. http://www.mdconsult.com/

 5. Orrell RW, Habgood JJ, Gardiner I, King AW, Bowe FA, Hallewell RA, Marklund SL, Greenwood J, Lane RJM, deBelleroche J. Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. Neurology 1997; 48 (3): 746-751. http://www.mdconsult.com/

 6. Rooke K, Figlewicz DA, Han F, Rouleau GA. Analysis of the KSP repeat of the neurofilament heavy subunit in familial amyotrophic lateral sclerosis. Neurology 1996; 46 (3): 789-790. http://www.mdconsult.com/

7. Ross MA. Acquired Motor Neuron Disorders. Neurologic Clinics 1997;15 (7):481-491. http://www.mdconsult.com/

8. Shaw CE, Enayat ZE, Powell JF, Anderson VER, Radunovic A, Al-Sarraj S, Leigh PN. Familial amyotrophic lateral sclerosis: molecular pathology of a patient with a SOD1 mutation. Neurology 1997; 49 (6): 1612-1616. http://www.mdconsult.com/

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