CREDIT The offi cial name of the illness is amyo-trophic lateral sclerosis (ALS), but in the U.S. it is better known as Lou Gehrig’s disease. The great New York Yankees fi rst base-man was diagnosed with ALS in 1939 and died two years later from the progressive neuromus-cular disorder, which attacks nerve cells that lead from the brain and the spinal cord to mus-cles throughout the body. When these motor neurons die, the brain can no longer control muscle movements; in the later stages of the dis-ease, patients become totally paralyzed.First described in 1869 by French clinician Jean-Martin Charcot, ALS is a misunderstood illness. Doctors once thought it was rare but now consider it fairly common: about 5,000 people in the U.S. are diagnosed with ALS every year. In total there are about 30,000 ALS patients in the U.S. and approximately 5,000 in the U.K. ALS typically develops between the ages of 40 and 70, but the disease strikes younger and older pa-tients as well. Other well-known people who suffered from ALS include British actor David Niven, Russian composer Dmitri Shostakovich and Chinese leader Mao Tse-tung. Researchers have found unusual clusters of patients with the disorder among Italian soccer players, veterans of the Persian Gulf War and residents of the is-land of Guam, although no one knows why.In his famous farewell address at Yankee Sta-dium, Gehrig called ALS “a bad break,” which was a heartrending understatement. People usu-ally succumb to the disease within three to fi ve years after diagnosis. (A notable exception is Ste-phen Hawking, the renowned physicist of the University of Cambridge, who has lived with ALS for more than 40 years and is still making major contributions to the fi elds of cosmology and quantum gravity despite his physical handi-cap.) Until recently, investigators had few practi-cal ideas for fi ghting the disorder, but in the past several years researchers have made great pro-gress in determining how motor neurons die in ALS patients. In the near future, scientists may develop therapies that could retard the progress of ALS and perhaps even prevent its onset.A Devastating DisorderYou can glean a basic understanding of amyo-trophic lateral sclerosis by parsing its name. MEDICINEResearchers have proposed potential therapies for a paralyzing disorder once thought to be untreatableBy Patrick Aebischer and Ann C. KatoPLAYING DEFENSE AGAINSTLOU GEHRIG’S DISEASEAP PHOTOKEY CONCEPTS■ Amyotrophic lateral scle-rosis (ALS) is a disease that kills motor neurons. Patients become para-lyzed and usually die within three to fi ve years of onset. The most fa-mous victim is legendary New York Yankees player Lou Gehrig (below).■ ALS was once considered nearly impregnable to a scientifi c attack, but re-searchers have recently discovered treatments that can slow the prog-ress of the disease in ro-dents by protecting the axons of motor neurons.■ Investigators are now pre-paring clinical trials to test the effec tiveness of the proposed ALS treat-ments in hum ans. —The Editors86 SCIENTIFIC AMERICAN November 2007“Amyotrophic” is an amalgam of Greek terms: “a” for negative, “myo” for mus-cle and “trophic” for nourishment. Put-ting it all together, the word conveys that the muscles in an ALS patient have no nourishment, so they atrophy or wither away. “Lateral” signifies the area of the spinal cord where portions of the dying nerve cells are located. As this area degenerates, it becomes hardened or scarred. (“Sclerosis” means hardening.) Per-haps the most devastating aspect of the illness is that the higher functions of the brain remain undamaged and patients are obliged to watch the demise of their own bodies.The most common form of the disease is called sporadic ALS because it appears to strike ran-domly, targeting anyone in any given place. Fa-milial ALS is a particular form of the disease that is inherited, but only about 5 to 10 percent of all patients fall into this category. Although the ear-ly symptoms of the disorder vary from one indi-vidual to another, they usually include dropping objects, tripping, unusual fatigue in the arms or legs, diffi culty in speaking, muscle cramps and twitches. The weakness that affects ALS patients makes it hard for them to walk or use their hands for daily activities such as washing and dressing. The disease eventually hampers swallowing, chewing and breathing as the weakening and pa-ralysis spread to the muscles in the trunk. Once the muscles responsible for breathing are at-tacked, the patient must be put on a mechanical ventilator to survive.Because ALS harms only motor neurons, the senses of sight, touch, hearing, taste and smell are not affected. For unknown reasons, the mo-tor neurons responsible for movements of the eyes and bladder are spared for long periods. Hawking, for example, still has control of his eye muscles; at one time he communicated by raising an eyebrow as an assistant pointed to letters on a spelling card. (He can also move two fi ngers on his right hand and now uses a speech synthesizer controlled by a hand switch.) The U.S. Food and Drug Administration has so far approved only one treatment for ALS: riluzole, a molecule that can prolong survival by several months, most likely by curbing the release of harmful chemi-cals that damage motor neurons.What do we know about the causes of this horrible disease? Investigators have put forward a vast number of theories to explain its origin, including infectious agents, a faulty immune system, hereditary sources, toxic substances, chemical imbalances in the body and poor nu-trition. Although scientists have not yet deter-mined what triggers the disorder in most patients, a breakthrough came in 1993, when a consor-tium of geneticists and clinicians discover ed a gene that was responsible for one form of hered-itary ALS that represents approximately 2 per-cent of a ll cases. This gene t urned out to code for an enzyme called superoxide dismutase (SOD1) that protects cells from damage caused by free radicals (highly reactive molecules produced DYING BACK: One of the key breakthroughs in the fi ght against ALS is the fi nding that the degener-ation of the motor neurons begins at the ends of the axon—the nerve cell’s main branch—and proceeds back to the cell body. SCIENTIFIC AMERICAN 87BRYAN CHRISTIE DESIGN88 SCIENTIFIC AMERICAN November 2007in the body by normal metabolic processes).Researchers
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