STUDY SUGGESTS LOSS OF ZINC FROM SOD1 COMMON TRIGGER FOR ALL ALS

Although genetic defects that affect an enzyme called superoxide dismutase 1 (SOD1) were identified in 1993 as the cause of some cases of familial (inherited) ALS, the way that this mutated enzyme leads to ALS is still not clear. Meanwhile, even less is known about the cause of the disease in the 98 percent of people with ALS who don't have mutations in the SOD1 gene.

Still, many researchers think that the ability of defective SOD1 to cause symptoms indistinguishable from those seen in the sporadic form of the disease provides an important clue to processes that the two forms may have in common.

Now Alvaro Estévez, John Crow and Joseph Beckman of the University of Alabama, Birmingham, have uncovered a plausible role for the malfunction of SOD1 in both sporadic and familial ALS. The work was in the Dec. 24 issue of Science.

SOD1 is an enzyme, a protein that encourages specific chemical reactions to occur. Its normal role in the cell is to help neutralize free radicals, oxidizing molecules that damage cell membranes, proteins and genetic material. In addition to its protein components, SOD1 also contains two atoms each of copper and zinc. The way in which altered SOD1 leads to the death of motor nerve cells in familial ALS has been the subject of much debate.

A new theory suggests that the loss of zinc from SOD1 may be a common factor in both familial and sporadic ALS.

However, what's become increasingly clear is that problems occur not so much because SOD1 can no longer do its normal job of neutralizing free radicals, but because the mutated version has gained some new and toxic property. Some researchers believe that the mutated form of SOD1 actually creates free radicals.

In an interesting twist to this theory, the UAB researchers found that the mutated SOD1 enzyme was only toxic to cultured nerve cells when it was deprived of its zinc molecule. However, if both the zinc and copper were removed, the resulting enzyme was not toxic, suggesting copper is necessary for the toxic effect of losing zinc. Researchers haven't yet tried removing only the copper, although they say copper is probably not toxic in itself.

Other experiments in test tubes demonstrated that zinc-deficient SOD1 produces more free radicals than it destroys.

These findings are intriguing because earlier results from Beckman's lab suggested that the SOD1mutant in familial ALS can't bind zinc as strongly as normal SOD1.

But the real significance of these results may lie in the finding that normal SOD1 also can be made harmful if it loses its zinc but retains its copper. This means that, even in the absence of a molecule-altering genetic mutation, SOD1 can behave like the mutated version under the right circumstances. Beckman speculates that, in sporadic ALS, the zinc in motor nerve cells may be sopped up by other molecules so that there isn't enough left to bind to SOD1.

This theory dovetails with previous findings by the UAB researchers that a protein called neurofilament, which is known to accumulate in degenerating motor nerve cells, can bind to zinc more strongly than SOD1. The group speculates that, in sporadic ALS, excess neurofilament or some other zinc-binding agent may sop up all of the cells' zinc and be the trigger that converts a helpful SOD1 into a harmful SOD1.

If the loss of zinc from SOD1 is to blame for ALS, it would be expected that the SOD1 in the motor nerve cells of people with familial and sporadic ALS is deficient in zinc. But, Beckman says, there's as yet no evidence that this is true. Part of the difficulty in determining the zinc status of SOD1 in nerve cells affected by ALS is the inability to isolate enough of the enzyme from these particular cells for analysis.

"It's a very challenging problem since motor neurons make up only 2 percent of the cells in the spinal cord," Beckman says. "I don't think it's possible in humans, but we are working on this in mice."

If the loss of zinc from SOD1 could be the trigger for both familial and sporadic ALS, could a person take zinc supplements to boost zinc in the affected motor nerve cells?

Unfortunately, zinc isn't very permeable to the brain and Beckman estimates that the amount of zinc needed to be therapeutic would probably approach levels that are toxic in humans. But there are other options.

Because the harmful effects of losing zinc from SOD1 depend on the presence of copper, another approach is to try to shut down SOD1 entirely by removing its copper molecule. Beckman says copper chelators, compounds that bind strongly to copper, have been used to try to remove copper from SOD1 in mice and humans with modest benefit.

But, he adds, "Our results indicate that only certain types of copper chelators can pull the copper out of SOD. We are trying to synthesize better derivatives and are testing existing compounds in mice. However, the existing compounds are too toxic, at present, to try in patients."

Beckman is also looking at specific antioxidants that may counteract the effects of losing zinc from SOD1. 

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THE ALS/VIRUS CONNECTION

New findings may provide the best evidence to date that a viral infection is associated with sporadic ALS

Although mutations in the SOD1 gene have long been the focus of scientific investigation into the causes of ALS, only 2 percent of people with ALS have mutations in this gene, and only 15 percent of people with ALS are likely to have the disease because of any genetic defect.

The vast majority of ALS cases are sporadic, meaning that the cause isn't known. One hypothesis that's been around for years is that ALS is triggered by a virus -- an idea made more plausible by the resemblance of ALS to polio, a disease caused by a virus that destroys the same population of nerve cells that are affected in ALS.

However, unlike in polio, evidence of a viral infection in ALS has been hard to come by. The disease doesn't seem to be contagious and viral particles haven't been detected in tissue samples or spinal fluid. There is also no evidence of an inflammatory reaction, as would be expected if the immune system were fighting off an invader, in tissue samples from people with ALS.

New, more sophisticated techniques for analyzing antibodies and genetic material have confused the matter even more by producing inconclusive or contradictory results that have linked ALS, in turn, to the HIV-1 virus, the herpes simplex I virus, the human T-lymphotropic virus, the hepatitis B virus and various enteroviruses (including the polio virus).

Now, in the January 2000 issue of Neurology, researchers led by Martina Berger, formerly of the National Reference Center for Enterovirus in France, present what may be the most convincing evidence to date demonstrating the association of a virus with sporadic ALS.

Using a very sensitive technique to amplify viral genetic material, the group found evidence for a particular virus in 88 percent of tissue samples taken from people who died of ALS, but in only 3 percent of tissue samples from people who died of other causes. Specifically, the viral material was found in the anterior horns of the spinal cord, a motor-neuron-containing region that's affected in ALS.

The virus is a member of the enterovirus family. This family includes the polio virus and viruses that cause meningitis. The virus identified in the ALS tissue samples most closely resembles a meningitis-causing virus called echovirus-7 and another virus, echovirus-6.

MDA grantee George Karpati, a neurologist at the Montreal Neurological Institute in Canada and the author of a commentary that accompanied the Berger article, is careful to point out that, although these results are intriguing, they show a correlation between the presence of this virus and ALS, not a cause-and-effect relationship. For instance, they don't show whether the virus causes ALS, or whether people with ALS are particularly susceptible to viral infection. More research is needed to determine the role of this virus, if any, in ALS.

But what would be the impact on treatment options if a virus were found to trigger ALS?

The scientific community has certainly learned a lot about viral suppression from studies of the AIDS virus (HIV), the flu virus and others. In fact, anti-enteroviral drugs already in existence may be of use in slowing or halting the course of the disease if an enterovirus is to blame. It's less likely that such a hypothetical treatment would reverse advanced symptoms of the disease.

Again, although these new findings make a strong case for the association of an enterovirus with ALS, there is no evidence yet that the virus causes ALS.

If a virus is found to cause sporadic ALS, does that mean all the other theories concerning glutamate excitotoxicity, oxidative stress, misfolded proteins, etc., are wrong?

In fact, these theories about the cause of ALS aren't mutually exclusive. It's more likely that several mechanisms play interrelated roles in the disease process. For instance, nerve cells infected with a virus may become susceptible to glutamate toxicity. Or nerve cells already suffering from glutamate toxicity may be more likely to succumb to the effects of a viral infection. Or viral infection may occur as a consequence of glutamate excitotoxicity, but not be, in and of itself, harmful to the nerve cells. More study is necessary to determine if, and how, these processes are related in ALS. 

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PATIENT CARE GUIDELINES ON THE WEB

The new practice parameters on ALS issued by the American Academy of Neurology (see The ALS Newsletter, vol. 4, no. 6) can be viewed on the Internet at www.aan.com.

When you arrive at this page, a dialogue box will open on your screen and invite you to register as a member or a nonmember guest. To find the practice parameters in the most direct manner, close this box without registering. Then click on "AAN Resources," then on "Practice Statements," then on "Official Practice Statements." On this page, scroll down to the section heading "Practice Parameters" and click on "Amyotrophic Lateral Sclerosis, the Care of the Patient With (1999)."

You'll need a free program called Adobe Acrobat to view the practice parameters. If your Web browser doesn't detect this program, you'll be given the option to download it.

The practice parameters are easier to read in their printed form than they are on the screen. It might be better to make a hard copy. 

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ARTIST FINDS NEW TIME FOR ART, COMMUNITY
ALS has given him an odd gift: time

George Burris Johnson, of Gay, W.Va., has found that, since his ALS diagnosis seven years ago, he's been able to devote himself to creating and teaching art. He also shares his new passion by volunteering for a variety of community projects.

George Burris Johnson

"This may sound strange, but in my whole life, this time has been one of the most rewarding times for me. I worked hard in bringing up my children and the family without a thought for myself," said Johnson, who together with his wife, Karen, has eight children and 16 grandchildren. "Now I have the choice, and only now are my dreams being fulfilled in helping others become better artists by teaching art part time." Johnson, 57, has enjoyed drawing and painting since he was a child. Today he specializes in "real pictures of real places," such as seascapes and nature scenes, with images ranging

The love and talent for art that Johnson discovered as a youngster have blossomed into a lengthy career that tapped his unique creativity. After studying advertising art at Philadelphia College of Art in Westport, Conn., Johnson worked for a variety of department store chains and large retailers overseeing store designs and displays.

He later opened his own design and promotion company, but when business travel kept him apart from his family too much, he decided to pursue a new career as an air heating and cooling technician that would allow more time at home. Johnson worked in this field until complications of ALS led to his retirement.

Today, Johnson continues his artwork despite physical challenges posed by ALS. When the disease made his arms and hands unsteady, he invented a unique shelf attachment for an easel to allow him to continue painting.

Johnson, who signs and markets his paintings under his middle name, Burris, has received many awards for his artwork and has sold paintings on the East Coast from Maine to Florida. One of his seascapes, "Cape May Boat Yard," was accepted by the MDA Art Collection last year.

"Cape May Boat Yard" demonstrates Johnson's ability to capture natural lighting in his acrylic paintings. See more of his creations online at artbyburris.homestead.com.

In addition to painting, Johnson enjoys using his computer, and has created a Web site to market his artwork, artbyburris.homestead.com. When he isn't painting on canvas, he can be found working on his Web site.

"I wake up every morning starting a new and exciting day for myself, and the computer is my link to the outside world," Johnson said. "I enjoy getting on it for hours, literally. Sometimes I miss lunch I get so caught up in my activities."

In addition to his art, Johnson volunteers as a designer for the Main Street revitalization program of Ripley, W.Va., and publishes the weekly bulletin for Mill Creek Baptist Church, which he and his family attend. Johnson also produces fliers and other printed materials for local businesses from his home computer. He writes poetry and is a member of the Lee Mays Poetry Society of West Virginia.

His contributions to his community garnered him the 1999 MDA Personal Achievement Award for West Virginia.

"Along with keeping myself busy most of the time, I find this gives me a purpose for living and is instrumental for my longevity," Johnson said of his numerous activities.

Johnson fights ALS with a positive outlook that he says is the result of the support he receives from his extended family, and his own loving and Christian-based upbringing. He stays in touch with his three brothers, although they are spread around the country.

"A strong family unit with all the love that anyone could ever want is part of my everyday life. Even though I am not living close to anyone, I find that is not a problem. Communication with them is very comforting," Johnson said.

He also says laughter is a powerful medicine.

"I have never been so happy and contented with my life as I am now. I know there are going to be times that are trying, but I try to look on the brighter side," Johnson said. "I laugh about the little mishaps like dropping eating utensils on the floor and turning a can of soda into my plate of food."

His advice for people living with ALS: "Just laugh a little...grab all the good times you can and be happy." 

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MDA OFFERS ALS SERVICE, INFORMATION

The Muscular Dystrophy Association offers people with ALS the most comprehensive range of services of any volunteer health agency in the country. Those affected by ALS and their families can turn to MDA for medical examinations, emotional support, advice on day-to-day issues and vital up-to-date information on research and health care.

People registered with MDA can receive services, which include diagnostic and follow-up examinations at MDA's nationwide network of 230 hospital-affiliated clinics; support groups, including groups for family members; assistance with purchase and repair of wheelchairs and leg braces; equipment loans; and information about participation in drug trials.

MDA offers information about its ALS program via its Web site at www.als-mda.org/disease/als.html. The Web site includes late-breaking news, MDA publications about ALS, back issues of The ALS Newsletter, and lists of ongoing and open clinical trials.

The following publications and videos are available at your local MDA office, from MDA National Headquarters at (800) 572-1717 or on the MDA Web site.

ALS: Maintaining Mobility. A 149-page book written specifically for people with ALS to assist in prolonging muscle function and enhancing independence. Prepared by the MDA/ALS Center medical team at Baylor College of Medicine. $6. (how to purchase)

ALS: Maintaining Nutrition. Designed primarily for use by health professionals who care for those with ALS, this 130-page book covers swallowing, diet, alternative feeding methods and tube feeding. Prepared by the MDA/ALS Center medical team at Baylor College of Medicine. $6. (how to purchase)

The ALS Newsletter. A bimonthly publication providing up-to-date news, with a focus on current ALS research. Mailed free to those registered with MDA who have ALS.

ALS Update. A 2-minute, 45-second review of ALS research progress as of summer 1998, hosted by MDA/ALS Center Director Stanley Appel.

Breath of Life and Breathe Easy. Two new MDA videos about ventilation options for people with neuromuscular diseases. The first, at 25 minutes, is for medical professionals; the second, at 27 minutes, is for patients, families and caregivers. Scheduled to be available in late March.

Datos Sobre la Esclerosis Lateral Amiotrofica. The Spanish translation of Facts About ALS. Free.

Facts About Amyotrophic Lateral Sclerosis. A detailed description of the disease's symptoms, causes, treatments and current research. Free.

Meals for Easy Swallowing. A 125-page book containing a collection of recipes for easy-to-swallow foods and beverages, as well as suggestions on food preparation and service. Prepared by the MDA/ALS Center medical team at Baylor College of Medicine. $6. (how to purchase)

Quest. MDA's bimonthly national newsmagazine has in-depth stories about issues of living with neuromuscular diseases, as well as Association activities, helpful products and research news. Mailed free to those registered with MDA; $12 yearly subscription for others.

When a Loved One Has ALS: A Caregiver's Guide. A comprehensive, 94-page, illustrated manual filled with practical advice for meeting the medical, emotional, financial and everyday challenges faced by primary caregivers for people with ALS, and including an extensive list of resources. The primary caregiver for anyone with a diagnosis of ALS who is registered with MDA can receive a copy of the guide free. For others, there's a charge of $10.

With Strength and Courage: Understanding and Living With ALS. A 24-minute video geared for newly identified ALS patients. Hosted by actor Ed Fry and featuring MDA/ALS Center Director Stanley H. Appel, the video was produced in 1996. It's available for viewing from local MDA offices. 

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MDA ALS RESEARCH AND CLINICAL CENTERS

MDA has designated 20 facilities at major medical institutions as ALS Research and Clinical Centers, indicating that they're focal points of MDA's ALS program. However, all of the 230 MDA clinics across the country serve people with ALS.

JERRY LEWIS MDA/ALS CLINICAL AND RESEARCH CENTER (213) 743-1611, (213) 743-1617 Fax W. King Engel, M.D. University of Southern California School of Medicine Los Angeles MDA/ALS CENTER AT UCLA (310) 825-2937, (310) 825-3995 Fax mcgraves@ucla.edu Michael C. Graves, M.D. UCLA Neurological Services Los Angeles FORBES NORRIS MDA/ALS RESEARCH CENTER (415) 923-3604, (415) 923-6567 Fax rmiller@cooper.cpmc.org Robert G. Miller, M.D. California Pacific Medical Center San Francisco MDA/ALS CENTER AT THE UNIVERSITY OF COLORADO (303) 315-7221, (303) 315-6797 Fax hans.neville@uchsc.edu, Steven.Ringel@uchsc.edu Hans E. Neville, M.D. Stephen P. Ringel, M.D. Health Sciences Center Denver MDA/ALS CENTER AT YALE UNIVERSITY (203) 785-4867, (203) 785-5694 Fax jonathan.goldstein@yale.edu Jonathan M. Goldstein, M.D. New Haven, Conn. KESSENICH FAMILY MDA/ALS CENTER AT THE UNIVERSITY OF MIAMI (305) 243-7400, (305) 243-1249 Fax wbradley@med.miami.edu Walter G. Bradley, D.M., F.R.C.P. Miami MDA/ALS CENTER AT EMORY UNIVERSITY SCHOOL OF MEDICINE (404) 727-3818, (404) 727-3157 Fax Jonathan Glass, M.D. Atlanta MDA/ALS CENTER AT THE UNIVERSITY OF CHICAGO HOSPITALS (773) 702-6390, (773) 702-9076 Fax rroos@drugs.bsd.uchicago.edu Raymond Roos, M.D. Chicago MDA/ALS CENTER AT THE UNIVERSITY OF KANSAS MEDICAL CENTER (913) 588-6997, (913) 588-6965 Fax Kpeters@KUMC.edu Arthur Dick, M.D. Kansas City, Kan. MDA/ALS CENTER AT JOHNS HOPKINS UNIVERSITY (410) 955-6435, (410) 955-1961 Fax ddrachm@welchlink.welch.jhu.edu Daniel B. Drachman, M.D. Jeffrey D. Rothstein, M.D., Ph.D. Baltimore

MDA/ALS CENTER -- MASSACHUSETTS GENERAL HOSPITAL (617) 726-5750, (617) 726-5677 Fax brown@helix.mgh.harvard.edu Robert H. Brown, M.D. Boston MDA/ALS CENTER AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE (314) 362-6981, (314) 362-2826 Fax pestronk@kids.wustl.edu Alan Pestronk, M.D. St. Louis THE ELEANOR AND LOU GEHRIG MDA/ALS CENTER (212) 305-2940, (212) 305-8398 Fax hm264@columbia.edu, bmd9@columbia.edu Hiroshi Mitsumoto, M.D. Columbia Presbyterian Medical Center Department of Neurology New York MDA/ALS CENTER AT SUNY HEALTH SCIENCES CENTER-SYRACUSE (315) 464-4627, (315) 464-5006 Fax shefnerj@vax.cs.hscsyr.edu Jeremy M. Shefner, M.D., Ph.D. Syracuse, N.Y. MDA/ALS CENTER AT CAROLINAS MEDICAL CENTER (704) 446-6257, (702) 446-6255 Fax jrosenfeld@carolinas.org Jeffrey Rosenfeld, Ph.D., M.D. Charlotte, N.C. MDA/ALS CENTER AT DUKE UNIVERSITY (919) 684-5422, (919) 660-3853 Fax Janice Massey, M.D. Durham, N.C. MDA/ALS CENTER AT THE UNIVERSITY OF TEXAS (214) 648-6419, (214) 648-9311 Fax rbaroh@mednet.swmed.edu, wbryan@mednet.swmed.edu Richard J. Barohn, M.D. Wilson W. Bryan, M.D. Southwest Medical Center at Dallas Dallas THE RONNY & LINDA FINGER MDA/ALS CENTER (713) 798-4072, (713) 798-3854 Fax sappel@bcm.tmc.edu Stanley H. Appel, M.D. Baylor College of Medicine Houston MDA/ALS CENTER AT THE UNIVERSITY OF UTAH (801) 581-6873, (801) 585-2054 Fax mbromberg@hsc.utah.edu Mark B. Bromberg, M.D., Ph.D. Salt Lake City MDA/ALS CLINICAL RESEARCH CENTER (608) 263-5421, (608) 263-0412 Fax Brooks@neurology.wisc.edu Benjamin R. Brooks, M.D. University of Wisconsin Hospital & Clinics Madison, Wis.

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WEB SITE OFFERS SHOPPING, MDACHAT

Shopping with some of the nation's hottest retailers can be as easy as a click of the computer mouse, thanks to the rapid evolution of "e-shopping." Now, you can shop and contribute to the fight against neuromuscular diseases at the same time -- without spending an extra penny -- at the MDA Shopping Village.

Begin your browsing at the MDA Shopping Village and 5 percent to 15 percent of the price of any online purchases you make at select "e-tailers" will go to MDA.

Here's how it works:

Start at MDA's Web site, www.mda.org. Click on the "Shop for Jerry's Kids" graphic, and you'll get a list of links to more than 80 participating retailers. Follow the links to shop at popular sites such as Amazon.com, eToys, L.L. Bean, the Gap, Starbucks, Pets.com and more.

The donations made through the Shopping Village will support MDA's programs, including its ALS research and services efforts. The MDA Shopping Village was created with the assistance of GreaterGood.com, the nation's leading cause-related e-commerce company.

MDA's Web site will soon be the place for a discussion or support group. MDAchat, a new, expanded component of the site, will allow people with ALS and other neuromuscular diseases to share points of view, experiences and interests via the Internet.

MDAchat is scheduled for launch by April 2000. People wishing to start ALS online groups for those affected or for caregivers are needed.

The first step will be formation of MDAchat Leadership Teams. To get involved, simply volunteer to form a team, ask two or three others to join and then complete a confidential application.

MDAchat organizers will make every effort to meet groups' scheduling requests. MDA retains responsibility for the management, operational policy, content and participation requirements of all MDAchat sessions and events. Discussion groups on MDAchat will have assigned schedules to help ensure participants will be online at set times.

Personal information on applications will remain confidential, and only MDAchat nicknames will be displayed during chat sessions.

Applications are available online on MDA's Web site, by e-mail at mdachat@mdausa.org, or by writing to MDAchat Web Center, 3300 E. Sunrise Drive, Tucson, AZ 85718. Please send applications as soon as possible, and check the MDA Web site's "What's New" page for more details and event calendars as they become available. 

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HELP FIGHT ALS

Many people who know the devastating effects of ALS are providing lasting support for MDA's battle against the disease. Through your will, you can designate a gift to MDA earmarked to support ALS research or services.

Bequests to MDA can be made with cash, securities, real estate, or other property. You can bequeath a percentage of the entire estate to MDA or make a bequest of the residue, donating property remaining after all bequests to family and others have been satisfied. You may also name a memorial gift in honor of a family or individual.

Your attorney or financial adviser can help you work out the details of a bequest to MDA's ALS program. For more information, call MDA's Planned Giving Department at (800) 572-1717. 

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DRUG UPDATE

Since we last updated our list of drugs in The ALS Newsletter (vol. 4, no. 1, 1999), there have been some additions and some subtractions.

The major themes remain boosting or supplementing neurotrophic factors, natural substances that help nerve cells in the lab, and partially blocking glutamate, a chemical that transmits signals in the nervous system but may build up to toxic levels in ALS.

New additions are creatine and coenzyme Q10, which act on cellular energy mechanisms. 

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The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
Muscular Dystrophy Association
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718-3208

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