RESEARCHERS NEED YOUR HELP TO SOLVE RIDDLE OF ALS

Clinical nurse specialist Nailah Siddique is part of a team that spans four medical centers in three regions of the United States, involves dozens of professionals (including her husband, ALS researcher Teepu Siddique at Northwestern University in Chicago) and hopes to attract thousands of people with ALS and their unaffected family members. It's no small job, and the researchers need help.

Teepu Siddique

"We're trying to determine whether there are genetic factors that make us vulnerable to sporadic ALS, which means one case in the family," Siddique says.

The term "sporadic" doesn't tell you whether a disorder is genetic or not, she says.

"It used to mean that it was not genetic. But, for virtually every disorder, people now recognize that there are genetic factors involved. Sometimes they play a minor role; sometimes they're basically the only player. It can be a continuum. Our hypothesis is that there will be a constellation of genetic factors that can be combined with or are influenced by environmental factors, and that when the wrong combination occurs, you have ALS."

To test that hypothesis, an MDA-funded, four-center study is under way at Duke University in Durham, N.C., under the guidance of medical geneticist and statistician Margaret Pericak-Vance; at Vanderbilt University in Nashville, Tenn., under geneticist Jonathan Haines; at Northwestern University, under neurologist Teepu Siddique; and at Massachusetts General Hospital in Boston, under neurologist Robert Brown.

The study requires blood samples from the person in the family with ALS and both unaffected parents, or from the person with ALS and a sibling, preferably one at least as old as the person with ALS. The researchers are hoping to get 800 sets of each of these. They're also interested in hearing from people with familial ALS — ALS that affects more than one person in the same family, even if the genetic mutation in the family has been diagnosed.

Although the study includes four centers, only Northwestern and Massachusetts General are collecting blood from patients. The blood can be drawn at those centers or by the family's own physician and mailed in. Duke and Vanderbilt will do the "behind the scenes" analysis only.

Margaret Pericak-Vance

A second part of the study involves a questionnaire with queries about lifestyle and where a person has worked and lived.

Nailah Siddique says there are at least two possible insights to be gained: One might be that there are genetic differences that account for why one person in a family gets ALS and the others don't, even though their environment may be very similar. The other might be that, despite identical genetic risk factors, environmental factors, such as exposure to toxins, viruses or injuries, may make the difference between developing ALS or escaping it.

With respect to the first hypothesis, Siddique explains the process of analysis this way: "You take those genes with possible 'culprit' functions. You make an educated guess here. You look at a group of patients and then look at the structure of the suspected gene in the patients and the structure of the same gene in an unaffected pool [group]. If you see lots of changes, or mutations, in the patient group and not so much in the unaffected pool, then that's probably something that's involved in this disorder."

On the other hand, if the gene suspected of being a "culprit" looks much the same in both groups but environmental factors are markedly different, the balance of the evidence would shift to the environment for that data set, she explains.

The researchers need about two tablespoons of blood from each participant. They can mail tubes for the blood and instructions for packaging it to the physician of your choice and will pay for shipping of the blood by overnight mail. If the physician or institution requires payment for the blood draw, that too can be charged to the research group.

If privacy is a concern, the investigators suggest that you ask your doctor to refrain from entering the blood draw into your medical record. Once the samples reach the research centers, they're coded with numbers.

If you'd like to help with this research, contact the following centers.

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MESSAGE FROM A STUDY PARTICIPANT

Fred Cantz of Arlington Heights, Ill., is participating in the ALS study being conducted by Teepu Siddique of Northwestern University in Chicago. He writes:

It is my pleasure to help publicize this important work. I am a 47-year-old white male and I was diagnosed with ALS four years ago on my 43rd birthday. Symptoms range back five and a half years, starting with weakness in my right ankle.

I was misdiagnosed twice, and twice assured that my condition would not get any worse. Obviously, it did, and today I have no use of my legs and limited use of my arms. Swallowing and breathing are steadily worsening. I live for my family, my wife and four kids, and I take each day as it comes and try to wring as much meaning and enjoyment out of it as my condition will allow.

Shortly after I was diagnosed, I was referred to Northwestern University Hospital where there is an MDA/ALS clinic. After an initial workup, I was informed of the study being done by Dr. Siddique, and immediately agreed to participate. All that was required was a simple blood draw, done right there in the office.

A kit was sent to my sister in Tennessee, and she was happy to help out. She had the blood drawn at her next checkup and was not even charged for it. The doctor's office sent the kit back for her, and the whole thing was taken care of by Northwestern. It could not have been simpler.

I didn't give it much more thought until I recently learned that the study was having trouble getting participants. This astounded me. Four years later, and they don't even have half the number of people with ALS they need to do a reliable genetic analysis! They need 800 patients and a family member of each one to participate. Currently, the count stands at less than half the patient-parent and patient-sibling sets needed.

Why has it taken four years to get less than half the number needed? Perhaps they don't see the benefit of such research. If a cure is ever going to be found for this terrible disease, it isn't going to come out of the blue. Basic ALS-specific research, especially genetic research, is going to be needed to uncover the causes and mechanism of what went wrong inside our bodies. We live in a day and age where we expect miracles from science, but these miracles only happen after years of research.

It is a slow process, but why make it slower when it is within our power to speed things up? Let's get this study fully enrolled, and then let science do its thing.

To sum up: We need your help. We need your blood! The people at Northwestern have done everything possible to make it free and simple to participate. All expenses are either prepaid or reimbursed. All you need to do is contact Nailah Siddique by phone or e-mail and let her know that you are ready to do your part to help conquer ALS. She will handle the rest.

Let's not wait another four years to get this done! 

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CEPHALON ENDS ACCESS PROGRAM FOR MYOTROPHIN

Cephalon, a West Chester, Pa., pharmaceutical company, has announced that as of Dec. 31 it will discontinue free distribution of Myotrophin, an experimental drug the company has been trying to market for the treatment of ALS since 1996.

Myotrophin is derived from the natural nervous system chemical known as insulin-like growth factor 1 (IGF-1), a neurotrophic (nerve-nourishing) factor that's shown promise in laboratory studies. The drug, however, has had a rocky history in patients.

Its sponsors, Cephalon and Chiron, of Emeryville, Calif., brought it before the Food and Drug Admin-istration for market approval in 1996 and again in 1997. Both times, approval was denied based on insufficient evidence that the drug was effective in ALS. Two large-scale clinical trials, one in Europe and the other in North America, showed contradictory results: The European trial showed no benefit and even raised questions about Myotrophin's safety, while the North American trial showed some slowing on measures of functional decline in ALS.

Cephalon has offered free Myotrophin to randomly selected applicants for three years under an FDA-approved "expanded access" program.

"The NDA [new drug application for the FDA] is still active," said Sheryl Williams, senior manager of product communications for Cephalon. "We have not made a decision about that."

Williams added, "We're not happy to have to discontinue the program, but the company has been providing the drug at no cost for three years." She said Cephalon couldn't afford to continue the program in the face of prolonged uncertainty about the drug's future. She estimates that about 160 people are now receiving free Myotrophin through the expanded access program.

Williams also noted that there is so far no "closure" on approval or disapproval of Myotrophin by the FDA. She noted that Cephalon's partner in Japan, Kyowa Hakko Kogyo, has completed a study of Myotrophin and is now analyzing the data, which should be in Cephalon's hands by the end of March. "When we see it [the results], we'll know what to do," she said.

Cephalon will maintain its information line for Myotrophin at (800) 896-5855. 

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CREATINE TRIAL OPENS

Last March, MDA grantee M. Flint Beal at Cornell University Medical Center in New York was among researchers who found that mice with ALS lived longer and showed better motor performance if they were given the dietary supplement creatine. (See The ALS Newsletter, vol. 4, no. 2, April 1999, and vol. 4, no. 3, June 1999, for more on creatine.)

MDA is now funding a clinical trial to test creatine in people with ALS. The trial is placebo-controlled, meaning some participants will receive creatine (5 grams a day), while others, randomly chosen, will receive a placebo (inert substance). Neither trial staff nor patients will know which participants are on creatine. This part of the trial is scheduled to last six months, followed by a one-year, open-label study of creatine in which everyone will receive free creatine.

The researchers are looking for men and women ages 18 to 80 with definite or probable ALS who have had the disease for less than five years; are willing to risk being off creatine for six months; and, if female, are willing to use birth control during the study. Participants may elect to take riluzole (Rilutek) during the trial. Other criteria will be discussed at the time of application.

For now, three centers (below) are participating. More are expected to join the trial later.

To apply or for further information, contact the following centers.

MARYLAND

Jeffrey D. Rothstein, M.D., Ph.D.
MDA/ALS Center at Johns Hopkins University, Baltimore
(410) 614-5972
jrothste@welch.jhu.edu

MASSACHUSETTS

Merit Cudkowicz, M.D.
MDA/ALS Center at Massachusetts General Hospital, Boston
(617) 726-9122
cudkowicz@helix.mgh.harvard.edu

NEW YORK

Carrie Bagley
State University of New York Health Science Center, Syracuse
(315) 464-5301
bagleyc@mailbox.hscsyr.edu 

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MDA BENEFACTOR RONNY FINGER DIES OF ALS

Ronald J. Finger of Houston, for whom the Ronny & Linda MDA/ALS Center at Baylor College of Medicine is named, died Nov. 9 of complications related to ALS.

Ronny Finger and Stanley Appel

Finger, 61, had received a diagnosis of the disease in April 1998. Shortly after his diagnosis, he and his wife, Linda, made a substantial gift in support of MDA's ALS center at Baylor, directed by Stanley Appel. MDA renamed the center in honor of the Fingers, who also supported the medical school's Lupus Research Center.

"In the all-too-brief time in which I was acquainted with Ronny Finger, I came to know him as an accomplished and caring man," said Robert Ross, MDA senior vice president and executive director. "The loss of yet another outstanding person in the prime of his life is a testament to the treachery of ALS, one we see much too often."

Ross added, "I hope Ronny's loved ones can take comfort in knowing that his generous support of MDA's fight against ALS will ultimately save lives by accelerating our search for an end to this destructive disease."

Finger, a national vice president of MDA, was a major developer of real estate in the Houston area, and a partner in The Finger Companies. He was active in community service as well as in local and national business organizations.

In addition to his wife, Finger is survived by two brothers, three children and four grandchildren.The family has requested that memorial contributions be made to the Ronny and Linda Finger MDA/ALS Center at Baylor. 

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WHY MOTOR NEURONS DIE: PUTTING THE PIECES TOGETHER

Despite years of study, the reason why motor neurons (nerve cells that control the muscles) are gradually lost in ALS remains a mystery. While some researchers are trying to understand the global genetic or environmental factors that may lead to ALS, others are studying the motor neurons themselves to see exactly what goes wrong during the course of the disease, with the goal of developing drugs to prevent specific problems.

At the recent annual meeting of the Motor Neurone Disease Association, researchers from around the world compared notes about how they're building on earlier findings to add a few more pieces to this complex puzzle.

Reconstructing the death of motor neurons in ALS is a problem similar to that encountered by the Federal Aviation Administration after a plane crash: There's plenty of evidence of destruction, but it's hard to tell what went wrong first.

For instance, in a plane crash, charred luggage or debris may indicate the presence of a fire. But did the plane crash because of an onboard fire, or did the fire start after the crash? Data recordings from the plane's "black box" may help investigators sort out the sequence of events that occurred in the final moments before the crash.

See an illustrated sidebar to this story, "Multiple Problems May Cause Motor Neurons to Die"

NO BLACK BOX

Unfortunately, there's no black box recorder equivalent in the motor neurons of people with ALS to tell researchers what went wrong. Instead, scientists must rely upon their observations of changes in the donated tissue samples of people who've died of ALS, or try to study the effects of ALS in animal "models" or in cells grown in laboratory dishes. These methods have revealed many specific problems in motor neurons faced with ALS, and these problems have in turn spawned different theories to explain why ALS leads to motor neuron loss.

At the November MNDA meeting in Vancouver, Canada, held in cooperation with the International Alliance of ALS/MND Associations, prominent ALS researchers from Europe, Japan and the United States reviewed some of those theories. These leading scientists, including many funded by MDA, presented evidence for "glutamate toxicity," "oxidative stress," "protein aggregates" and "axonal strangulation" as causes of motor neuron death, among others. You may wonder why there are so many theories, many of which have been discussed in The ALS Newsletter. Are some groups right and others wrong?

An emerging theme reiterated by many speakers at the meeting is that these theories aren't mutually exclusive and that one type of problem may trigger or reinforce another. For instance, glutamate toxicity may cause oxidative stress, which, in turn, may overtax the cells' ability to repair proteins that are incorrectly folded, leading to protein aggregates and axonal strangulation. It's also possible that motor neurons may be resistant to one or more threats, but may eventually succumb to combinations of problems brought on by environmental factors or age.

THEORIES AND THERAPIES

ALS research only appears disjointed because we haven't yet figured out how the pieces fit together to cause the symptoms, investigators say. Now, some researchers are saying it isn't necessary to know exactly how all the pieces relate to one another to start designing therapies based on their multiple parts.

Frank Walsh, a representative of the United Kingdom pharmaceutical company SmithKline Beecham, reported that his company is looking at a number of different strategies to beat neurodegenerative diseases that might together form a multidrug "cocktail." This sort of multidrug strategy has been pursued with some success in the development of treatments for AIDS and cancer, and may be the wave of the future for ALS treatments.

SmithKline Beecham is currently focusing on development of small, nonprotein drugs that block cell death pathways and stimulate cell survival pathways, Walsh said. 

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TALES AND TRAVAILS OF THE TELETHON

by Glenn Harwood

[Editor's note: Glenn Harwood of Crofton, Md., who works for the U.S. Small Business Administration, appeared on the 1999 Jerry Lewis MDA Telethon with his wife, Fran. Harwood, who has ALS and whose vocal powers have been compromised by the disease, used his DEC Express speech synthesis system to communicate his thoughts about living with ALS to the national Telethon audience. In this anecdotal account of his Telethon experience, Harwood shares some special memories, while also shedding light on the challenges and rewards travel can bring to people with disabilities.]

In April 1999, Fran and I were approached by MDA to be a "profile family" on the upcoming Jerry Lewis Telethon. We felt honored.

On a Friday morning in May, a crew of six TV production veterans pulled up to our house in two minivans loaded to the gills with tools of their trade. When they left late on Saturday afternoon, it seemed they had been here a week. They put us through their paces and made us enjoy it. Boy, were we pooped.

Toward the end of the shoot, we were asked, if invited, would we be willing to travel to Hollywood to appear live on the Telethon? Again, we felt honored and, again, said "Sure!" No promises were made; they'd be in touch.

In early August, the official invitation came in the form of a message on our answering machine. We were going to Hollywood!

"Charo loves me!" says Glenn Harwood, who met her during a Telethon makeup session.

FRIDAY, SEPT. 3

We arrived at LAX airport. Two ebullient MDA representatives met us at the gate. But it turned out that at BWI (Baltimore/Washington International) airport, the baggage handlers broke one of the wires to my wheelchair's batteries. The ground crew at LAX couldn't get it working and we were delaying the departure of the next leg of the flight. The plane's captain came to the rescue. He arranged for an electrician to fix it. He was our "angel of the moment."

Now all we had to do was pick up our baggage and take a van to the hotel. We were told that we had to go back through security and onto another terminal because the elevator was broken. We were so late getting to the baggage area that our bags had been removed from the carousel. It took another 20 minutes to find them. Onward to the van. Would you believe the van's lift couldn't handle the weight of my chair? Another van was called and we finally made it to the lovely Hotel Sofitel.

Fran had arranged a dinner party for Friday evening. It was a way to see family and friends while we were there. After dinner, I decided to spruce up my comments and make sure the laptop and voice synthesizer were fully charged. But the charging unit for the synthesizer was missing; it hadn't made the trip. Hollywood? It felt more like Panic City.

SATURDAY, SEPT. 4

Saturday morning we called home to get the technical information we needed for a replacement. Fran ran, or rather taxied, to the nearest Radio Shack. She returned after about an hour and a half (or was it an eternity?) and plugged the unit into the synthesizer. Success! Meanwhile, Fran's taxi driver had offered to give her a tour of Hollywood and Beverly Hills. I thought that was a great idea, so off she went. She had a ball and got to see all the highlights.

After all these adventures, we were picked up and taken to the CBS Television studio for rehearsal. We were given a grand tour of the facility and met with Jerry Auerbach, the producer for all the family profiles, and Dr. Stanley Appel, who would join us during our first of two live appearances. Dr. Appel directs the Ronny & Linda Finger MDA/ALS Center at Baylor College of Medicine in Houston, one of the premier ALS research facilities in the world. I had drafted a three-page script for my segment. Jerry A. told me I would be given 10 to 15 seconds for comments, then read my script and selected one portion which both he and Dr. Appel thought was right on the money. The rest of my work ended up on the cutting room floor. That's show biz!

Saturday night found us at dinner for the five profile families and the MDA staff. Another dinner was being held honoring the corporate sponsors of the Telethon. Jerry Lewis came from that party to visit us and made an inspirational speech. I got a big smile and handshake from him. Since I always carry a page of jokes with me, I whipped them out and presented them to him.

SUNDAY, SEPT. 5

Sunday afternoon, we were escorted off to the studio for the big show. En route from the commissary, Fran exclaimed, "There's Dick Van Dyke!" So we rolled over and interrupted his conversation with some members of the fantastic barbershop harmony group, the Masters of Harmony. Dick was most pleasant and graciously gave his autograph. At the gentle urging of our MDA guide, we then continued our journey to makeup.

Glenn Harwood encounters Telethon Anchor Ed McMahon.

While we were waiting our turn, Jerry A. came by to listen to the final draft of my speech. Confidently, Fran and I set up the machine. No sound! Panic City again. Having charged the synthesizer all night, we didn't have the charger with us. So Fran was rushed back to the hotel to get the charger. We plugged it in and still no sound! There next followed a parade of "techie" types all trying to get this annoying and recalcitrant little box to talk. Finally, Chris French, who'd been on the team that shot our video profile, arrived and started pulling some wires while jiggling others. Well, guess what, with Chris and the Lord on our side, it worked! It was decided that we'd stay there in our private makeup room and charge the synthesizer until it was our turn to go on.

So now we were sequestered in the makeup department for several hours while the synthesizer was charging. All the performers came through here on their way to the studio. We'd been warned that taking pictures while in the studio was strictly prohibited. We did sneak one of Charo, though, with her encouragement. What a beautiful and energy-packed lady she is! Fran also collared Jason Alexander and Norm Crosby.

Soon we were marching on stage and were directed to our "spot." Fran was equipped with a microphone, and my voice synthesizer was hooked up to a power cord and an audio lead that would send my comments out to the studio and to the world. Wow, what a heady moment. Meanwhile, a phalanx of TV cameras, lights, sound booms and still cameras marshaled in front of us. All this and no blindfolds! All of this was going on while our three-minute-and-15-second video profile was airing.

The profile concluded. Jann Carl of "Entertainment Tonight" fame made some comments and gracefully handed off to me. An eerie calm descended over me as I pushed the computer's button. My mechanized comments sputtered to life as the sound technician tweaked my output. It worked! All went well until the machine decided to omit the last two sentences. As luck would have it, the break was at a logical point and nobody knew the difference. It was now Fran's turn. She lit up like a Christmas tree and delivered her piece concisely and flawlessly. I was very proud of her.

We exited to a stirring ovation. On the way out, I hit the button again, and guess what, the last two sentences popped out! Go figure!

We stayed and watched the show until midnight, then returned to our hotel and adjourned to the bar. A party of six came in and the patriarch of the group signaled the bartender to put our drinks on his tab. When Fran returned, we went over to thank him. It turned out he was Eddie Foy III, who was in charge of assembling all the talent acts for the Telethon.

MONDAY, SEPT. 6

Monday found us back at the studio early. We returned to our personal hideaway in the makeup department and plugged in the voice synthesizer. Chris came by to check up on us, as did Jerry A. and the MDA staffers. After Sunday's experience, Monday was a breeze. This appearance was hosted by Cynthia Garrett of VH1-TV fame. Everything went well and the computer performed perfectly. It even spat out the last two sentences in a timely manner. Cynthia became quite emotional during our segment together, and Fran's performance was better than Sunday's.

The grand finale came after the final tote was announced, $53.1 million. I cried. And then came the confetti and balloons. Wave after wave came flittering down. I still have some confetti stuck in my chair. I'm just going to leave it there.

Entertainers, hosts, hostesses, profile families and MDA staffers congregated on the stage to celebrate what had been accomplished. It was really very moving. On the way out, we encountered Ed McMahon, who had some nice words for me.

MDA put on a marvelous show. It's amazing how well organized everything was and how smoothly it ran. I can't say enough about MDA staffers Mike, Michelle and Sheri who were always there when we needed them. After this experience, my lasting impression of MDA is that it's a class act all the way.

TUESDAY, SEPT. 7

Tuesday morning we left for Phoenix to visit a dear friend and enjoy a two-day swing up to the Grand Canyon. What a fantastic natural site. Our visit was highlighted by a private two-and-a-half-hour tour by a park ranger and a bird's-eye view of the canyon from a helicopter! But that's another story.

Saturday we arrived home safely and settled in. It had been a hoot! 

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COOKING UP A FIGHT AGAINST ALS: IDAHO MAN WANTS YOUR RECIPES

Jim Driever has many rich memories of his days as a fire fighter: camaraderie, good friends and, of course, lifesaving work.

He also remembers some tasty food at the firehouse.

That's because many fire fighters among Driever's colleagues were also gourmets who took advantage of time between calls to dabble in creative cooking.

It's these memories that have motivated Driever, of Pocatello, Idaho, to launch an effort to collect enough recipes to create an "ALS Cookbook."

Driever hopes to produce a book that not only features delicious recipes for all kinds of dishes, but one that's also a journal of those who have been touched by ALS. Driever said he plans to give 50 percent of proceeds from sales of the cookbook to MDA for ALS research.

Driever, 44, was forced to retire from his fire-fighting career 15 years ago after he received a diagnosis of ALS. He quickly lost the use of his arms, legs and speech, but gradually found a way to paint and use a computer by wearing an infrared mouse simulator on his head.

Driever said he wants the cookbook to include favorite recipes of people with ALS, friends, family members, caregivers, researchers and doctors who treat people with the disease. He'd also like to include "In Memory of..." recipes that honor people who have died from the disease. Each of those entries would include a photo and some personal history.

"If you're in the fight against ALS, you qualify," Driever said. "I want this cookbook to be something that people want, not only because it's a great cookbook, but I'd like to put a face on those behind the scenes because very few realize the vast numbers of people there really are in research and treatment."

Driever plans to keep the cost of the book at less than $25.

To contribute a recipe, send it to:

ALS Cookbook
c/o Jim Driever
790 Natalie St.
Pocatello, ID 83202

If you wish to send a photo, include a self-addressed, stamped envelope, and Driever will return the photo to you.

Driever prefers to get recipes by mail, but he'll also take recipes by e-mail at TRTLTYPE@aol.com.

Anyone interested in purchasing a copy of the cookbook should send Driever a short e-mail and he'll notify you when the book is completed. 

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PATIENT CARE GUIDELINES RELEASED

The Quality Standards Subcommittee of the American Academy of Neurology (AAN) has released the first set of recommendations, or practice parameters, devoted to improving care for people with ALS.

The task force reviewed a large body of scientific literature and created official recommendations for all areas of ALS treatment, including, for example, nutrition, respiratory management, saliva management, terminal care and withdrawal of ventilation. The resulting document serves as a resource for physicians and may also be of interest to people with ALS and their families and caregivers.

The practice parameters were published in the August issue of Muscle and Nerve (vol. 22, no. 8). The document can also be viewed on the AAN Web site at www.aan.com. Click on "AAN resources" and then "Practice Statements." You'll need Adobe Acrobat to view the document. If you don't have this program, there are instructions on the site that explain how to download it at no cost. 

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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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