NEW INSIGHTS INTO MOTOR NEURON DEATH IN SOD1-LINKED ALS

About 10 to 15 percent of people with familial (inherited) ALS have mutations in a protein called superoxide dismutase, or SOD1. Although the majority of people with ALS don't have mutations in this protein, SOD1 mutations are the only specific cause of ALS that has been identified. Researchers hope that knowledge gained by studying the way in which SOD1 mutations damage motor neurons will be applicable to other types of ALS.

MDA researchers believe that mutant SOD1 may lead to ALS by slowing down the movement of proteins through the axon of the nerve cell.

MDA grantees Don Cleveland and Toni Williamson of the University of California, San Diego, have uncovered evidence suggesting that the mutant SOD1 protein either directly, or indirectly, interrupts supply lines from the motor neuron cell body to the ends of the axon (the long, thread-like appendage on nerve cells). In the motor neurons of mice engineered to produce mutant SOD1, the researchers reported a reduction in a specific type of intracellular transport called "slow axonal transport" months before the mice developed any clinical signs of muscle weakness. They reported their findings in the January issue of Nature Neuroscience.

Neurons, unlike the classic round cell seen in biology texts, are made up of two major parts: the cell body, which contains the DNA and protein-making machinery, and an axon that can be up to a meter long (imagine a basketball with two miles of rope attached to it). In motor neurons, the cell body often represents less than 0.1 percent of the volume of the cell, yet it's charged with making all of the proteins needed to support the long axon. These proteins are shipped down the axon either by a fast pathway (like sending a package by airmail) or a slow pathway (like sending a package by boat).

Cleveland and Williamson found that it's the slow transport pathway that seems to be slowed even further in the presence of the mutant SOD1 protein. "It's kind of like the freeway experience." Cleveland explains. "You have a little fender-bender yet the freeway is still moving at a snail's pace. If you have anything more than that, the freeway comes to a complete stop. So, we argue that we have found a fender-bender and it happens very early [in the disease process]."

Cleveland says that it's unclear if slow axonal transport is the primary target of the mutant SOD1, but even if it's a secondary effect, the decrease in transport rate is almost surely harmful to the cell. "Because what you're going to do is start slowly strangling this axon that gets all of its goodies from the cell body," he says.

The effects of this transport impairment may not be felt right away, Cleveland explains, because the mechanism is so very slow. "You wouldn't necessarily see that instantaneously -- you could even argue that the effects could build up over a course of years," he says. 

Return to Top

DRUGS FOR ALS -- WHERE ARE WE NOW?

The pace of clinical research in ALS seems agonizingly slow to patients and their families. But it can be helpful to reflect that, as recently as 1990, there were few viable theories of the causes of ALS and no drug trials even on the drawing board.

Over the past decade, MDA-supported research has led to several important ideas about ALS, to trials of experimental medications and to the approval of one drug (Rilutek).

Fighting Glutamate Toxicity

One line of research and clinical development in ALS has been that of glutamate toxicity. Glutamate belongs to a class of molecules known as neurotransmitters, chemical carriers of nerve signals in the body. Glutamate carries signals between nerve cells (neurons) in the brain and from brain neurons to spinal cord neurons. It's considered an "excitatory" neurotransmitter, because actions "excite" (activate) its cellular targets. For example, a glutamate signal coming from the brain to a spinal cord neuron causes the spinal cord neuron to send a signal of its own to muscle. (Other transmitters in the nervous system are "inhibitory," meaning they dampen incoming signals from elsewhere in the nervous system.)

A few years ago, neuroscientists, particularly MDA grantee Jeffrey Rothstein at Johns Hopkins University in Baltimore, found that a buildup of glutamate around neurons was toxic to the cells. Recently, Rothstein found that, in many people with ALS, glutamate isn't cleared away from the fluid around neurons quickly enough.

Glutamate normally leaves a neuron, flows across a small gap between cells (a synapse) and then "docks" at structures called receptors on its cellular target. Then, proteins known as glutamate transporters quickly whisk away the glutamate and send it back for recycling.

Rothstein and others traced the glutamate problem to a defect in one of these proteins, known as excitatory amino acid transporter 2, or EAAT2. More recently, Rothstein showed that the problem with EAAT2 stems from a mistake in a key step in its formation known as RNA processing.

The cause of the aberrant RNA processing and the resulting devastating effect of ineffective glutamate transport remain elusive. In the meantime, medications like Rilutek (riluzole) and Neurontin (gabapentin) seem to be a finger in the dike of glutamate overload. These drugs inhibit glutamate at different points in its synthesis, release or reception (see table).

Note: Researchers say that eating food containing monosodium glutamate or other forms of glutamate doesn't lead to excess glutamate in the nervous system. The glutamate implicated in ALS is made in the body. Similarly, "calcium toxicity" isn't caused by calcium from food or milk.

Neurotrophic Factors

Another line of research is that of the neurotrophic (nerve-nourishing) factors, molecules that preserve neurons under a variety of laboratory-created adverse conditions, such as nerve injury. At least some also play a role in the development of the nervous system before birth.

Since the early 1990s, researchers and drug companies have tried to see if these naturally occurring molecules could be used to protect motor neurons (the muscle-controlling nerve cells, which are the most affected cells in ALS) from disease-related destruction.

Among the first of these molecules to go all the way to clinical trials was IGF-1 (insulin-like growth factor 1), now known by the brand name Myotrophin. The companies Cephalon and Chiron, along with dozens of physicians and hundreds of patients, had high hopes for Myotrophin as a treatment for ALS. Two large-scale clinical trials, one in North America and the other in Europe, failed to prove the effectiveness or even the safety of Myotrophin. Its future, still in the hands of the Food and Drug Administration, is dim (see table).

Myotrophin is given by subcutaneous (under the skin) injection. Is its lack of effect at least partially due to poor penetration into the central nervous system? Or is the drug simply not a good choice? No one knows for sure.

BDNF (brain-derived neurotrophic factor) is another of this group. To answer the question about nervous system penetration, Amgen and its partners have decided to test this molecule by delivering it directly into the fluid surrounding the spinal cord (intrathecal delivery). An earlier trial of subcutaneous delivery failed to show effectiveness for this substance, but the method is being tried again. (See information on the trial.)

Glial-derived neurotrophic factor, or GDNF, is being tested using direct delivery into the fluid part of the brain (ventricles).

Meanwhile, the drug company Sanofi has developed an oral compound that seems to boost the body's own production of neurotrophic factors. Results of a large-scale trial, which aims to get around the drug delivery problem, are anxiously awaited.

Are neurotrophic factors effective if they reach neurons? They protect neurons in lab dishes and in animals whose nerves have been cut, so researchers are hopeful. Do they have dangers and side effects? And, what happens if you "artificially" prolong the life of a motor neuron that's been mortally wounded by another event, making it "sick"? These are questions that research is striving to address.

New Directions

Another class of potential medications is being explored by Guilford Pharmaceuticals of Baltimore. These molecules, known as neuroimmunophilin ligands, or NILs, are modifications of well-known immunosuppressive drugs, such as FK506, rapamycin and cyclosporine. It seems these immunosuppressive drugs also preserve neurons, via actions completely separate from their immunosuppressive properties.

Researchers have separated these two functions of NILs, and in so doing have created compounds that are neuron-preserving without being immunosuppressive.

NILs have now been licensed to the biotechnology company Amgen, which plans to develop them for neurodegenerative disorders, starting with Parkinson's disease. They could have important implications for ALS.

And what of glutamate transporters themselves? Could they be targets of drug development? So far, all efforts to block glutamate toxicity have been on glutamate itself, not its transporters, which may be closer to where the real problem lies in ALS. The key to fixing the transporter problem probably lies in repairing the RNA processing mechanism, investigators say. That, although daunting, is not so far-fetched, as RNA processing becomes increasingly understood.

Another line of inquiry is motor neurons' ability to handle calcium. Motor neurons are particularly poor at buffering the intracellular calcium that acts as part of the cell's signaling mechanism. Compounds that mitigate the effects of this calcium could be helpful, and MDA researchers such as Stanley Appel at Baylor College of Medicine in Houston are busy studying these. 

Return to Top

DOVES PREVAIL THROUGH ADVERSITY

When Norman Dove no longer had the strength to crush aluminum cans he'd find on his 160-acre farm, he'd run them over with his scooter.

After all, the job had to get done. And that's how Dove, 63, lives with ALS. Whatever has to be done, is done. Dove and his wife, Mary Louise, 55, are no strangers to tackling the odds.

In 33 years of marriage, living on the same farm in Green Ridge, Mo., the couple raised four children; tended to crops, cattle, hogs, laying chickens and roosters; and then faced down the cancer Mary Louise fought 10 years ago.

A year ago, after Norman was found to have ALS, the family faced the changes to come with the same resolve and spirit.

"He's not a quitter," Mary Louise says of her husband. "Whatever you have to do, you do. He's not intimidated. He has accepted the oxygen, the tube feeding."

Crediting Dove with an inventor's mind, Mary Louise says her husband always finds ways to improve an idea or fix a problem. About 12 years ago, Dove enhanced used equipment so he could offer seed cleaning to other farmers; the process removes debris and dirt from seeds for hay, grass, soybeans and other crops for replanting.

Recently, Dove wanted to track the distance he was riding when he drove his scooter along the road for exercise and fresh air, so he put an odometer on the cart. Shortly after, Dove added a rearview mirror and found a way to hook up a small radio and headlights.

Among the most heartfelt needs Dove answered was raising $1,217 for MDA's Be a Star program for the 1998 Jerry Lewis Telethon. Dove, who was still driving his truck at the time, went door-to-door to the many businesses he worked with asking for contributions.

His speech was becoming unclear, so, true to his ingenuity, Dove prepared a card explaining the reason he was raising money.

When he approached his business associates, he jokingly gave them a choice -- take the time to listen to him explain the program or read the card. They all read the card, smiled and handed him money.

"They already gave but they gave more," Dove says. "Some gave $100 right out of their pockets."

Not surprising. Such determination is what the business community has come to know as Dove's way. He regularly helped other farmers when his own work was done. Sometimes they'd need his heavy equipment. Other times he'd lend a hand cleaning out barns and fixing water leaks.

"You had someone who did the whole nine yards," Mary Louise says.

Dove was working on his farm through last summer, counting calves and feeding livestock using his scooter to get around -- a scooter, he says, that saved his life. Fiercely independent, Dove wasn't about to stop his life's work despite the difficulty he had moving about his land. When the Columbia, Mo., office of MDA provided Dove with a golf cart from its loan closet, he was renewed.

"The golf cart has opened my life again," Dove wrote in a thank-you note to the local MDA office. "I can turn the water on for the calves, rest, then shut it off. This cart allows me to be outside where I feel best. My wife can be with me, too. I really appreciate all your kindness in helping obtain this cart for my mobility again."

Today, most of the farming responsibilities have been turned over to his two sons. Timothy, 29, oversees the seed cleaning business and Adam, 28, is in charge of crops and livestock. Daughters Theresa, 31, and Amy (Dove) Jackson, 26, also help when they can.

Dove says that when his children were young they used to sit in his truck and watch him.

"Now I'm sitting in the truck watching them," he says, proudly.

That sense of family pride and a strong bond of love are a big part of what keeps Dove moving on to the next challenge. Mary Louise says they acknowledge their accomplishments, no matter how small, and don't focus on what is lost.

Each day, the Doves share a special thought: "We've had a good life, but we've had a great day." 

Return to Top

I HAVE LOU GEHRIG'S DISEASE, BUT PLEASE, DR. KEVORKIAN (AND CBS), NO HOUSE CALLS

by David Feigenbaum

A few Sundays ago [Nov. 22, 1998], I watched "60 Minutes" with more than the interest of a casual observer. That was the controversial show where Dr. Jack Kevorkian proudly demonstrated how he euthanized (the prosecutor says murdered) 52-year-old Thomas Youk of Oakland County, Mich. Youk was suffering from ALS -- Lou Gehrig's disease.

I, too, was diagnosed with this fatal neuromuscular illness about two years ago at a similar age. Watching Youk on TV, I could see that his speech was worse than mine, but only slightly, and his neck was somewhat weaker. We are both in wheelchairs. However, his hands were stronger -- he could sign his death warrant; I can't sign my name, not even an X.

Anxious to garner a great audience, the network played up Kevorkian's name for all it was worth, with frequent promos beforehand. In its rush, "60 Minutes" Mike Wallace accepted the doctor's statements and assumptions about ALS without taking the trouble to check their veracity or ask the hard questions he likes to pride himself on. So much for any pretense at investigative journalism.

Kevorkian gave two reasons for Youk wanting to end his life: he was in agonizing pain. And he had tremendous anxiety about choking to death. If Youk was indeed in pain, it didn't show in either of the two videotapes aired on "60 Minutes." And it's something of a mystery because pain isn't normally associated with ALS. I get frequent muscle cramps but, though painful, they never last long and are quite tolerable. If Youk's pain was caused by something else, Wallace should have revealed it.

In fact, people with ALS often die peacefully in their sleep, as recently happened to my e-mail friend Molly Franco in Queensland, Australia. And to John Cahalan of Portland, Ore., whose wife, Cathy, said of his last moments: "It was a beautiful dawn, the start to the type of day that John loved. He was the picture of serenity."

I don't want to belittle Youk's anxiety, but plenty of medications exist to help soothe fears. I occasionally take one myself and it can be quite effective.

So something is wrong with the picture painted by Kevorkian. And CBS chose to run right past it for the greater ratings of the euthanasia aspect. After all, Youk had a wife, mother and brothers standing by his side, full of love. It makes you wonder: In this circumstance, does someone normally want to kill himself? Was he receiving adequate medical advice? Did he have medical insurance? Or if he didn't, was he going to one of the many Muscular Dystrophy Association-funded ALS clinics? Had he heard that some PALS (people with ALS) live productive lives for many years -- like famed British physicist Stephen Hawking? Questions we would have liked CBS to address.

I'm not saying CBS had to turn this into another ALS-focused story, but they were obliged to look past Kevorkian's self-serving statements about his patient's pain and anxiety before leaping into the euthanasia fray.

For the record, though recognizing the potential for abuse, I believe a competent adult has the right to end his own life or ask someone to help him if he can't do it himself. But I hate to see Kevorkian trample on the truth for the sake of his own agenda. And I hate to see him mislead the public and give a wrong impression to new ALS patients like baseball great Jim (Catfish) Hunter and their families, who all suffer enough.

One problem with being euthanized is that you can't change your mind. Another e-mail pal, Shirley Adams, recently described the ALS "journey" her husband, Dean, went through in Millbury, Mass. After his diagnosis, Dean thought he might wish to end his life by taking sleeping pills. His doctor refused to go along with this but assured him of pain medication if Dean chose to stop eating and drinking. But the family prevailed on Dean to wait for the holidays -- first Thanksgiving, then Christmas.

He died naturally the following May.

"Without those extra months," wrote his wife, "he wouldn't have given his family and friends the sense of peace and rightness that we have now..."

In every PALS' experience, there comes a natural stopping point when the body no longer has the muscles needed to breathe on its own. The vast majority choose to end their lives here, even though technology allows them to live on indefinitely and their minds are unaffected by the disease.

When I reach this stage, I'll choose to live ... to be there with and for my wife, to watch my family grow and to see the Miami Dolphins blow another season. There's no place for Dr. Kevorkian in my life.

David wrote this column for the Virginian-Pilot, Norfolk, Va. It was distributed by The New York Times wire service and published in newspapers across the country. The column can also be found on MDA's Web site, www.mda.org. "60 Minutes" plans to air a follow-up to its Kevorkian report this month. 

Return to Top

MDA LEADS IN ALS SERVICE, LATEST INFORMATION

The Muscular Dystrophy Association's services for people affected by ALS and their families are the most comprehensive offered by any agency in the country. Besides its cutting-edge worldwide research program, MDA offers:

• medical care at its nationwide network of 230 hospital-affiliated clinics
• support groups for people with ALS and their family members
• referrals to other community agencies
• assistance with purchase and repair of wheelchairs and leg braces
• equipment lending programs
• vital information

Contact the health care service coordinator at your local MDA office for details about services.

For complete information on MDA's ALS program, you can also visit MDA's Internet home page at www.mda.org. The World Wide Web site includes late-breaking MDA news, lists of ongoing and open clinical trials, and a zip code directory for locating the nearest MDA office or clinic.

A new feature is a page for each disease, which will serve as a "headquarters" for the disease on MDA's Web site. Users can reach the ALS Web page by clicking on "Diseases" on the MDA home page, then ALS. The ALS page gives the disease definition and symptoms, as well as brief descriptions of all the relevant items on ALS within the MDA Web site.

Other ways to find ALS information on the Web site are through the Search feature and ALS Materials under "Publications."

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

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.

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.

The ALS Newsletter. A bimonthly publication designed to provide 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. See at www.mda.org on RealPlayer (free download available).

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

Datos Sobre la Esclerosis Lateral Amiotrofica. The Spanish translation of Facts About ALS. 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. Pre-pared by the MDA/ALS Center medical team at Baylor College of Medicine. $6.

Quest. MDA's bimonthly national newsmagazine has in-depth stories about issues of living with any of the 40 neuromuscular diseases MDA covers, 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. The guide contains an extensive list of resources, including books, organizations and Web sites. 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. 

Return to Top

MDA ALS RESEARCH AND CLINICAL CENTERS

While all MDA clinics across the country serve people with ALS, MDA has designated 17 facilities at major medical institutions as ALS Research and Clinical Centers. The amount of ALS research taking place at these centers, along with the vast experience of the staff in dealing with this disorder, make them focal points of MDA's ALS program.

The names, directors and contact information for each MDA/ALS Research and Clinical Center are always available on MDA's Web site at http://www.mda.org/clinics/alsserv.html. 

Return to Top

MUSCLE AND NERVE BIOPSY IN DIAGNOSIS OF ALS

The role of muscle and nerve biopsies (surgically extracted tissue samples) in the diagnosis of ALS has diminished in recent years because of the greater availability of noninvasive methods of diagnosis. Neuroimaging studies, such as MRI scans, and electrophysiologic testing have made these biopsies less important. However, there are still situations in which the diagnosis of ALS, after many noninvasive tests, is still unclear, and it's at these times that the physician may wish to perform a biopsy to be absolutely certain that the disorder isn't one of the more treatable conditions that sometimes mimics ALS. The role of biopsies in ALS is mostly to "rule out" other conditions, rather than to "rule in" the diagnosis of ALS, because there is so far no specific test result that is unique to ALS. Here, neurologist and pathologist Robert Shebert gives an overview of this aspect of ALS diagnosis. Clarifying additions to the original text are in brackets.

by Robert T. Shebert, M.D.

ALS is a condition that involves weakness of voluntary muscles, avoiding for some reason the muscles that control the eyes and the sphincter muscles of the bowel and bladder. Smooth muscles (involuntary) such as are found in the stomach, bowel, blood vessels, etc., aren't involved.

But one must understand that ALS isn't a disease of the muscle itself. Voluntary muscle is controlled by numerous complexly integrated microscopic switches that reside in the brain and the spinal cord or neurons [nerve cells]. ALS attacks the controller neurons in the surface of the brain; the lower motor neurons in the brain stem (deeper brain) leading to the speech and swallowing mechanisms; and those in the spinal cord, which control the extremities and muscles of the chest, abdomen and back. The pattern of involvement, i.e., area and degree of involvement of upper motor neurons and lower motor neurons, is unique in any given victim, but is usually distinguishable by the expert physician.

The variability of course may cause the generalist to first think of some other cause, such as pinched nerve, carpal tunnel syndrome, stroke, etc. This is reasonable to pursue in some cases in which the diagnosis isn't initially clear. The correct diagnosis of ALS usually becomes increasingly clear due to the unfortunately progressive nature of the disease.

In many cases, other conditions may be mimicked by the initial presentation, and it's occasionally necessary to perform tests to correctly decipher the potential possibilities, particularly if some treatable condition may be present such as inflammatory neuropathy. Rarely, even advanced disease may mimic other conditions as well. So many investigations are available to the physician to help in securing a diagnosis, but ultimately the physical examination in an expert's hands is still the most reliable diagnostic code. That's where muscle and nerve biopsies are occasionally used.

Keep in mind that it's the spinal cord and certain brain neurons that control muscle, and that are the targets of ALS. Muscle is one tissue that can develop structural changes and loss of bulk due to a disease that affects a completely different tissue, in this case, the neurons. A neuron may control between five and 2,000 individual muscle fibers. When the neuron dies for any reason, the muscle will wither (atrophy or amyotrophy), and eventually the whole muscle will become weakened. At this point, numerous neurons have been involved and the muscle develops certain characteristic changes of denervation [loss of nerve supply]. If a healthy nerve fiber is close by, it may even become reinnervated [gain nerves], which occurs in many conditions, including ALS, as a form of compensation for the loss of muscle.

Unfortunately, in ALS, the neuron controlling the reinnervated muscle will eventually become involved, and the muscle can no longer compensate for weakness effectively. By the time weakness is noted, the degeneration of neurons is already advanced to some degree. Biopsy of muscle at this point will show characteristic changes of denervation.

But denervation on muscle biopsy cannot alone specifically diagnose ALS, since the nerve cell can be damaged by many much more common conditions, so the ultimate diagnosis relies on the experience of the physician. If the picture of ALS is clear, and no other condition would seem reasonable, a muscle biopsy need not be performed. If there appears to be a possibility of another disease involving muscle, even if remote, a muscle biopsy is sometimes performed. Treatable conditions such as polymyositis, or less severe conditions that have a better prognosis, may be discerned, to the relief of the doctor, patient and family. But be clear about the fact that a muscle biopsy doesn't make a diagnosis of ALS, since the effect of muscle is secondary to nerve degeneration, not degeneration of muscle by itself.

The muscle biopsy is a specialized procedure best done by someone familiar with neuromuscular diseases so that the muscle(s) chosen for biopsy give the most and best information. A markedly weakened muscle is usually not a good choice, since the damage may be so great as to give an end-stage, or non-diagnostic, specimen. A mildly weakened muscle usually gives the best information. The procedure should be done under local anesthesia, since it's much safer than general anesthesia, particularly in the older or weakness-compromised patient.

It's generally a well-tolerated procedure, frequently painless, depending on the technique used. The muscle biopsied itself can't be anesthetized (injected with local anesthesia), but techniques are available which can make the procedure relatively or completely painless. And some muscles (such as triceps and tibialis anterior, in the arm and leg respectively) are intrinsically less likely to be uncomfortable when biopsied, for reasons which elude this physician. At the time of biopsy, several pieces are usually taken. Rarely, an adequate piece can't be taken if the muscle is unexpectedly severely affected.

State-of-the-art histochemical pathologic processing [examination of what goes wrong in tissues from a biochemical standpoint] should be used in virtually all muscle biopsies. If you're scheduled for a biopsy, and histochemical processing is not routinely done, ask your doctor for a center that performs them on every specimen. Routine pathologic processing and facilities for possible electron microscopy should also be available on the same specimen.

Serious complications of muscle biopsy are rare. A more common problem is bleeding under the skin -- hematoma formation -- which generally can be minimized by resting the biopsied muscle for 12 to 24 hours, with limited use of the biopsied limb for another 24 to 48 hours.

Nerve biopsy is also sometimes used with ALS, and is performed for very much the same reasons as muscle biopsy, that is, searching for explanations for the disease other than ALS. The nerve biopsy is generally less helpful in diagnosis, unless certain extremely rare conditions are present. Again, state-of-the-art processing, which is usually more scarce than muscle histochemistry, should be performed. Someone familiar with nerve biopsy processing should perform the procedure, to ensure that the best possible specimen is obtained and is of adequate size to perform the more numerous tests required for full evaluation. The nerve biopsy itself, like a muscle biopsy, will not give specific diagnostic information. It's only used in the unusual circumstance of the possibility of some other extremely rare conditions.

The procedure of nerve biopsy isn't as bad as it would seem. It's done under local anesthesia, and the discomfort is usually minor, even when the nerve is severed, except for a frequently minor electrical sensation similar to the sensation of a nerve conduction study, or hitting the "funny bone" at the elbow.

The risks of nerve biopsy are somewhat more than those of muscle biopsy, since the incision is frequently larger, and usually near the ankle, where good blood supply is sometimes compromised by atherosclerosis (partially blocked blood vessels). Healing problems such as wound breakdown, infection, etc., can create the need for prolonged wound care. Permanent numbness in the area served by the nerve is the usual result. This area is generally on the top of the foot and over the back of the heel. The nerve stump may "act up," particularly when mechanically stimulated (bumped), resulting in an electrical shock-like sensation, usually for less than six weeks. Prolonged or permanent pain in the distribution of the nerve is also reported, and must be accepted as one of the risks. This is extremely uncommon in my experience.

The nerve chosen is usually the sural nerve [in the calf], another sensory nerve or a nerve that doesn't control muscle, simply to avoid biopsy-related weakness. The findings in sensory nerves in ALS are much less impressive than in motor nerves, since the majority of the damage is in the motor neurons, not the sensory neurons. Again, because the nerve tissue isn't the primary site of the disease process, a specific diagnosis of ALS by nerve biopsy is also not possible. The need for a nerve biopsy is less common than that of muscle.

Your physician should explain the need for performing either of these somewhat invasive tests prior to performing the procedure. Some communication between the ordering (diagnostic) and performing (surgical) physicians is also recommended. In neuromuscular centers, the organization is optimal to obtain the best results with the least difficulty.

Robert T. Shebert is an associate professor of neurology and pathology at the University of Miami School of Medicine. This article first appeared in the fall 1998 issue of the Kessenich Family MDA/ALS Center Newsletter. The Kessenich Center is at the University of Miami. 

Return to Top

NEW STUDY OF GENETIC FACTORS IN NONFAMILIAL ALS

Investigators under the direction of neurologist Teepu Siddique at Northwestern University Medical Center in Chicago need people with ALS and their relatives to donate blood for a study of genetic factors that may predispose people to develop ALS. Siddique is an MDA research grantee and co-directs the MDA clinic at Northwestern Memorial Hospital in Chicago.

There is a known genetic type of ALS caused by any of a number of mutations in a gene known as SOD1 on chromosome 21. How-ever, many investigators have long suspected that there are also genetic "susceptibility factors" that may make the difference in whether or not someone develops ALS if he's exposed to other substances, such as environmental toxins or infectious agents. There's no clear evidence that any of these toxins or organisms cause ALS by themselves, but various genetic mutations, so far undefined, could tip the balance toward ALS in their presence.

The study is seeking individuals with sporadic ALS, who have no other identified ALS cases in their bloodlines, and unaffected relatives of the person with ALS.

If you are interested in participating, please contact Nailah Siddique, clinical nurse specialist, telephone (312) 503-2712; fax (312) 908-0865; e-mail, nsiddique@nwu.edu; or Joyce Kaplan, genetic counselor, telephone (312) 503-1054; e-mail, jkaplan@nwu.edu. 

Return to Top

PROTEIN "CHAPERONES" MAY BE ONE KEY TO LATE ONSET IN ALS

Basic research on the lowly fruit fly may have provided part of the answer to the question of why the onset of ALS tends to be later in life, even in people with familial ALS who presumably have the genetic background for ALS at birth.

The answer may lie with a group of small molecules called "chaperones" that perform a variety of functions in the cell, the most prominent of which is to "fold" freshly made proteins into their proper shapes. Some proteins naturally fold correctly, but others require chaperones to guide the folding process. Chaperones can also keep proteins from sticking to one another when they shouldn't -- hence the name.

Research on fruit flies reported in the journal Science suggests that chaperone proteins, in addition to guiding the folding process in normal proteins, are able to hide the effects of mutated proteins, possibly by helping these proteins to fold into their normal shapes, then by holding them in their correct shapes. In this way, chaperones could presumably ward off the effects of harmful mutations for many years, until the chaperone system is overtaxed by other sources of cellular stress such as environmental chemicals or age-related problems.

The theory sounds nice, but is there any evidence that chaperone proteins can protect cells from the effects of ALS-causing mutant proteins? Wendy Bruening, a postdoctoral fellow in the lab of MDA grantee Heather Durham of the Montreal Neurological Institute, had been trying to get cultured cells to make the mutant SOD1 protein that's linked to 10 percent to 15 percent of the cases of inherited ALS in humans. Unfortunately, many of the cells died. Recently, however, she discovered that the cells that survived had an increased number of chaperone molecules, and thus were better able to protect themselves against the continued presence of mutant SOD1 proteins.

Bruening also found that many tissues from mice that were engineered to have the mutant SOD1 protein demonstrated increased or normal chaperone activity, with the notable exception of cells from the spinal cord, which showed a decrease in chaperoning activity. The researchers suggest that the chaperone system may not be as robust in motor neurons as it is in the other cell types that weren't harmed by the mutant SOD1.

Could it be possible that, in humans, motor neurons are able to cope with incorrectly folded SOD1 proteins or other unidentified genetic problems for many years, until their chaperone systems become overtaxed by other sources of cellular stress?

"The ability of [certain chaperone proteins] to hide mutations until times of stress may be the key to explaining environmental interactions with the 'susceptibility' or 'modifying' genes that we suspect are the basis of neurodegenerative diseases," Durham says.

She says that interactions with the chaperone system may explain why the disease progresses at faster or slower rates in different people, as well as provide a possible explanation for the apparent manifestation or worsening of the disease following traumatic stress.

Durham suggests that one approach to treating ALS might be to try to make the chaperone system in motor neurons kick in faster at times of stress. However, she cautions that there is evidence that just having the chaperones in high gear all of the time may ultimately harm the cells. "What we want to do is have the system primed. Now the cells see the stress and activate the whole chaperone program at a lower stress threshold than they would normally require."

As for how to manipulate the chaperone system, a technique such as gene therapy in which the DNA instructions for making proteins are delivered to the cells in the body is one approach. Current methods of delivering new DNA to cells in humans haven't been very successful to date, but "people are working on that and eventually we'll figure it out," Durham says.

Another possibility is drug therapy. "We're looking now for existing drugs that might be helpful," Durham says, "but it's pretty early to talk about that specifically."

The work of Durham and MDA grantee Denise Figlewicz at the University of Rochester (New York) appears in the February issue of the Journal of Neurochemistry. 

Return to Top

NEW TRIAL OF BDNF NOW OPEN

Amgen/Regeneron Partners will begin testing BDNF given by subcutaneous (under the skin) injection during the first quarter of this year at nine U.S. sites. Exact criteria for eligibility aren't clear, but investigators are interested in talking with anyone with ALS about participation.

The sites are:

UCLA, Los Angeles, (310) 825-2937
University of California, San Francisco, (415) 476-1986
University of Colorado, Denver, (303) 315-7214; (303) 315-7221
University of Miami, (305) 243-7526
Washington University, St. Louis, (314) 362-6981
Columbia Presbyterian Medical Center, New York, (212) 305-8550
MCP/Hahnemann, Philadelphia, (215) 762-7692
University of Texas Southwestern Medical Center, Dallas, (214) 648-6419
University of Wisconsin, Madison, (608) 263-9057 

Return to Top

JAMES KELLER VISITED BY FAMOUS NEWSMAN

James Keller, the award-winning college baseball coach from Austin, Texas, who has been waging a battle against ALS for over six years, recently received a notable visitor at the Austin health care facility where he now resides.

TV journalist Dan Rather, who was visiting a family member at the same facility, had heard of Keller but never met him. He requested permission to meet Keller. On several occasions, Rather spent time visiting with the coach and expressing his personal admiration to Keller.

Keller, a devoted father of two boys, retired as baseball coach at Concordia Lutheran College in Austin on May 3, 1997, due to the progression of his ALS. In a moving ceremony, Keller's number 19 coaching jersey was permanently retired in honor of the coach's years of service to the team and the college. Keller attended the ceremony in his wheelchair, with sons Louis and Wesley at his side.

"That's the kind of honor that's traditionally reserved for extraordinary men like Lou Gehrig," MDA Executive Director and Senior Vice President Robert Ross said. "If you know Coach Keller, then you know that, for spirit and bravery alone, he easily ranks among that caliber of human being."

In the mid-1990s, Keller was a mainstay of the Jerry Lewis MDA Telethon, appearing in video vignettes that, at first, showed a vibrant, athletic man frolicking with his young sons at home and encouraging his college players at work. At the time, the effects of his ALS were hardly noticeable. Keller also appeared on the cover of the 1994 Labor Day weekend issue of Parade magazine, along with a story about his battle with ALS and his role on the Telethon.

As the disease progression continued, and as his mobility and speech became noticeably affected, Keller returned to the Telethon to speak of his faith that MDA-funded research would lead to new and better treatments for ALS. In 1996, Rilutek, the first FDA-approved ALS drug, appeared on the market, and researchers continue to strive to develop more effective therapies for ALS.

Ross, who stays in touch with Keller, says Keller's integrity and strength of character deeply impressed Jerry Lewis and everyone else involved with the Telethon. "You just felt honored to have him on your broadcast," Ross said. "He's an amazing man."

Although his formidable skills as a speechmaker have been compromised by ALS, Keller is still able to speak and write using an eye-directed communication device that can construct words and sentences and play them back as a synthesized voice.

Recently, the Greater Austin Sports Foundation presented its third annual James Keller Award. The award went to another distinguished college coach, Cliff Gustafson, former coach of the University of Texas baseball team.

"I'm deeply honored and humbled to be the recipient," said Gustafson, who, like Keller, has garnered praise for serving as a role model for players in his charge. "James Keller has earned the respect and love of everyone who ever knew him." 

Return to Issues Index