GENE MAPPED FOR EARLY-ONSET, SLOWLY PROGRESSIVE FORM OF ALS

The gene for an early-onset but slowly progressive form of ALS has been mapped to a small region of chromosome 9. The disorder is considered a juvenile-onset form of ALS.

"Unlike classical ALS, this form has a very slow progression and is probably compatible with a normal life span," said MDA grantee Phillip Chance, who headed the research team that published its findings in the March issue of the American Journal of Human Genetics. Chance, a neurologist and genetics researcher, was at the University of Pennsylvania in Philadelphia at the time of the study but has since moved to the University of Washington in Seattle.

"The disorder involves wasting of the muscles of the lower legs, forearms, upper arms and thighs, and people are frequently in wheelchairs in their 50s and 60s, with little functional hand use," said Chance, noting that the average age of onset of this form of ALS is 17, as opposed to late middle age for the classical form of ALS.

"It was really through the generous participation of this huge family, the Mattingly family, that we were able to carry out the genetic studies that resulted in mapping the gene to chromosome 9," Chance said.

David Cornblath of the Neurology Department at Johns Hopkins University School of Medicine in Baltimore is also an MDA grantee and also worked on the project. "Juvenile ALS is not so terrible as later-onset ALS," Cornblath noted, recalling that some members of the Mattingly family were originally told they had a much less severe disease known as Charcot-Marie-Tooth disease, a peripheral neuropathy. Cornblath said the new gene finding may provide "another pathway for studying ALS."

The doctors say Andrew Jackson, a retired Black and Decker executive from Baltimore, was the family member most responsible for getting the genetic studies accomplished. Jackson, now 70, has had this slowly progressive form of ALS since he was a young man. He now uses a wheelchair and has little arm or hand function.

Contributing to ALS research has meant a great deal to him, Jackson said. "I was a true workaholic at Black and Decker," he said, "because I couldn't do things that others could do, physically. But I always wanted to get a research project started for this disorder after I retired."

Jackson, whose mother was a Mattingly, helped organize a family reunion on Solomon's Island, Md., in June 1994, that was the kickoff for the family study.

Chance emphasized that, at this time, the precise gene for the disorder isn't known, and its identification is a crucial step in developing further understanding of or treatments for this genetic disease. "There are a number of interesting genes in that region on chromosome 9 that will be tested," Chance said. "We're well on the journey."

Understanding the gene's normal and abnormal functions will provide researchers with another mechanism to explain the loss of muscle-controlling nerve cells (motor neurons) in ALS, Chance said, with potential implications for other forms of ALS and other motor neuron disorders.

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NEW MECHANISM MAY EXPLAIN MANY SPORADIC ALS CASES

An MDA-supported research team at Johns Hopkins University School of Medicine in Baltimore has uncovered a previously hidden but possibly very common mechanism to explain many cases of sporadic, or non-genetic, ALS.

Neurologist and neuroscientist Jeffrey Rothstein, a longtime MDA grantee at Hopkins who also co-directs the MDA clinic at that institution, led the research team. Rothstein has been receiving MDA funding for several years to study the role of glutamate, a natural substance that carries signals between nerve cells but can be toxic under some circumstances. The only drug currently on the market for the treatment of ALS is riluzole (Rilutek), a glutamate inhibitor.

Researchers have known for some time that a phenomenon known as glutamate transport -- the clearing away of glutamate from the area between cells after it has transmitted a signal -- is often inadequate in people with ALS. This clearing process is normally accomplished by proteins known as glutamate transporters, one of which Rothstein had previously found to be deficient in many ALS patients. Now we understand why.

In a landmark paper published in the March issue of Neuron, the team reported that it found that the problem with an important glutamate transport protein known as EAAT2 isn't in a gene but, rather, is in the processing of the genetic message after the DNA, or gene, stage.

"These studies tell us two things," Rothstein said. "They explain why there is loss of the glutamate transporter in ALS and, perhaps more importantly, they provide us with a new mechanism for a neurodegenerative disease. It will be a great challenge to unravel this mechanism."

The initial "code" for all proteins is found in the DNA, or genes, arranged on chromosomes in every cell. When there's a signal to manufacture a protein, the DNA code is transcribed into an RNA code; from there, the actual protein is made. RNA is the chemical step between DNA and a protein. RNA itself has multiple steps in its own processing. The final step leads to the final code, which is messenger RNA, or mRNA.

Rothstein has solid evidence that what goes wrong with the glutamate transporter EAAT2 in ALS is a problem in the processing of RNA so the mRNA code for this protein is wrong.

Rothstein found one kind of garbled mRNA code for the glutamate transporter EAAT2 in 20 out of 30 tissue samples from people with ALS and found another kind of garbled mRNA for this protein in 11 of the 30.

In another part of the study, garbled mRNA was found in the cerebrospinal fluid (CSF) in 12 of 18 patients. Rothstein said this finding might "provide us with a new diagnostic tool. A much larger study will be necessary to determine if the CSF analysis will be useful clinically." Earlier diagnosis might allow earlier treatment with glutamate-inhibiting drugs.

These mRNA abnormalities weren't found in the control groups, which included people with other types of neurological disease.

The garbled mRNA codes decrease the amount of effective glutamate transport protein, which decreases glutamate removal from the area around motor neurons. Such transport deficiencies probably lead to a toxic buildup of glutamate and to the development of degeneration of motor neurons in the brain and spinal cord, the hallmark of ALS. In the brain, the mRNA abnormalities were specific to those areas that degenerate in ALS.

The findings support the current use of glutamate inhibitors such as riluzole in the treatment of ALS and indicate the need for further studies of glutamate transporters and of RNA processing mechanisms that affect these proteins. Such studies could lead to better treatments.

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HEARING ON MYOTROPHIN CANCELED
FDA Clock Runs Out May 11

The scheduled April 9 Food and Drug Administration hearing on the experimental ALS drug Myotrophin didn't take place for reasons that aren't entirely clear.

According to a press release from the drug companies Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.), makers of Myotrophin, the hearing was canceled "to allow the agency [FDA] to continue its review of the companies' new drug application (NDA) seeking clearance to market Myotrophin (mecasmerin) injection for the treatment of ALS."

Kori Beer, spokeswoman for Cephalon, said: "All that we know is that the FDA has canceled the advisory committee hearing. It is our understanding that they were not prepared to make a presentation to the committee. Under the Prescription Drug User Fee Act, which establishes performance standards for the agency, the FDA has until May 12 to render a decision on the NDA. We're anxious to offer Myotrophin to all patients with ALS and hope the agency will approve it."

Susan Cruzan, spokeswoman for the FDA, said that the hearing was postponed "because we haven't completed our analysis. Further analysis by the agency and the sponsor [Cephalon and Chiron] were not complete and ready for discussion. The FDA sets up meetings, but they are tentatively planned. They haven't completed the things they need to do for this; a lot goes into it."

The drug Myotrophin is based on a natural substance known as insulin-like growth factor 1, or IGF-1. It has to be injected. Animal and laboratory data have suggested that this substance might help preserve nerve or possibly muscle cells in people with ALS. However, the drug approval process for Myotrophin has not been smooth.

Cephalon and Chiron first went before the FDA in January 1996, at which time the agency turned down their application to distribute the drug to people with ALS in an "early access" program (a program of limited free distribution for a drug not yet approved for marketing). In June of that year, however, that application was approved, and the access program began shortly thereafter.

In May 1997, the drug companies again went before the FDA to try to get full marketing approval for the drug, submitting a New Drug Application, or NDA. This application was denied by a vote of 6 to 3 by the Peripheral and Central Nervous System Drugs Advisory Committee. The committee was especially concerned that, in a large European trial of Myotrophin, more patients died in the treated groups than in the untreated group. In a large North American trial, patients on Myotrophin fared somewhat better than untreated patients. The committee asked for more data to "break the tie" of the two contradictory trial results.

Following an outcry of protest from some members of the ALS community over the denial of the application for Myotrophin, the FDA announced it would make a final decision about the drug on Aug. 11, 1997. On that date, the decision was postponed until Nov. 11. That date also came and went, with the understanding that the FDA had to make a decision about Myotrophin within six months (May 11, 1998).

You can keep up with developments regarding Myotrophin by calling Cephalon's hot line at (800) 896-5855.

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SEVERAL PROPOSED BILLS MAY AFFECT ALS FAMILIES

Some 90 cosponsors in the House of Representatives have signed on to support the Amyotrophic Lateral Sclerosis Research, Treatment and Assistance Act of 1997, but more sponsors are needed, backers say.

The bill was introduced in June by Rep. Walter H. Capps, D-Calif., who died unexpectedly in October. The primary sponsor is now Lois Capps, who was elected in March to fill her late husband's seat.

The major provision of H.R. 2009 would waive the 24-month waiting period for Medicare eligibility on the basis of disability for those with ALS. The bill would also provide Medicare coverage for outpatient drugs and therapies for ALS. In addition, it would double federal funding for ALS research.

A spokesman in Capps' office said the bill will probably be attached to other health legislation for debate. Broad bipartisan support will enhance the likelihood of its being passed.

You can encourage your congressional representative to cosponsor H.R. 2009. Since many lawmakers aren't familiar with ALS, a letter, phone call or visit from a person with the disease, explaining how you'd be personally affected by passage of the bill, can have a great impact.

In other government action, President Clinton has proposed allowing Americans ages 62 to 65 to purchase Medicare coverage for about $300 a month. In addition, displaced workers ages 55 to 62 who have involuntarily lost their jobs and health insurance could purchase Medicare coverage for about $400 a month.

The Clinton administration estimates that this targeted reform would help about 10 percent of the 3 million uninsured Americans between ages 55 and 64, but acknowledges that the cost could price it out of the range of many. This reform would be most advantageous to those with pre-existing conditions who lost coverage when their spouses retired or joined Medicare.

Several new and proposed regulations to protect consumers enrolled in managed health care plans such as health maintenance organizations (HMOs) have also been introduced. (See "Democracy Takes on Managed Care," Quest, MDA's newsmagazine, Vol. 4, No. 6.)

Last year's Balanced Budget Act protects Medicare beneficiaries by prohibiting restrictions limiting the advice doctors can give about treatment options; guaranteeing the right to appeal care denials; guaranteeing payment of emergency room visits if a prudent layperson would have thought he was in jeopardy; and protecting the confidentiality of health records.

The president, by executive order, has extended a health care "bill of rights" to nearly 90 million Americans enrolled in federal health care programs. He's also proposed that these rights, including guaranteed access to specialists, become part of private managed care plans.

Members of Congress have introduced several counterproposals to the president's proposed "bill of rights," all of which would increase consumer choice and protections in health care.

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YOU CAN HELP MDA FIGHT ALS THROUGH WILLS, TRUSTS

Bequests and other gifts earmarked for ALS research have long been a significant part of MDA's planned giving program. In the latest year measured, planned gifts designated for the ALS program made up about 16 percent of the total funds MDA received through planned giving. In a recent six-year period, MDA was the beneficiary of more than $1 million left to its ALS program through wills.

MDA supporters have bequeathed amounts varying from $1,000 to $500,000 for ALS in their wills. Donors may leave cash, specific properties or assets, a percentage of their estates, or a percentage of the remainder of their estates after other beneficiaries have been provided for.

For those who want to designate $100,000 or more to MDA's fight against ALS, the best means is often one of the trusts that MDA can arrange for you.

Among these planning tools are the charitable remainder trust and the charitable lead trust. To create a charitable remainder trust, you first select the assets that will fund the trust -- cash, stocks, bonds, mutual funds, other property -- and then name a trustee to manage the funds.

Your trust can provide you, or another family member, with regular payments from the trust's earnings for a designated period of time or until the death of the last beneficiary. Then MDA, as the named charitable recipient, receives the assets remaining in the trust when it "dissolves."

A charitable lead trust allows you to direct payments to the Association and have the property returned to you or others you name when the trust terminates. This can be an attractive way to pass assets on to loved ones by reducing estate and gift taxes.

For example, a man in Maryland whose wife died of ALS established a charitable remainder annuity trust of $100,000 in 1991. He receives an annual income from the proceeds of the trust, and the principle will go to MDA at the end of his life.

A Florida family designated $500,000 in trust to MDA in memory of their daughter, who had ALS. A similar gift of $250,000 was made to MDA by a California family as a way to remember their daughter.

Trusts are an advantageous way to produce income, create tax savings and help MDA fight a disease that's touched your life.

To learn more about wills, trusts and other planned giving opportunities, contact Fred Stecker, MDA's director of Planned Giving, at (800) 572-1717, for detailed information that can help you save money by taking advantage of tax provisions. You should consult your own financial adviser as well.

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NEW MDA ALS CENTER OPENS IN UTAH

The 17th multidisciplinary MDA center devoted to ALS care and research opened in April in Salt Lake City. The MDA/ALS Center at the University of Utah will operate within the Department of Neurology under the direction of Dr. Mark B. Bromberg.

Bromberg, a former MDA research grantee and an investigator into possible treatments for ALS, has served as co-director of the MDA clinic at the university since 1994.

To contact the center, write to: MDA/ALS Center at the University of Utah, Mark B. Bromberg, M.D., Ph.D., Department of Neurology, School of Medicine, 50 N. Medical Drive, Salt Lake City, Utah 84132.

For further information, call David Ricketts, MDA's local program service coordinator, at (801) 278-6200.

MDA/ALS centers offer highly focused programs of research and medical management directed at combating ALS. For a complete list of MDA/ALS centers, visit the ALS site. The list also can be found in the February 1998 issue of The ALS Newsletter (Vol. 3, No. 1).

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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
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