Gene Found for Early-Onset ALS May Shed Light on All ALS Forms

by Margaret Wahl on Sat, 2004-05-01 07:00

An international research group that received significant MDA support has isolated a gene for a rare, slowly progressive, early-onset form of ALS. The disease, called ALS4,has been known since 1998 to result from a defect on chromosome 9.

The finding, published this month online in the American Journal of Human Genetics, shows that mutations (flaws) in the gene for a newly identified protein known as senataxin are responsible for this unusual form of ALS.

Although senataxin’s cellular function is far from completely understood, it appears to play a role in the way RNA — the chemical step between DNA and protein manufacture — is processed inside cells.

Clue to ALS mechanisms

Jeffrey Rothstein
The ALS4 research team at the University of Washington, Seattle. Left to right: Craig Bennett, Huy Huynh, Ying-Zhang Chen and Phillip Chance.

The finding will certainly lead to genetic diagnosis and perhaps to treatment for ALS4, but researchers are optimistic that it may have broader implications for ALS in general.

Phillip Chance, professor of neurology and pediatrics at the University of Washington in Seattle, led the international team, which pooled DNA samples from four countries.

“Given that mutations in senataxin associated with ALS4 lead to motor neuron degeneration, a shared disease mechanism in all forms of ALS, both juvenile- and adult-onset types, might exist,” Chance said.

MDA grantee Craig Bennett, research assistant professor of pediatrics at the UW, also thought the new finding might have meaning beyond ALS4.

“While it’s very early in our analysis, it’s quite an intriguing suggestion that pathways that lead to ALS4 may overlap with those that lead to motor neuron death in other [contexts],” he said. “More specifically, we hypothesize that common pathways may involve defects in RNA processing in motor neurons. Such questions may be addressed and answered in systematic research studies.”

Another research team has already discovered that a different mutation in the senataxin gene can lead to the neurologic disorder ataxia-oculomotor apraxia.

Early onset, long survival

ALS4 begins in childhood or adolescence and progresses slowly throughout life. Like other forms of ALS, the disease causes progressive weakness of the limbs, particularly of the lower legs, feet, forearms and hands.

But, unlike other forms of ALS, which usually lead to death within a few years from respiratory impairment, ALS4 doesn’t appear to affect the respiratory muscles. The muscles involved in chewing, swallowing and speaking (the bulbar muscles) are likewise spared, in contrast to adult-onset ALS.

People with ALS4 can lead a long life, albeit one eventually affected by severe disability.

In its early stages, the disease is so mild it’s sometimes been diagnosed as Charcot-Marie-Tooth disease, a much less severe condition than ALS.

The research team, which included MDA grantees Ying-Zhang Chen at the UW and Klaus Wagner at Karl Franzens University in Graz, Austria, pooled DNA samples from families with juvenile-onset ALS in the United States, Belgium, Austria and Australia (originally from England). Mutations in the senataxin gene were identified as the cause of the disease in all but the English family living in Australia.

Chance said the new finding wouldn’t have been possible without the assistance and determination of Andrew Mattingly Jackson, patriarch of the Mattingly family, in which some 50 people have been affected by ALS4. Chance was also a member of the team that found in 1998 that the ALS4 gene lay within a small region of chromosome 9.

Recruitment for the U.S. part of the study, which included a large family reunion in the mid-1990s, was “organized almost single-handedly by Andy Jackson,” Chance said (see “Energy and Curiosity”).

Margaret Wahl
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