Motor neuron disease is a rare, devastating illness in which nerve cells that
carry brain signals to muscles gradually deteriorate. One form of it, Lou
Gehrig's disease or ALS (amyotrophic lateral sclerosis), is familiar to the
public in the lives of scientist Stephen Hawking and Morrie Schwartz, about whom
Mitch Albom's "Tuesdays with Morrie" was written.
For most MND patients,
the cause is unknown. Figuring out why these people develop the disease, which
causes muscles to weaken, atrophy and cease to function, is an important step in
developing therapies to treat or prevent motor neuron disease.
team of University of Michigan scientists has gotten a step closer:
They have discovered mutations in one key gene (neuropathy target esterase, or
NTE) that cause a previously unknown type of inherited motor neuron disease.
* The discovery paves the way for better diagnosis and research on
* Most intriguing, the scientists found the mutations caused
changes in a protein already known to be involved when people develop neurologic
disorders as a result of exposure to toxic organophosphates - chemicals commonly
used in solvents and insecticides and also as "nerve gas" agents. This discovery
points to a new lead in the search to understand MND.
there may be gene-environment interactions that cause some forms of motor neuron
disease," says John K. Fink, M.D., professor of neurology at the U-M Medical
School and senior author of the new study, which appears in the March issue of
the American Journal of Human Genetics
. He also is a researcher at the VA
Ann Arbor Healthcare System.
"Our findings support the possibility that
toxic organophosphates contribute to motor neuron disease in genetically
vulnerable people," says Fink. He believes the results suggest that altered
activity of the gene found in patients in the study may also contribute to other
motor neuron disorders, possibly including ALS. Motor neuron disease affects
five per 100,000 people.
The findings are an exciting first step in
uncovering a possible link between the environment and motor neuron disease,
says Shirley Rainier, a research assistant professor at the U-M Department of
Neurology and the first author of the study. "Why does one person in a family
get it, and another doesn't?" Piecing together a puzzle
In the 1930s, an estimated 50,000 people in the U.S. became lame or
otherwise neurologically affected by neurotoxic organophosphates when they drank
a contaminated batch of "ginger jake," an alcohol-containing potion that was
legal during Prohibition.
Ginger jake suppliers substituted a
lubricating oil for the oil usually used, castor bean oil, when castor bean
prices went up. A 2003 article in the New Yorker detailed the sad results, which
led bands like the Mississippi Sheiks to write songs about the "ginger jake
More recently, there have been incidents in Fiji, India and
Africa when accidental consumption of oils containing neurotoxic
organophosphates (instead of cooking oil) caused death or nerve damage for tens
of thousands of people. Although scientists don't yet know the exact manner in
which toxic organophosphate exposure leads to progressive and permanent nerve
damage, they have learned that this process involves disturbance of an enzyme,
NTE, contained within nerves.
Fink examined members of two families who
had progressive weakness and spasticity (tightness) in their legs, as well as
muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M
professor of neurology and an expert in neuromuscular disorders, studied nerve
and motor function. Rainier performed genetic studies and determined that the
gene for the condition was on a region of chromosome 19.
Ph.D., co-chair of human genetics at the University of Utah, and his team
performed genetic analysis that confirmed this location and excluded other areas
in the genome. Among the many genes in this region of chromosome 19, one gene
stood out as particularly likely: the gene that encodes for NTE. Because of its
known role in organophosphate-induced neurological disease, the NTE gene was
considered an important candidate gene and was studied immediately.
Analysis showed that the affected people in each family had NTE gene
mutations. These mutations altered a critical part of the NTE protein called the
esterase domain. Fink has named the inherited condition "NTE motor neuron
disease." It begins in childhood and progresses slowly, with symptoms of
weakness and spasticity in the legs and muscle atrophy in the hands and lower
Next, Fink and his team want to learn if mutations in the NTE gene
happen in other types of motor neuron disease such as ALS, and if the mutations
make a person more vulnerable to neurological damage from organophosphate
exposure. Fink's lab is currently using fruit flies as a model to study the NTE
mutations, with the goal of finding treatments for people with motor neuron
----------------------------Article adapted by Medical
News Today from original press release.