Amyotrophic lateral sclerosis (ALS), also called
Lou Gehrig's disease, is a devastating disorder characterized
by progressive degeneration of the motor cells in the spinal
cord and brain (central nervous system). This degeneration
inhibits nerve impulses from getting to the muscles. Eventually,
a person with ALS experiences muscle weakness and deterioration,
particularly of the muscles used to move the arms and legs
as well as those involved in speech, swallowing, and breathing.
The cause is unknown, and at present there is no cure.
Approximately 90% of people with ALS (non-familial form) do
not have a family history of ALS in any closely-related family
members. In these individuals, the cause of ALS is complex,
resulting from a combination of both genetic and environmental
variables. Genes involved in the non-familial form of ALS
are sometimes called susceptibility genes
because they increase the risk to get the disease. Susceptibility
genes are believed to interact with other genes as well as the environment
to cause ALS.
The remaining 10% of individuals with ALS have the familial form of
the disease, in which multiple family members are affected
by ALS. The familial form of ALS includes both small families
where as few as 2 family members have ALS to families with
many family members with the disease. Genes that are involved
in the large families with many individuals with ALS are sometimes
called causative genes because
they are usually sufficient to cause ALS without any other
genes or factors involved. Genes involved in the smaller ALS
families can either be susceptibility or causative genes.
Many genes contribute to the cause of ALS. Identifying these
genes is the first step to understanding why someone gets
Our ultimate goal is to translate this information
into effective treatments for ALS.
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ALS research at the Duke Molecular Physiology Institute, formerly the Duke Center for Human Genetics, is multi-faceted. We
work collaboratively with many different groups and institutions
to find the genetic causes of ALS. We search for the genetic
factors involved in both the familial and non-familial forms
of ALS. We also focus specifically on those rare large ALS
families that have many family members with the disease. We
also study how the environment interacts with genes to cause
Some genes responsible for familial ALS are already known.
For example, a gene called superoxide dismutase 1 (SOD1) located
on chromosome 21q22 accounts for 20% of familial ALS. A second
gene, the alsin gene (ALS2) located on chromosome 2q33, causes
rare and slowly-progressive early-onset juvenile inherited ALS.
Researchers at the DMPI helped identify both of these ALS genes.
Collaborative research is the key to success.
The DMPI works closely with other researchers in order to find
the ALS genes.
For more than 20 years, the ALS group has been collaborating with
researchers at Vanderbilt University, Massachusetts General
Hospital, and Northwestern University to identify the gene(s)
which predispose some families to develop ALS.
Our Collaborative Amyotrophic Sclerosis Study (CALSS) has
greatly extended the genetic knowledge of ALS to include genes
on chromosomes 9, 16, 18, 20 and X in very large families
with many family members with ALS; as well as additional genes
on chromosomes 2, 7, 8, 17, 18, and 19 in the smaller and
non-familial ALS cases.
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DMPI researchers are also leading efforts to conduct a large-scale
genetic study of ALS in collaboration with the VA Medical Center (VAMC) in Durham,
North Carolina. Since ALS is a disease of high priority for the Department of
Veterans Affairs, the VA funded the establishment of a National
Registry of Veterans with ALS in 2003, which includes a DNA bank for storage
of patients’ blood samples. This effort is directed by the Epidemiologic
Research and Information Center (ERIC) at the Durham VAMC, with cooperation from
the VAMC in Lexington, KY. The ALS Association (ALSA) is advising the study leaders.
All living veterans who were diagnosed with ALS and related neurodegenerative diseases
were encouraged to participate in the research registry.
Registry enrollment ended in September 2007
but the registry continues to conduct follow-up interviews every 6 months
with living enrolled veterans. The registry has enrolled over 2100
veterans and banked over 1200 DNA samples. Collection of DNA samples will
continue through March 2008. In addition to follow-up interviews the
registry is focusing on helping researchers conduct multiple studies using
information collected as part of the registry. There have been 12 studies
approved to use registry data for epidemiological, observational and
This DMPI-led study uses the Registry as a resource to
specifically examine genetic and environmental risk factors
for ALS in veterans. Participants in the nation-wide Registry
are asked to provide information about their occupational,
residential, medical, and military history, as well as other
lifestyle factors (smoking, physical activity, etc.) during
a telephone interview.
In addition, we are currently enrolling healthy veterans without
ALS to serve as “controls.” Controls are individuals
who may have been exposed to similar environmental factors
but did not develop the disease. These healthy veterans are
asked to provide a DNA sample and complete the same telephone
interview about environmental exposures.
By comparing both genetic variants
and environmental exposures of veterans with and without ALS, the DMPI and VAMC
researchers hope to identify factors that may trigger the development of ALS in
genetically susceptible individuals.
Ultimately, we hope understanding the complex genetics of
ALS will provide us with insights into the causes of this
devastating disease and will help guide us to novel therapeutic
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As DMPI researchers continue to define the genetic causes
of ALS, they publish their findings in leading academic journals and share their
knowledge with colleagues at meetings and conferences.
Duke ALS Clinic
27001 Agoura Road, Suite 150
Calabasas Hills, CA 91301
Phone: (818) 880-9007
Patient Hotline: (800) 782-4747
Fax: (818) 880-9006
Muscular Dystrophy Association
3300 East Sunrise Drive
Tucson, AZ 85718-3208
Phone: (602) 529-2000; (800) 572-1717