The Below Information Is Reproduced From:
http://alsawareness.com/lou_gehrig
What is ALS? Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease,
first described in 1869 by the noted French neurologist Jean-Martin Charcot.
Although the cause of ALS is not completely understood, the last decade has brought
a wealth of new scientific understanding about the disease that provides hope
for the future.
Lou Gehrig first brought national and international
attention to the disease in 1939 when he abruptly retired from baseball after
being diagnosed with ALS. Most commonly, the disease strikes people between the
ages of 40 and 70, and as many as 30,000 Americans have the disease at any
given time. ALS has cut short the lives of other such notable and courageous
individuals as Hall of Fame pitcher Jim "Catfish" Hunter,
Senator Jacob Javits, actors Michael Zaslow and David Niven,
creator of Sesame Street Jon Stone, television producer Scott Brazil, boxing champion Ezzard
Charles, NBA Hall of Fame basketball player George Yardley, pro
football player Glenn Montgomery, golfer Jeff Julian, golf caddie
Bruce Edwards, British
soccer player Jimmy Johnstone,
musician Lead Belly (Huddie Ledbetter),
photographer Eddie Adams, entertainer Dennis Day, jazz musician Charles Mingus, composer Dimitri Shostakovich, former vice
president of the United States Henry
A.
Wallace and U.S. Army General Maxwell Taylor.
ALS is a neurodegenerative disease that usually attacks both upper and lower
motor neurons and causes degeneration throughout the brain and spinal cord. A
common first symptom is a painless weakness in a hand, foot, arm or leg, which
occurs in more than half of all cases. Other early symptoms include speech
swallowing or walking difficulty.
The biological mechanisms that cause ALS are only partially understood. The only
known cause of ALS is a mutation of a specific gene: the SOD1 gene. This
mutation is believed to make a defective protein that is toxic to motor nerve
cells. The SOD1 mutation, however, accounts for only 1 or 2 percent of ALS
cases, or 20 percent of the familial (inherited) cases.
Familial ALS represents between five to 10 percent of all cases. The rest arise
spontaneously and mysteriously, making seemingly random attacks on previously
healthy adults. ALS can strike anyone, anytime.
Physicians have limited choices for treating ALS, and the options that do exist
have come into use within the last 10 years. Studies suggest that patients'
length of survival and quality of life are enhanced by night-time breathing
assistance early in the course of the disease and by aggressive application of
alternate feeding options to assure good nutrition once swallowing becomes
difficult. At this time, RiluzoleŽ (Rilutek) is the only
drug that has been approved by the FDA for treatment of ALS. In clinical
trials, RiluzoleŽ has shown a slight benefit
in modestly increasing survival time.
Stem cell and gene therapy are promising areas of research. In a variety of
studies, ALS mouse models are being used to develop treatments that may someday
lead to similar human clinical trials. Gene therapy is one field of research
where The ALS Association is concentrating support for more study.
More significant advances of research into ALS has occurred in the last decade
than all of the time since Charcot identified the disease. Advances in
technology and the genetic revolution are aiding researchers in unlocking the
ALS mystery. As more scientists focus on this perplexing disease, the outlook
for new understanding brightens each day.
The Below Information Is Reproduced From:
http://www.catfishchapter.org/learn/about/genetic.pdf
Genetic Testing for ALS
Written by Mara Gaudette, MS, Genetic Counselor
Formerly of Northwestern University
Updated November, 2004 by Lisa Dellefave
Q. Is ALS hereditary?
Formerly of Northwestern University
Updated November, 2004 by Lisa Dellefave
A.
ALS is directly hereditary in only in a small percentage of families. The majority
of patients with adult-onset ALS (90%) have no family history of ALS, and
present as an isolated case. This is called sporadic ALS (SALS), and although
there is likely a genetic predisposition involved, SALS is not
directly inherited in a family. Rare exceptions are when familial ALS (FALS) is
masked due to an incomplete family history, such as if the patient is adopted
or the patient's parents died at ayoung age. The remaining10% of persons with
ALS have a close second family member with ALS, which is referred to as
familial ALS (FALS).
Currently the best tool to distinguish between SALS and FALS is the family history. A neurologist or genetic counselor will ask whether anyone else has ever been diagnosed with ALS, and if anyone else in the family had progressive walking or speech problems. If so, they will likely ask additional questions to see if the health problems were related to ALS or any number of other causes. They will also inquire about the ages that family members passed away to see if any close relatives passed away at a young age, meaning that a long health history is not available. It is very common to have limited information on one's family, but most families can still be reassured since the majority of instances of ALS are not hereditary. Older relatives are often good sources of family history information, and medical records can often be obtained with the help of a hospital's medical release form.
Q. How is FALS inherited?
A.
To answer this question, it is helpful to review background information on
genetics as it pertains to FALS. Every cell in the human body contains genes.
Genes have many functions. Some genes contribute to traits like eye and hair
color while other genes are responsible for making proteins that determine how
our bodies circulate blood or send nerve signals to muscles. When a gene is
disrupted by a change in its sequence (called a gene mutation), the gene cannot
function correctly.
Genes are packaged in chromosomes. Chromosomes are present in pairs. The genes
that reside within chromosomes are therefore also present in pairs. In each
chromosome pair, one chromosome is inherited from the mother and one is
inherited from the father. We have 23 pairs of chromosomes, giving us a total
number of 46 chromosomes. The first 22 pairs are the numbered chromosomes in
which both males and females share them in common. Only the 23rd pair differs
between males and females since this pair is the sex chromosome
where females typically have two Xs and males have an X and a Y.
There are at least 3 different inheritance patterns for FALS. The most common
inheritance pattern for FALS is called autosomal dominant. Autosomal means that
it is equally likely that a female or male would inherit the gene mutation for
FALS because the gene is located on a numbered chromosome that both males and
females share in common. Dominant refers to the fact that a person only needs
one gene to have a mutation coding for FALS to have an increased risk for
ALS. So someone who has FALS would have one gene with a mutation and one gene witout
a mutation. Therefore, a child born to someone who has FALS has a 50% chance to
inherit the FALS gene mutation and conversely, a 50% chance to not inherit the
FALS gene mutation. The 1 in 2, or 50% chance, comes from the fact that parents
randomly pass on only one member of their gene pair, so that either the gene
with the mutation will be passed on or the gene without the mutation will be
passed on. Even though parents often feel responsible for their children's
health, they have no control over which gene they pass on, just as their parent
had no control which gene they passed onto their child. It is also important to
remember that inheriting the gene for FALS in no way guarantees that a person
will develop symptoms of ALS. If a child does not inherit the
gene mutation for ALS, they cannot pass it onto their children.
Q. Is there a genetic test for FALS?
A. Yes,
although genetic testing is still limited in FALS. Changes in one gene located
on chromosome #21 and called superoxide dismutase (SOD1) have been found in
about 20% of families with FALS. The SOD1 gene is composed of five regions
called exons. If you think of your genetic material as a string of letters that
together make up a book of instructions for the human body, the SOD1 gene is
one chapter and composed of 5 different pages. SOD1's normal role is to
detoxify substances called free radicals, which can be harmful to cells.
Changes in the SOD1 gene are thought to create a new but still undefined
function that is toxic to motor neurons. Most often, SOD1 changes are inherited
in an autosomal dominant manner.
Prenatal
genetic testing technology for the SOD1 mutation exists. Patients and their
families should discuss questions and concerns with their neurologist and
genetic counselor for more information about this complex and personal matter.
Of particular note is that the majority of families with FALS (80%) will not
have a change in their SOD1 gene and therefore, a normal SOD1 genetic test is
not informative in a family where an SOD1 change has not been identified.
Although researchers are diligently looking for other genes, at this time there
is no genetic testing to offer non-SOD1 families. Therefore, the determination
that an individual has FALS is typically based on family history rather than a
genetic test.
A.
No. Since the vast majority of patients do not have the hereditary type of ALS,
diagnosis of ALS is not determined by a genetic test. Instead, a neurologist
makes the diagnosis after a review of a person's symptoms, a neurological exam,
and results on nerve and muscle function tests. Clinically, FALS and SALS are
basically identical.
Q. Who is appropriate for genetic testing?
A.
Anyone who has symptoms of ALS in addition to a family history of ALS, such as
a parent, grandparent, aunt or uncle, or a brother or sister. Additionally, if
one's family history is unknown or a parent passed away at a young age, testing
is also appropriate. However, only about 2% of all patients with ALS will have
an SOD1 genetic change. Those patients with ALS without a family history
can also be offered genetic testing but it is extremely important that it is
offered in the context of genetic counseling or discussion with a neurologist
about the implication of finding a mutation, as a mutation would mean the ALS
is now hereditary in an apparently sporadic situation.
Q. What would the results of the genetic test tell me?
A.
A positive test means that the genetic cause of FALS has been identified.
Researchers have developed a mouse model with the same genetic change so that
they can better understand how a change in the SOD1 gene can lead to the
symptoms of ALS. Currently, new therapies are being tried on this animal model
to slow or halt the progression of ALS. Although still in the distant future,
gene therapy to correct the genetic change is also being researched. A positive
test does not change medical treatment at this time and may or may not provide
prognostic information. Even though the inheritance may already be established
by the family history, an individual may feel furthered burdened by learning they
carry a change in their SOD1 gene as concerns for children resurface. Others
prefer to have this knowledge and may feel comforted that there is much
research aimed specifically at ALS caused by changes in the SOD1 gene.
A negative test means only that the genetic cause of ALS has not been
identified. However, this does not rule out familial ALS since there are still
other unidentified genes that cause ALS in 80% of FALS families.
Q. If I have a family history of FALS, should I have a genetic test even if I don't have symptoms?
A.
This situation is called presymptomatic testing. The decision to have presymptomatic
genetic testing is highly personalized and often individuals in the same family
will disagree whether to pursue it. However, in order for the test to be
meaningful, a genetic change in the SOD1 gene needs to first be found in a
family member affected with ALS. When an SOD1 change is not identified in
a symptomatic person, presymptomatic genetic testing is not available for other
family members, because the ALS is being caused by an unidentified gene, thus
we cannot test for it.
Benefits of presymptomatic genetic testing in ALS is limited by the absence of
preventative treatment, the inability to predict the age at which someone who
is a gene carrier will get ALS, or even that a gene carrier will definitely get
ALS. Since both a negative or positive presymptomatic test result in a known
SOD1 family can have a great emotional impact, genetic and psychological
counseling is usually required before undergoing such testing (A presymptomatic
genetic testing protocol is typically followed). Individuals often consider
how the information that they did or did not inherit the predisposing
gene would affect their lives, who they would tell about the results, and how
relationships may change depending on the results.
Individuals who learn they do not carry the SOD1 change often feel great
relief, although they can sometimes wonder why they escaped while another
family member did not. They may regret past decisions made based on the
presumed at risk status, or find it hard to let go of that part of their
identity. Learning that one does carry a predisposing gene, is usually more
difficult and that person may need ongoing professional support. Ambiguity is
not entirely erased as the question may change from do I carry the gene to when
or will I get symptoms? Commitment to friends and family may be strengthened.
However, knowledge of the testing by insurance companies or employers is a
concern regarding future coverage. A genetic counselor can further discuss the
issues involved in presymptomatic testing.
Q. How is the genetic test done?
A.
A blood sample is taken and sent to a specialized lab where the genetic
material, also called DNA, is removed. Special laboratory techniques allow the
SOD1 gene to be replicated and then tested. One form of testing is runnign
the sample on a gel to generate a series of bands. If a genetic change is
present, the bands will be in a different location compared to a control sample,
which is known not to have a genetic change in the SOD1 gene. This method is
called single strand conformation polymorphism or SSCP for short. Another
method called sequencing may also be used to either initially test or confirm
results. Sequencing is able to view the DNA on a finer scale by displaying the
actual letters of the "instruction book" so that changes can be seen.
Q. How long does the genetic test take?
A. Because five
different parts of the SOD1 gene need to be looked at, the testing usually
takes about 2-3 months. The cost is about $300-500 depending on the clinical
laboratory that is doing the testing.
For more information, contact:
Sandra Donkervoort,
M.S.
Genetic Counselor
Neuromuscular Disorders Program
Northwestern University Feinberg School of Medicine
300 East
Superior Street
Tarry Building 13-715
Chicago, IL 60611
Phone: 312-503-0154
s-donkervoort@northwestern.edu
Fax: 312-908-0865
www.neurogenetics.northwestern.edu