questions in this newsletter will focus on the genetics of ALS
Is ALS inherited?
often it is not. ALS can be divided into an inherited type (familial
ALS) and a non-inherited type (sporadic ALS). About 5-10% of cases of ALS are familial.
The majority of those cases show a pattern of inheritance
which is called autosomal dominant. To understand inheritance, it helps to understand
some basic genetic principles.
All genes come in pairs, known as alleles. Individuals with a dominantly inherited disease
possess one copy of a mutated gene and one copy of a “normal”
gene. Because the mutated
gene is dominant, the affected individual usually shows the features
of the disease. When that
individual has children, he or she will pass on one allele of
each pair in each egg or sperm cell.
Because half of the alleles code for the disease and half
are normal, there is a 50-50 chance that each egg or each sperm
cell will have the abnormal allele.
Assuming that this individual has a child with an individual
who is unaffected (has 2 normal alleles), there is a 50% chance
that the child of such a union will have the genetic basis for
developing the disease (one mutated allele, one normal) and a
50% chance that the child will be unaffected. Thus, the child of someone with familial ALS
generally has a 50% chance of developing ALS.
This probability is no different in males than in females. But, if someone with ALS has no family history
of the disease in close family members, then it is highly unlikely
that he or she has familial ALS.
Such a person with sporadic ALS can assume that the chance
of his or her children developing ALS is no greater than that
of the general population.
has been found to produce familial ALS?
in the SOD1 gene have been found to be present in about 20% of
individuals with familial ALS. The SOD1 gene codes for the enzyme superoxide
dismutase. Because only
5-10% of cases of ALS are familial, and because only 20% of these
familial cases have an SOD1 mutation, this means that an SOD1
mutation can be identified in only about 1-2% of all individuals
with ALS. So, 98-99% of
individuals with ALS do not have a known genetic basis for their
disease. It gets more complicated, because many scientists
and physicians who study ALS now believe that genetics may play
a larger role, even though the genes responsible for ALS have
not been identified. Why
else should some individuals develop this disease, while others
do not? The search for other genes, particularly in
sporadic ALS, is being led by Dr. Robert Brown at Harvard, and
Dr. Teepu Siddique at Northwestern, who are collecting blood samples
on individuals with sporadic ALS and their family members in an
attempt to identify a possible genetic basis for some cases of
testing be done in people with ALS?
usually. Most neurologists
and geneticists do not recommend genetic testing for individuals
with sporadic ALS or their families, because the SOD1 mutation
is virtually never found in such individuals.
For those with a family history of ALS that fits the pattern
of autosomal dominant inheritance described above, genetic testing
is sometimes done, but a decision about whether or not to have
such testing performed should be carefully considered.
Is the diagnosis uncertain, so that genetic testing is
being done for confirmation of diagnosis?
If that is the case, then only 20% of individuals with
familial ALS will have the SOD1 gene mutation, so that the genetic
test will be negative 80% of the time even if dominantly inherited
ALS is present! If the
test is being done so that other family members can be screened
for the gene, then a positive test for the mutation in the affected
individual will lead to accurate screening.
That is, if the person with ALS has the SOD1 mutation,
then a negative blood test on his or her children rules out the
possibility that they will develop familial ALS, but a positive
blood test is more complex. It
means that they are highly likely to develop familial ALS, but
tells nothing about when. Usually
the age of onset is similar, but not always.
And, in rare cases, the individual may carry the gene but
still not develop ALS. Also, not everyone wants to know if they are
carrying the gene. For
some, the stress of knowing that they are likely to develop ALS
is unbearable, while in others the stress of not knowing is even
worse. The bottom line
is that a good understanding of genetic testing is necessary before
such testing is performed. A
genetic counselor or a an experienced neurologist who is an expert
in ALS can and should provide such guidance.
Can you tell
me about the “ALS mice” that are used to help scientists understand
The mice are
known as “transgenic mice.” These are mice who have the human SOD1 mutation
inserted into their own genetic material, thus causing them to
develop a motor neuron disease as they age.
The value of transgenic mice is that they may lead to a
better understanding of the disease, and they permit studies of
possible treatments. If a drug looks promising, it can be given to
transgenic mice, who can be studied to determine whether or not
they develop ALS at the expected age, and whether the disease
progresses at the usual rate.
A treatment that delays the onset of the disease or slows
the rate of progression eventually may be a candidate for human
trials. Of course, the
model is not perfect for several reasons:
1) only a small fraction of human ALS is associated with
an SOD1 mutation; 2) the disease that develops in mice is not
precisely the same as human ALS; and 3) we cannot treat humans
before the disease develops to see if the onset of disease is
delayed, so we don’t really know what it means if the treatment
delays onset in mice. But,
the use of transgenic mice has led to a greater understanding
of human ALS, and is being actively used to test new treatments
and expand our knowledge of the underlying mechanisms of the disease.