Here is something I picked up on the me-list. I did
think the bit about SSRIs was interesting but alas, I
still think that *for my child* they have not been
particularly useful.- A.C.
The Hunt for Autism Genes:
A Conversation With Researcher Ed Cook, M.D.
by Catherine Johnson
You have to kiss a lot of frogs to get a prince," Ed
Cook says, remembering the time he and partner Eric
Courchesne thought they had found the perfect candidate
gene for autism. The gene-now known to cause
Angelman's syndrome-looked remarkably promising: it
expressed itself only in the hippocampus and in the
Purkinje cells of the cerebellum, two areas of the
brain known to be affected in autism. How could it not
have something to do with the disorder?
But so far it hasn't panned out.
For gene-hunters like Cook and his colleagues,
brilliant hypotheses that don't work are more the rule
than the exception. So it is impossible to exaggerate
the excitement generated among autism researchers when,
in just the course of the past couple of years, several
leads finally began to pay off.
And thus far Ed Cook, of the University of Chicago,
along with department chair Bennett Leventhal; Cathy
Lord, co-creator of the Autism Diagnostic
Interview;Valerie Lindgren, the team's cytogeneticist;
and Courchesne and his group are central figures in the
tale. Cook and his colleagues are the first to report a
gene-not just a region on a chromosome, but a single
gene-related to autism. This is the famous (or
infamous, considering how slippery the thing has been
so far) serotonin transporter gene, located on
chromosome 17. Now, with his new findings concerning a
connection between chromosome 15 and autism, Cook and
his colleagues have published another paper that has
placed the field of autism research squarely within one
of the hottest areas of genetics research today.
Genetics 101
Autism is now known to be one of the most genetic of
all genetic disorders. To many of us this news has come
as a shock; in my own family's case my husband and I
were told, in 1991, that though "statistically" our
chance of having a second child with autism was
approximately 3%, in actual practice, none of the
genetic counselors on staff at the major urban hospital
handling our case had ever seen a
family with more than one child with autism. Needless
to say, we weren't happy when, just a couple of years
later, we started to hear that autism was not only
"genetic" but that it was among the most strongly
genetic disorders known to the scientific community.
Today, depending upon whom you ask, parents are told
that the chance of having a second child with
autism varies anywhere from 5 to 10%-with a roughly 25%
chance of having children with related problems. In the
meantime we had gone on to have twins, one of
whom-surprise-is indeed autistic. We parents need the
science to be moving a great deal faster than it is.
Still, these percentages are not quite as bad as they
sound. To begin with, Susan Folstein, the first
researcher to study identi-cal twins with autism,
believes that the 10% figure will tur out to be wrong;
her work tells her that the correct figure will
probably be 7 to 8% (Cook uses a range of 5 to 9%).
Still too high, but not 10%. And of course this also
means that a family's chance of the next child not
being autistic is 90 to 95%; the odds are in parents'
favor that it won't happen again.
Perhaps more importantly, the 25% figure for related
problems does not mean that 25% of a family's
non-autistic children will have severe and
life-altering problems. Some of these kids will have
problems with spelling, for instance, and that will be
the end of it. Some of them will be poor readers who
will improve with age, as almost all dyslexics
do with proper intervention. Only about 15% will show
social reticence, and this won't be social reticence at
the level of HFA or Asperger's.
And some of these "differences" in the siblings of
children with autism will actually be beneficial.
In Folstein's words, "I think that some of these
various traits are valuable traits-or at least they are
not in themselves bad things. A case of autism results
when you get all of them together. They don't
just add up; instead, whatever negative effects they
have multiply. "
In other words, the real problem for parents of a child
with autism is the 7 to 8% chance of having a second
child with autism- --not the 25% chance of having a
child who can't spell, or who isn't the life of the
party.
One last note. As parents, you will continue to see the
3% figure cited as the "prevalence rate" in siblings.
What this means is that when researchers go out and
simply count how many families have more than one
autistic child, they find that approximately 3% (some
say 3 to 5%) of families with one child with autism
also have another child with autism. However, from the
perspective of family planning, the 3 to 5% range
underestimates the danger. The true risk of having a
second child with autism should be the "recurrence
rate," which is 7 to 8% (or 5 to 9%,
depending upon the source). The reason there are fewer
"multiplex" families than we would expect is that
families who have a seriously handicapped young
child-any handicap, not just autism-frequently stop
having children. Researchers call this on "stoppage,"
and it obviously lowers the number of autistic siblings
in families. If you stop having children after having a
child with autism-or choose to have
fewer than you would have otherwise- you limit the
population. Sadly, the real risk of having a second
child with autism is the higher figure.
We know that autism is highly genetic through studies
of identical twins in which the index twin has been
diagnosed with the disorder. Recent studies, such as
that of Bailey, et. al., (1995), have found that the
odds of a "co-twin" also having autism are as high as
73%; that is, if the index twin is autistic, there is a
73% chance that his or her co-twin will be, too. This
is the "concordance" rate.
Schizophrenia, by contrast, which is understood by all
to be a genetic disorder, has a 46% concordance rate.
And diabetes, another complex disease passed down
through generations, has only a 30% to 50%
concordance rate, with a risk to siblings of 6%. So 73%
clinches it, particularly when you compare this figure
to the rate in the studies of fraternal, or
non-identical, twins which is extremely low. (In both
the
original group of fraternal twins, studied by Folstein,
et. al., and the group recruited later by Bailey, et.
al., none of the fraternal twins
were concordant for autism.)
But as it turns out, the 73% concordance rate for
autism is not the whole story. When researchers went
back to revisit the original twins from the very first
twin study, who were now grown, they discovered that
the typical twins were no longer quite so typical. Most
of them, in one
researcher's words, had "something genetic" going on.
They were not
autistic; they would not even qualify for the label
"high-functioning
autistic" or "Asperger's." But only 1 of 7 had married
and was living
independently, and just 3 had managed to achieve
full-time employment.
Looking at these grown non-autistic twins of index
twins with autism,
the researchers concluded that the concordance rate for
this group was
60% for a diagnosis of autism-but 92% for "a broader
spectrum of related
cognitive or social abnormalities."
Thus, autism may well be more strongly influenced by
genetic makeup than
schizophrenia, possibly even more strongly genetic than
manic
depression, which was previously thought to be the most
powerfully
genetic of all the mental illnesses.
This much makes sense, but for parents confronting such
data the
immediate question is: if our child inherited his
autism from us, why
aren't we autistic?
The simple answer is that autism is a "complex
disorder"; in many or
most cases it is "oligogenic," meaning that it takes
more than one gene
to develop the disorder. Say autism requires a precise
combination of 5
genes: if a husband has three of these genes and his
wife has two, their
child can be autistic while they themselves are not.
Moreover, some of
the 5 genes may be dominant, others recessive-which
would mean that for
the recessive gene the child would have to inherit two
copies, one from
each parent.
Alternatively, either husband or wife-or both-could
have some symptoms
of autism, but not enough to actually be autistic. One
spouse might have
had a language delay as a child, one spouse might be
obsessive, one
might be anxious or depressive-any or all of these
traits might signal
the presence of a gene or genes for autism. A student
of Cook's recently
constructed a Venn diagram with five intersecting
circles, each circle
representing a gene for autism. She showed that at the
point where all
five circles intersect you get autism, but at the point
where only 3
circles intersect you get something else, at the point
where two circles
intersect you see a different symptom, and so on.
But Cook says what is most interesting to him is that
you can also show
that it would be possible to have four of the
intersecting circles and
yet show no symptoms at all. This is a particularly
intriguing
possibility in terms of what it would take to treat or
to cure some
cases of autism: if it is possible to have four autism
genes with no
symptoms, theoretically all you would need to treat is
the one gene that
"tips" the person into the disorder. A child or adult
with autism, after
having just this one gene remediated, could-with proper
education and
behavioral support-climb out of his autism even though
four of his
autism genes are still fully functional.
Which brings us to another critical point concerning
"bad" genes and the
mischief they work in human beings: the very same gene
can have variable
"expression" from one person to another. A really bad
gene, for a
progressive, wasting disorder, say, might send one
child to an early
death, while leaving another child only minimally
affected.
This is why you can have such incredible variation in
identical twins,
who share the same genes. Identical twins are
essentially clones, and
yet one twin can suffer from a terrible genetic
disorder while the other
does not (although this is rare). Cook cites the even
more startling
case of identical octuplet mice who have had a critical
gene "knocked
out" or removed from their genotype. When you have
eight genetically
identical baby mice, they are all phenotypically
different-they come out
looking different. Cook recalls a set of identical
octuplets who had a
genetic mutation that should have caused the mice to be
born with
malformed ears. Some of the mice had no ears, but
others had just one
ear missing, on one side; still others had one ear
missing on the other
side; and another one or two had some deformities to
the ear, but only
very mild. "What this tells us," says Cook, "is that
there's something
that's not genetic about even very simple developmental
biology-it could
be as simple as where the mouse was carried in the
womb, but we often
don't know. This is an example where genetics may
provide focused
approaches to studying environmental effects."
In fact, data on non-concordant identical twins may one
day tell us how
to use the environment to prevent autism in the first
place. Most of us,
when we hear the word "prevention," think
"abortion"-but abortion is a
drastic and tragic means of preventing a genetic
disorder. Down the line
we may be able to use the environment to protect
children with autism
genes in the same way the environment may have
protected Folstein's
non-concordant twins. Remember: these are children who
carry all of the
genes for autism-who are genetically identical to their
co-twins who do
have autism-and yet they themselves are not autistic.
When we know why,
we may be able to use this knowledge.
Getting back to parents: a parent could have all kinds
of autism genes,
and yet have been lucky enough that they were not
expressed in him or
her. Instead, the bad luck hits his child. Even more
intriguing: a
parent might carry autism genes that have actually
benefited him in his
own life-given him special skills or talents he would
not have had
otherwise. Cook himself pointed out, after reading this
paragraph, that
he wouldn't have been able to spend his weekend
finishing the team's
latest updated analysis without being willing to give
up social contact
and focus on the details of his work "in a somewhat
repetitive manner. "
This is easily the kind of useful and productive
ability that could come
from an autism gene that doesn't result in autism.
Last but not least, the parents could have few to none
of the autism
genes themselves, and yet still end up with an autistic
child because of
random mutations that take place during the complicated
and sometimes
perilous process of recombination that unites the
mother's DNA with the
father's. (And of course the reality of environmental
pollutants and
toxins adds another dimension to the story: a child can
become autistic
because of a spontaneous mutation in his parents' genes
caused by a
virus or a toxin.)
Why We Need to Find the Genes
Most of us were taught, in high school or college, that
genes are the
blueprint for the human organism. Every middle-aged
college graduate
remembers the drill for eye color: you inherit a gene
for blue eyes from
your father, a gene for brown eyes from your mother (or
vice versa) and
bang: you've got brown eyes, end of story. In fact, eye
color is more
complicated than that, but this is what our college
professors described
to us as the one-gene-one-trait law of "Mendelian"
genetics. In the
popular view of genetics, a baby is conceived, its
genes make it who it
will be, and that's it.
As a result, most of us don't immediately see what is
to be gained by
discovering the genes for autism other than a prenatal
test like the one
for Down syndrome. What good does it do, for that
individual child, to
find out that a gene located on chromosome 15 may have
caused him or her
to be born autistic?
The answer is that finding the genes for autism may
well mean finding
treatments or cures for autism.
This is why. Broadly speaking-very broadly-there are
two different
classes of genes: "developmental" genes, and "operating
system" genes.
Developmental genes are the genes that guide the baby's
development in
the womb (though some are active throughout life). The
genes that
determine eye color are developmental genes.
Developmental genes turn
on, do what they were designed to do, then turn off and
are not heard
from again (except, interestingly, in cases of cancer
which some
re-searchers believe result from old developmental
genes accidentally
becoming active again and causing out-of-control cell
growth).
Operating-system genes are different: operating system
genes are the
genes that are operating all day long; they are the
genes that underlie
and make possible everything we do. My own "operating
system" genes make
it possible for me to write this page; your
operating-system genes make
it possible for you to read this page. Other "system"
genes make it
possible for our lungs to breathe air, our hearts to
pump blood, and our
muscles to maintain a seated position in the meantime.
Everything we do
in life is "run" by genes.
This is where the possibility for treatment comes in.
But first: another
basic principle. Each gene "codes for"-or creates-one
or more proteins.
These proteins then go out to do their job: they might
foster a chemical
reaction in the brain or gut or heart or anywhere in
the body; they
might serve as receptors to allow one cell to receive a
message from
another cell; they might turn on another gene, which
will produce
another protein. But whatever they do in the body,
proteins have to be
shaped correctly in order to work. Just one tiny flaw
in the gene can
result in a fatal flaw in the structure of the protein.
(It doesn't have
to; a gene can undergo mutations that are entirely
harmless. But some
mutations are deadly. ) Babies born with PKU, for
instance, are missing
one enzyme, the enzyme that metabolizes phenylalanine,
an ordinary amino
acid found in food. Enzymes are made of proteins, and
for PKU babies,
that one missing enzyme, due to one mutated gene,
causes profound mental
retardation unless identified early so that dietary
changes can prevent
this fate. (For the sake of accuracy I should mention
that PKU can be
caused by either one of two different genes. But both
genes cause the
disorder alone, neither requiring the presence of the
other.)
Or-and this has been covered extensively in the
press-they might take
the route of creating a gene therapy that would replace
the bad gene
with a new, good one. However, what is not often
reported is the fact
that gene therapy is currently the least attractive of
these options,
because it is the most complex-needlessly complex, in
the view of many.
Because genes not only produce proteins, but can also
be turned off or
on or slowed down or speeded up by proteins, most
biotechnology
companies are instead trying to create medications that
will, like
proteins, modify the gene's action. As Ed Cook says,
"Gene therapy is
something you turn to when you don't think you'll find
an orally
administered, more typical medication. "
In all likelihood, autism will involve both mutated
operating system
genes and mutated developmental genes. Patty Rodier of
the University of
Rochester is looking into a connection between the Hox
genes and autism
(her work is covered in the Summer 1997 issue of
NAARRATIVE. ) A
mutation in a developmental gene is more worrisome,
because the
developmental genes guide the creation of the brain in
the first place,
determining its structure. When a developmental gene is
damaged, the
brain ends up misformed -essentially, the baby is born
with a birth
defect of the brain. Many of the "thalidomide" babies
of the 1960s were
born not only with birth defects of the limbs and ears,
but also with
birth defects in the structure of their brains that
caused them to have
autism. This is not reason to lose hope, however,
because structural
differences in the brain can be, and have been, treated
with medication
in other brain disorders like schizophrenia and
Parkinson's disease.
More on this later.
The Serotonin Gene
The serotonin transporter gene has been a puzzler. Cook
and his team
looked at genes controlling serotonin in the first
place because one of
the most robust findings in the biochemistry of autism
has been that
approximately one quarter to one third of people with
autism show
abnormally high levels of serotonin in the blood. And
sure enough, Cook
and his team found, in three separate studies, a
statistically
significant association between autism and a shortened
version of the
promoter of the serotonin transporter gene, HTT.
However, while it was no surprise to find a serotonin
gene involved in
autism, it did surprise everyone involved that the
short form of HTT
turned up in all three studies. In simple terms, the
"transporter"
portion of the gene transports serotonin inside blood
cells-and the long
form is better at doing this than the short. Thus if
people with autism
have more serotonin inside their blood cells than
average, which they
do, you would expect that people with autism would also
have higher
levels of the long transporter than typical people. But
this is not what
Cook's three studies found.
The precise relationship between serotonin in the blood
and serotonin in
the brain is complicated, of course, but basically
blood cells are
analogous to brain cells-which means that the long form
of the
transporter would lead to more serotonin inside the
brain cells, and
less serotonin outside the brain cells. Generally
speaking (and again
this is a simplification) we want good levels of
serotonin outside our
brain cells where it is free to work its magic. All of
the "SSRIs"
(selective serotonin reuptake inhibitors), -Prozac,
Paxil, Zoloft and
Luvox-are thought to work by increasing the level of
serotonin in the
spaces, or synapses, between brain cells.
HTT was the first susceptibility gene for autism found
using appropriate
family-based controls, and it was big news. Without
consulting Cook, the
University of Chicago dispatched a press release to
EurekaNet asking
them to post it on May 1, the day of the paper's
release. Just days
before the release was to be posted, word reached Cook
that Fritz
Poutska, Annemarie Poutska, and K. Peter Lesch's group
in Germany had
found no evidence either way, for short or long form
being associated
with autism. Cook contacted Eureka at once, but it was
too late; for
some reason the service did not have a provision for
altering an
announcement just before it was scheduled to be posted,
and thus all the
world was given the impression that Cook and his team
considered their
finding to be absolute. Cook has been trying to explain
the provisional
nature of published research to parents and journalists
ever since,
causing his wife, in their Christmas letter, to call
him "the boy who
cried gene." (Though Cook fondly points out to his wife
that she said
the same thing about a gene for ADHD he and his
colleagues identified a
few years back which has now been replicated twice,
albeit after a
two-year delay . . . )
Naturally, these conflicting reports have led to
confusion among parents
trying to follow the science: is the HTT gene involved
in autism or not?
The answer, for the time being, is "maybe." Eric
Courchesne speculates
about where these findings may lead down the road:
"We're uncertain whether there is an association
between autism and the
short variant, or whether the short variant is a
signpost that there is
something somewhere else on that gene that is the real
problem. Both
groups are wondering whether these two findings may be
telling us that
it's not long vs. short that matters; maybe it's not
the promoter
region, but somewhere else in the gene that we should
be looking. "
In other words, for parents, clinicians, and
researchers alike the
message is: stay tuned.
In the meantime, it is possible to draw some useful,
although tentative,
conclusions from work on HTT. To begin with, the HTT
gene is probably
normal; it is not a mutation. This means that it does
not cause autism
in and of itself, but may instead amplify the effects
of mutations that
do cause the disorder. The good news is that since the
HTT gene is a
normal variant (also called an "allele") we can use
data collected from
non-autistic people to think about people with autism.
In the normal population the short form is extremely
common: over 60% of
the general population carries at least one shortened
form; 16% carry
two. Furthermore, generally speaking, the short form is
dominant over
the long form: if you have one short and one long,
behaviorally you'll
act more "short" than "long." (Though researchers do
not yet know
whether the short is always dominant in all tissues of
the body, or
whether having two shorts is different behaviorally and
emotionally from
having one long and one short. )
In any case, the extremely common short form is
associated with higher
levels of normal anxiety. That is, on average, people
who have the
shortened form are more anxious than people who have
two longs, but they
are not pathologically anxious; they do not qualify for
a diagnosis of
generalized anxiety disorder (GAD), unless of course
they do for other
reasons. Ask a room filled with 500 people, half with
the short form and
half with the long, how they feel about speaking in
public, and the
group with the short form is going to be more anxious
on average-though
of course there will be plenty of "short-form" people
with low anxiety,
as well as "long-form" people with high anxiety.
Nothing is absolute.
At this point, of course, any parent reading this
account may be feeling
confusion setting in for real, since many of us do see
a great deal of
anxiety in our autistic children-why shouldn't the
short form,
associated with higher anxiety, be exactly what
researchers expected to
see?
The answer is that, for the time being, there is no
answer. That's the
difference between designing a hypothesis according to
behavioral data
(autistic people have high anxiety) versus designing a
hypothesis
according to physiological data (autistic people have
high blood
serotonin). As we've said: the research is extremely
complex.
"...serotonin may be involved in autistic learning and
social deficits
as well as in mood and aggression. This is an exciting
possibility given
that the large pharmaceutical companies...are spending
billions trying
to develop new and better serotonin medications."
For his part, Cook, who is a clinician as well as a
geneticist, has
given a great deal of thought to what these findings
may mean directly,
in day to day life, for the children he sees: "My
latest hunch is that
the short/long distinction may be related to
aggression. Aggression is
one aspect of autism we don't currently have ratings of
in our samples,
because as a group we've been appropriately focused on
whether our kids
did or did not have autism, and there is nothing about
aggression that
is diagnostic of autism. The most aggressive people in
the world, the
kids with childhood onset conduct disorder, don't have
a touch of autism. "
Fortunately, we know that medications that affect the
serotonin
sys-tem-the SSRIs, the older antidepressant Desyrel,
and atypical
antipsychotics like Risperdal-treat anger,
irritability, and aggression
in many clinical populations, including people with
autism, and this is
where Cook sees the HTT gene findings as eventually
being useful:
"What I'm most interested in with this gene is whether
it will give us a
way to predict what dose of an SSRI a child needs. Some
of these drugs
are metabolized by enzymes that vary a great deal in
the population. So
in 90% of children and adults with autism the usual
administration dose
may make sense, but the other 10% might be completely
different. There
isn't a real predictable relationship between blood
serotonin levels and
clinical response, and I think there's a good chance
we'll get some
practical clinical data from this research soon. "
Apart from this, the serotonin-autism connection may
give us clues to
other aspects of autism quite apart from anger and
aggression. Cook
again, "In broad strokes, if there's more mental
retardation, there's
higher serotonin-though we do see high-functioning kids
with high
serotonin as well. "
Which points to the very real possibility that
serotonin may be involved
in autistic learning and social deficits as well as in
mood and
aggression. This is an exciting possibility given that
the large
pharmaceutical companies (which smaller start-up
biotechnology companies
call the "big pharmas") are spending billions trying to
develop new and
better serotonin medications.
Cook explains:
"Right now there are limits to how high you can push
the serotonin
system. If you push the dose too high you get a
worsening of symptoms-in
depression, autism, or any problem you're treating-and
that's usually
because you're triggering the 'autoreceptors.' The
autoreceptors are
like a thermostat in the system: they say, 'Oh-oh,
there's too much
serotonin, I have to shut the system down. '"
In other words, push the dose too high and you end up
with less
serotonin in the synapses, not more. Up to a point, an
SSRI like Prozac
will increase the amount of serotonin in the synapse;
after that point
the autoreceptors turn on and start pulling serotonin
back out of the
synapse.
Fortunately, the big pharmas are working feverishly to
find a way around
this barrier-not on behalf of people with autism, but
in order to help
people with depression, schizophrenia,
obsessive-compulsive disorder,
and other anxiety disorders.
Cook says:
"A lot of people are trying to figure out how to get
around the
autoreceptors, either to get a faster antidepressant
response or to
treat resistant depression. One model of doing this
that has been shown
to reduce the time to antidepressant response and treat
non-responders
is to add pindolol to the SSRI. Pindolol is a beta
blocker normally
prescribed for hypertension, but it has the 'impure'
effect of also
blocking the serotonin autoreceptors."
Unfortunately, when Cook has tried this combination in
a few of his
patients with autism, he has not seen any improvement.
But he's
confident that sooner rather than later we'll have
something that can
block the serotonin autoreceptors in our kids:
"It's possible that our understanding of the serotonin
system is
insufficient, but I'm very excited because Prozac is
coming off patent
this year or next, so Eli Lilly has to come up with
something else. And
when they do, we could start to see medications that
can treat social
and learning issues, too. " [Editor's note: See C. T.
Gordon's article
on page 6 for another view on SSRI treatment of autism]
Trouble on Chromosome 15
"This is the hottest story in autism genetics," says
Eric Courchesne,
speaking of the recent confirmation of a link between
autism and
chromosome 15-a connection that has now been found by
two separate teams
in three separate studies. With chromosome 15, we move
directly into
genes affecting the cerebellum, one of the main brain
structures that
UCSD's Courchesne (as well as, in Boston, Margaret
Bauman, and earlier,
at UCLA, Ed Ritvo) has found to be affected in cases of
autism.
First off, it's important to remember that with
chromosome 15 we are
talking about a chromosome, not a gene. Chromosomes are
the squiggly
lines expectant parents see on their amniocentesis
reports; the baby's
100,000 separate genes lie on these 46 chromosomes
(which are arranged
in 23 pairs, one from the mother, one from the father).
The new finding on chromosome 15 is of an affected
region on that
chromosome- a region that does not "look right." This
puts the
chromosome 15 finding in a different category from HTT:
as Courchesne
puts it, "I would bet a dinner at the nicest restaurant
in San Francisco
that this is a mutation, not a normal variant."
He and Cook looked at Chromosome 15 because Christopher
Gillberg, author
of The Biology of the Autistic Syndromes, suggested
that 15 would have
problems. In 1991 he reported several cases of autistic
people with
duplications of genetic material on 15. Sure enough,
Gillberg was right.
And while often in the history of "behavioral" genetics
initial findings
have not been replicated, so far this one has.
The biggest news about chromosome 15-the finding that
suddenly places
autism research in one of the hottest areas of all
genetics research-is
that children who develop autism due to an anomaly on
chromosome 15 do
so only if they received the anomaly from their
mothers. In other words,
for the first time ever, researchers have established a
mode of
transmission of autism-in this case, through the
mother, not through the
father. (Cook says fathers will get equal time once all
the genes are
discovered; it just so happens that this first anomaly
comes from the mom.)
In the science of genetics this phenomenon is called
"imprinting," and
it is one of the most exciting-and most active- areas
in the field
today. Courchesne explains: "Imprinting refers to the
concept that the
gene will become differentially active-or
"expressed"-based on whether
it came from the father or the mother. Some genes
remember where they
came from; they care whether they came from the mother
or whether they
came from the father. And that "memory" determines
whether or not they
are expressed in the child. "
With a maternally-expressed gene (or mutation) the gene
has to come from
the mother in order to be expressed in the child. If
the child gets the
exact same mutation from his or her father, nothing
happens; the
mutation is not expressed. With a paternally-expressed
gene it's the
opposite. The child has to inherit the gene or mutation
from his father
in order to have the traits that gene causes. Otherwise
the mutation
remains silent.
This is exactly what Courchesne and Cook found in the
first family with
the chromosome 15 abnormality whom they studied
closely. There were
three children, a girl with classic autism, a boy with
atypical autism,
and a third child, a girl, who was developing
typically. (The unaffected
sister was actually a step-sibling; the mother had
remarried before
conceiving her.) Both of the affected children had a
duplication of
material on chromosome 15. When Cook looked at the
mother and the father
of these two children he found that the father's
chromosome 15 was
normal; it was the mother who had the duplication.
But the mother herself was completely average; she
showed no signs of
autism at all, not even subtle ones. Cook then went
back to her parents,
and found that she had inherited the abnormal
chromosome from her
father-whose own version of 15 was normal. In the
transmission of 15
from father to daughter, the chromosome had undergone a
spontaneous
rearrangement, which the daughter then passed on to her
own children.
The mom was normal because she had received the
mutation from her dad;
if she had received it from her mother, in all
likelihood she would have
been autistic, too.
Cook and Courchesne have now looked at 140 children
with autism in all,
and have found one more, a boy, with a duplication on
15. He inherited
the duplication from his mother- who did not have the
mutation herself.
In this case the duplication arose "de novo" when the
particular egg
that was to become this boy was originally formed many
years ago. (Which
means that this mother's chance of having a second
child with autism is
near zero, since the duplication on 15 cropped up
simply as a random
mutation in a random egg). The 2-out-of-140 rate may be
low, of course,
because at this point researchers are dealing with
anomalies on
chromosome 15 so large they can be seen under a
microscope- or picked up
by having 3 alleles at a locus instead of the normal 2.
Any of the other
138 children could also have duplications on 15 that
are too small to be
picked up in this way. (One note: in all, Cook and his
group have found
3 children with the chromosome 15 duplication: the
brother and sister
from the first family, and then the boy whose mother
did not have the
duplication. But the official figure is 2-out-of-140
instead of
3-out-of-140 because the one very high-functioning boy
was too mildly
affected to meet the diagnostic criteria for inclusion
in the 140. The
research team picked him up by accident, after they
found the
duplication in his sister and so decided to look at the
whole family. )
Interestingly, further evidence for
maternally-imprinted duplications on
chromosome 15 has just come from Browne's team in
England, which has
been studying the genetics of language disorders. They,
too, found that
the genes they were looking at had to come from the
mother in order to
produce a language disorder in the child. When their
paper recently
appeared in the December 1997 issue of the American
Journal of Human
Genetics, the authors mentioned Cook and Courchesne's
paper and said
that while they hadn't been looking for autism, now
they would.
And finally, Cook's work has been duplicated and
extended in the
laboratory of Margaret Pericak-Vance (an expert in
gene-mapping and 1997
NAAR Research Award winner) at Duke Univeristy.
Previously Pericak-Vance
had also found anomalies on 15; she has now replicated
the maternal
inheritance, and has added two important pieces to the
puzzle:
1. Pericak-Vance found an "increase in recombination"
on chromosome 15
in families with autism. "Every time people have a
baby," Pericak-Vance
explains, "it's like a deck of cards being shuffled. "
Say you have a
deck of cards with all four suits separated out from
each other, and the
numbers put in order. Then you shuffle that deck of
cards once. The
families that end up with an autistic child will show a
much more
pronounced "reshuffling" than the families that end up
with a
non-autistic child. In physical terms, Pericak-Vance
and her team found
that the autistic person's markers on chromosome 15
appear further apart
than they are in the typical person. And: this
difference came from the
mother.
2. Having confirmed Cook's findings, Pericak-Vance then
looked at
chromosome 15 in families with a different neurological
disorder,
unrelated to autism. She found that in these families,
this region of
chromosome 15 was normal, further evidence that the
duplication on
chromosome 15 is specific to autism-not a general
genetic anomaly you
might find in many brain-based problems. More evidence
for 15. (Cook,
too, has a paper in press in which his team looked for
duplications on
15 in over 250 non-autistic children with moderate to
profound mental
retardation, and did not find any duplications on
chromosome 15,
although they did find 4 cases of Angelman syndrome in
which there was a
deletion of the same portion of chromosome 15 that is
duplicated in
autism. )
Pericak-Vance notes that there are a number of
different possibilities
as to what could cause this anomaly. You might see
perfectly normal
genes that for some reason have been duplicated, giving
the child an
extra copy. Having extra copies of otherwise normal
genes can be very
damaging to the organism. This is the problem in Down
syndrome. Or you
might see some kind of incorrect rearrangement of
otherwise normal
genes; you might see a mutated gene that is causing the
chromosomes to
break and reshuffle. There are other possibilities as
well.
Time will tell-and most researchers feel we'll know
sooner rather than
later. The next step is to pinpoint a narrower region
on the chromosome,
or a single gene within this region that is key to the
disorder. Ed
Cook's prediction: "Within the next two years there's
going to be some
very hot and definitive information about specific
genes involved in
autism."
Where Does Your Child Fit In?
At present we can't tell the autistic children who have
chromosome 15
duplications from the ones who don't simply by looking
at them. However,
there do seem to be characteristics specific to these
kids. "The one I'm
sure of," Cook says, "is increased epilepsy and
epileptiform EEGs. One
autistic woman we studied didn't have her first seizure
until her late
teens, but she had abnormal EEGs as a child in the way
autistic kids
often do. "
The chromosome 15 children studied so far also show
regression. Between
12 and 24 months in their development, they lost
skills. As well, these
children have low muscle tone. "They walk on time,"
Cook says, "and they
can eat OK; it's not severe. But they might have a
little trouble
holding their heads up as infants, and show a history
of low tone in
other ways. Most kids with autism aren't like that, so
the floppy ones
stand out a little bit. " He continues: "A lot of them
visually look
like Fragile X, with hyperextensibility of the joints,
double-jointedness, and ears that may be a bit longer
than normal, and
incorrectly 'rotated' backward. "
As preliminary as these impressions are, they are
extremely significant
for any parent of an autistic child who is
contemplating having another
baby. Cook gives this advice to parents: "You can find
this on an amnio,
but most labs don't do it. You have to look very
carefully. But people
who are trying to get pregnant now, and already have
one autistic child,
should look for it. It's much more important than
looking for Fragile X,
though we still recommend checking for Fragile X, too."
Ed Cook's prediction: "Within the next two years
there's going to be
some very hot and definitive information about specific
genes involved
in autism."
Bear in mind, of course, that any lab that agrees to
look for a
duplication on chromosome 15 is going to come up with a
large number of
"false negatives," since at this point all anyone can
look for is an
anomaly large enough to be seen under a microscope.
Bear in mind, too,
that we don't know what a chromosome 15 duplication
found on an
amniocentesis is going to look like in the actual
child. Of the two
original children Cook and Courchesne studied, the
sister was much more
severely autistic than her brother, who was so mildly
affected that the
school system did not want to provide him with
services. His IQ,
language, and academic performance were normal, and the
school system
was not concerned with his narrow interests or poor
social skills.
This is the mystery of gene expression, the mystery of
why a gene
mutation can be devastating in one person, only mildly
troublesome in
another, and silent in yet a third. Ed Cook comments:
"Even in this family the little girl probably has a
second gene
involved. So here is a major finding and you can't even
use it to
distinguish a child who is mildly retarded and has
classic autism from a
child who has normal intelligence and is only mildly
autistic. "
Parents of children with autism who are contemplating
having another
child and would like to check for duplications on
chromosome 15 should
tell their physicians that a possible region may be
15q11-q13, so that
the chromosomal analysis will be done with attention to
this region as
well as to the other chromosomes. Be sure to discuss
this very early on
in the pregnancy, since locating a lab that can do this
test may take time.
Other Hot Spots: Chromosomes 7 and 16
The results of the first full genome-wide screen of
autism were
published this March in Human Molecular Genetics. This
study, by the
International Molecular Genetics of Autism group,
reported linkage for
chromosomes 7 and 16. Previously, Sue Smalley of UCLA
had suggested a
connection between autism and tuberous sclerosis (TS)
that excites
people; one of the genes for TS is on 16, though it
looks as if this
gene is not going to be the same one the International
group is looking
at on 16. Nevertheless, researchers feel there is
fairly strong evidence
for an autism gene on the long arm of chromosome 7,
weaker evidence for
an autism gene on the short end of chromosome 16.
Geneticists are in the
stage of working across groups to find out which gene
hypotheses hold up
and which do not; we'll report their discoveries as
they emerge.
At this point we have no idea how many
autism-susceptibility genes
researchers will eventually identify. Assuming it takes
a combination of
5 genes to produce the disorder, there is nothing to
say that these 5
genes will be the same 5 genes in every person with
autism. There could
be 20 autism-susceptibility genes, with some people
having one
combination of 5, other people having other
combinations of 5. And of
course, it is likely that there also exist dominant
genes for autism,
genes that can cause autism acting entirely on their
own. We just don't
know yet. As Clarence Shutt, a structural biologist at
Princeton and
Executive Vice President of NAAR, says: "In science,
everything's a
mystery until it happens."
Can Chromosome 15 Lead Us to a Treatment?
The prospects for chromosome 15 leading to a biomedical
treatment for
autism-not a "cure" (or not necessarily) but a genuine
treatment-are
high. This is so because the affected region on
chromosome 15 contains
three genes that code for the neurotransmitter GABA-and
the
pharmaceuticals are already pouring buckets of money
into the GABA
system, and have been for years. GABA, or
gamma-aminobutyric acid, is
the neurotransmitter involved in anxiety. Alcohol,
anticonvulsants like
Gabapentrin and Vigabatrin (note that the drug
companies have been
helpful enough to include "gaba" in the names of these
two) and
antianxiety medications like Xanax and Valium all work
by attaching to
the GABA receptor.
GABA is an "inhibitory" neurotransmitter; it prevents
cells from firing.
Some call it the brain's "braking system." This brings
us to another
line of converging evidence: in the cerebellum, the
Purkinje cells-which
Margaret Bauman has found to be diminished in number in
the autistic
brain-release GABA.
The problem with antianxiety drugs like Valium and
Xanax, as anyone who
has taken either for sleep knows, is that although they
can work wonders
at first, the effects do not last. Shortly before last
Christmas, Cook
used a GABA medication to treat a severely behaviorally
disordered young
man with autism, and it helped. But the effect was
fleeting. As a
result, the pharmaceuticals are engaged in an ongoing
quest to develop a
GABA drug that can work over the long term- the
financial payoff would
be enormous. And the chances that one or more of this
new generation of
improved GABA drugs could be helpful to our children
are good. It is
also possible that an existing compound-a medication
that has already
been developed and tested for safety but never
marketed-could work for
autism. Drug companies cannot legally test medications
in humans without
having a biological "target," and until now it was not
known that GABA
was involved in autism. As a result, none of the GABA
medications has
ever been formally tested in people with autism; the
tests were all run
on people with anxiety disorders. A medication that
does not work for an
anxiety disorder in fact might work for autism. It's
possible.
"I think the differences between the autistic brain and
the normal brain
are relatively subtle. Of course a structural
difference can be small
but critical, but even so I don't see anything in the
neuroanatomical
studies that says autism is untreatable."
As Ed Cook says, "Now we need to think about the GABA
system as much as
we think about serotonin. " Happily, more work on GABA
is being done all
the time. The Cook team's findings on GABRB3-a gene for
one part (or
subunit) of the GABA receptor-are in press, and will
appear in May in
the American Journal of Human Genetics.
Other Paths to a Treatment
As to the question of whether the missing Purkinje
cells are the "real"
problem, as opposed to a "chemical" anomaly in the GABA
system-it is at
least theoretically possible that an autism-specific
GABA medication
could compensate for missing cells by drastically
increasing the GABA
production of the Purkinje cells that are present. This
has been done in
other brain disorders like Parkinson's disease. Or,
eventually, the
structural differences in the autistic brain may be
treated by
"neurotrophic factors" or "nerve growth
factors"-chemicals that cause
new brain cells to grow. (See related story on p. 10 in
the Summer 1997
issue of NAARRATIVE.)
But Cook believes-and here there is disagreement among
researchers-that
the structural flaws we see in the autistic brain are
not drastic enough
to be insurmountable: "There's nothing that's that
abnormal in the
brains of people with autism. If you compared a young
autistic person's
brain to the brain of his healthy 60-year old
grandfather, the
grand-child would have the better looking brain. "
[Editor's note: Men's
brains shrink with age-as do women's, though to a
lesser degree.]
"I think the differences between the autistic brain and
the normal brain
are relatively subtle. Of course, a structural
difference can be small
but critical, but even so I don't see anything in the
neuroanatomical
studies that says autism is untreatable. With the right
nerve growth
factor, you might get maturation of those structurally
different parts
of the brain. " The fact is, it is possible to treat
autism now: both
Anafranil and the SSRIs have been shown to diminish
core symptoms of the
disorder, not just behavioral "add-ons. " (see article,
p. 6.)
In Ed Cook's words: "The SSRIs are very exciting. With
these medications
we can treat something we couldn't touch just 10 years
ago. I think
there's a lot of excitement about where we can go with
autism treatment
medically, and in general I see SSRIs as giving us 5
percent of what
we'd like to be able to do. Say we get 5% every five
years-that doesn't
sound like a lot. But there are going to be a number of
kids out there
who, with just a 5% bump up in functioning, will have
their lives
significantly changed. Then you keep adding onto that,
and adding on,
until you get as far as you can go.
"Will we eventually be able to cure autism? I don't
know. Maybe there
would always be something left over; maybe you could
never give an
autistic person the fluidity of thought and movement
normal people have.
But I don't see anything about the neuroanatomy that
says we can't bring
everybody up to Temple Grandin's level, except that the
rest of us
aren't as bright as Temple.
"But we're very far away from that today. "
This is where parents come in. What we can do-what we
must do as
parents-is to push the science forward. Raise the
money, raise the
awareness, make it happen. That is our job, and our
hope.
A Note From Ed Cook: We would like to thank the NIMH,
NICHD, NINDS, the
University of Chicago Brain Research Foundation Seed
Grant Program, the
Jean Young and Walden W. Shaw Foundation, the Irving
Harris Foundation,
the Daniel X. and Mary Freedman Academic Psychiatry
Fund and the MRC in
the UK. None of what has been done in our laboratories
would be possible
without this support.
Catherine Johnson, Ph.D., co-author with John Ratey,
MD, of Shadow
Syndromes, is a member of NAAR's Board of Trustees and
the mother of two
children with autism.
1 NAARRATIVE, Number 2, Winter/Spring 1998 Newsletter
of the National
Alliance for Autism Research 1-888-777-NAAR