rare mutation that causes an epileptic
disorder in Old Order Amish children
observed that all the children with
two copies of a recessive gene — called
contactin associated protein-like 2, or
CNTNAP2 — developed frequent seizures in early childhood, followed by
features of autism.
Further studies followed, linking
CN TNAP2 and autism. In January 2008,
three groups of researchers independently reported that they had identified
defects in the gene in larger groups of
subjects. The three groups used different
strategies and different populations to
look for possible autism links, and found
different mutations — some common
and some rare. Still, the labs arrived at
the same conclusion: Variations in CNT-
NAP2 predisposed carriers to autism.
State’s group is now pursuing studies to figure out exactly how. CNTNAP2
normally makes a type of protein called
a neurexin, which is located in neurons.
The protein helps brain cells link up
during the development of the nervous
system. It also appears to help growing
cells adapt and alter axons, projections
through which brain cells send electrical impulses essential for normal
brain function.
In test-tube experiments and in zebra
fish, State’s team is engineering cells that
lack the gene completely. “If we can find
out what goes wrong in the protein that
we know leads to this rare syndrome of
bad seizures and autism, then we can use
that as a benchmark and can begin to ask
questions of the mutations that we are
seeing in other people,” he says.
Tracing lines of evidence
Meanwhile, Geschwind and his group
are working to catch the gene suspects
in action. Studies show that during early
development, CNTNAP2 is highly active
in parts of the human brain important for
language processing. Other studies have
implicated CNTNAP2 in certain language
disorders. Together, the studies suggest
that a disrupted version of the gene could
throw a monkey wrench into the works
during the earliest stages of development.
Using functional MRI, the scientists
are looking to see whether the brains
of people with and without autism activate differently in specific regions during language-related tasks. The next step
will be to see whether activation patterns
can be linked to genetic variations. Other
labs are using similar approaches to show
how autism-associated genes might work
on distinct brain regions.
Still, solving the puzzle of autism will
be daunting. The fact that identical t wins
do not always share the disorder suggests that environmental factors as well
as genes are at play, Geschwind says. The
task is made even more difficult because
the genetic aberrations that have been
implicated in autism do not present
a clear, one-to-one relationship with
patients’ symptoms or abilities. Some
of the submicroscopic changes found in
autistic children, for example, are also
seen in one of their parents, though the
parent may have only mild symptoms
or no symptoms at all. Other mutations
found in autistic children are seen in kids
without autism as well.
And new questions will arise. As
research pieces together a more complete picture of the various genes
involved—showing which they are,
where they work and how they control
brain circuits — it may reveal ways to tie
particular features of autism to specific
derangements in DNA. Like the movie
version of Clue — which had multiple
endings with different killers committing the same crime — the findings will
probably finger multiple molecular missteps leading to the same behaviors and
outcomes.
Understanding how the brain functioning of one child with autism differs from
that of another could help in developing
treatments tailored to specific behaviors
or problems. Whether kids with similar
symptoms but different genetic variations will respond to the same treatments
is unknown, Geschwind says. “But that’s
a question that we have to ask and begin
to look at.”
Explore more
s Nih autism fact sheet: www.ninds.nih.
gov/disorders/autism
Autism spectrum
disorders
Autism is often used as a catchall
phrase to describe a spectrum,
or range, of disorders that affect
a person’s ability to communicate
and interact socially. autism spectrum disorders include conditions
with a wide variety of symptoms
that range in severity and come in
many different combinations. the
autism spectrum disorders include:
Autistic disorder:
also known as “classic autism,” this
disorder affects a person’s ability to
communicate, form relationships and
respond appropriately to the environment. Some people with autistic disorder are high-functioning and can speak
and interact, while others are more
severely affected and nonverbal.
Asperger syndrome:
individuals with asperger syndrome do
not have a delay in spoken language
development, but they can have serious
deficits in social and communication
skills. people with asperger syndrome
often have obsessive, repetitive
routines and preoccupations with a
particular subject, such as trains.
Childhood disintegrative
disorder:
children with this disorder typically
develop normally for two to four years
before the condition, which resembles
autistic disorder, arises. previously
mastered language, social and toileting
skills may be lost.
Rett syndrome:
this disorder almost always affects
girls. babies with rett syndrome
develop normally until 6 to 18 months
of age, when development slows and
their heads no longer grow normally.
affected children don’t develop normal
speech and may exhibit unusual hand
movements and walking patterns.
Pervasive developmental
disorder/not otherwise
specified:
also known as atypical autism, this
diagnosis is often used when some,
but not all, of the symptoms of classic
autism or another disorder are seen.
like other autism spectrum disorders,
it is characterized by social and speech
problems.
SoUrceS: Nih, NatioNal rett SYNdrome
foUNdatioN
october 23, 2010 | science news | 21
