CNTNAP2, an Autism Susceptibility Gene
January 11, 2008 by Kristina Chew, PhD
Filed under Gender, Genetics, Language
Language has always meant a lot to me: I taught myself to read when I was four years old and reading immediately became one of my favorite things to do. I started studying languages—French, a little Cantonese, then Latin and ancient Greek, German, Mandarin, Arabic—-when I was in elementary school and have always been drawn to literature, to poetry and novels, and poetry and novels and plays written in other languages. So when people hear me describe Charlie—-who’s not fond of books, has learned to sight-read several nouns on flashcards (he does not recognize them in a book, not yet), and severely speech delayed—I sense some perplexity. Shouldn’t I be disappointed that I have a son so impaired in precisely the areas that I excel in?
I am sure that I went through some sad and wrenching moments around the time of Charlie’s diagnosis when I realized that I wasn’t going to be teaching Charlie to count in Cantonese (yet, yee, sahm……) and that it would be a struggle for him to learn to be put the final /n/ on “one.” But even then I found that studying so many languages—-a German professor once told me that I had “interference” because I was studying too many languages—-has somehow been key to my understanding and “translating” of Charlie. I’ve spent a lot of nights with a page of a foreign language in front of me, a dictionary, some commentaries, a notebook for writing down every vocabulary word: It’s not just a matter of figuring out what a word in another language means; you have to think of the context of the passage, and the grammar, and the time period in which the text was written, and the genre of the text. You have to have a feel for the author and for how he or she uses words. So with Charlie saying “white bed” when he walked in after school, pulling the sheets and blankets off, and trying to turn the mattress perpendicular to the boxspring, I divined that he wanted the bed to be made with a certain cover that we no longer have—-that he wanted the bed to look as it did at some other time, in some other place, that he still remembers well. And maybe he wanted the bed to look so because there’s some feeling or memory he was trying to recall, when things looked like that.
That’s what I divine from watching and listening to Charlie day in and day out. Yes, he has a severe speech delay, but his desire to communicate and express himself is as great as anyone’s and maybe even more: Words don’t come so easily for Charlie.
Charlie’s speech delay makes me particular interested in one of the articles about CNTNAP2 published in the January 10th American Journal of Human Genetics. The article is by Maricela Alarcón (of the UCLA Center for Autism Research and Treatment ) et al. and is entitled Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene. CNTNAP2 is contactin-associated proteinlike 2; it is like a blueprint “for an important protein involved in the ability of brain cells to communicate with each other properly” (ABC News). In early brain tissue, CNTNAP2 is the gene that is the “most active in developing brain structures involved in language and thought,” as the January 11th Science Daily notes; CNTNAP2 may provide a “‘tangible link between genes, the brain and behavior,’” in the words of Dr. Daniel Geschwind, principal investigator and Gordon and Virginia MacDonald Distinguished Professor of Human Genetics at the David Geffen School of Medicine.
The study notes that “language problems are one of the essential features of autism, and substantial language delay, defined as a lag in the age of the first spoken word or the first spoken phrase, is seen in approximately half of children with autism and is observed in their unaffected siblings at increased rates.” In an earlier study, UCLA researchers analyzed the DNA of 291 families nationwide who had donated blood samples to the Autism Genetic Resource Exchange; they found that a specific region of Chromosome 7, called 7q35, was connected to autism. Science Daily continues:
In the current study, the researchers scrutinized every gene in the 7q35 region using DNA samples from 172 families. They identified four promising genes; one of the candidates was CNTNAP2.
To verify their findings, the scientists conducted a second test on a new group of 304 families. The CNTNAP2 gene showed up consistently, confirming its implication in language development.
In a second approach, the researchers examined CNTNAP2’s presence in early brain tissue and discovered that the gene was most active in developing brain structures involved in language and thought.
Postdoctoral fellow Brett Abrahams, who led this part of the research, explains the finding’s significance by comparing the brain to a house.
“We know that different rooms in houses serve different purposes,” said Abrahams. “For example, if an item only appears in the kitchen, it makes sense to assume it’s involved in cooking. Or if we find an object only in the bedroom, it’s likely connected to sleeping.
“The fact that we found CNTNAP2 concentrated in the brain’s structures that are involved in higher cognition gives us strong clues about how its disruption might adversely shape brain development, including speech and language,” he said.
In an unexpected third finding, the scientists found that statistical evidence for the gene was strongest in families with autistic boys. Less of an association appeared in families with autistic boys and girls, or in families with autistic girls only.
“Autism strikes boys three times as often as girls,” said Maricela Alarcon, first author and UCLA assistant professor in residence of neurology. “This finding may partly explain why.”
The 3:1 gender ratio between boys and girls also applies to rates of attention deficit disorders, learning disabilities and language disorders.
The researchers show how “variation within CNTNAP2″ contributes to “variability in age at first word in males”; one piece of evidence cited is a “rare recessive mutation in CNTNAP2″ that is associated with seizures, developmental language delay, and autism in an extended Amish kindred. They note in closing that their work “provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder.”
When Charlie was one year old, he had four semi-distinct sounds; a year later he mostly said “duh” or “edah.” He began Early Intervention (speech therapy, occupational therapy, and ABA) around that time and by the time he was a few months shy of three years old, he could say several sounds and was trying to imitate (”bubbles” were “muh-muhs”; “want” was “yeh”; “chip” was “ip”). It has only been in the two or so years that he has been able to say almost any sound clearly (the initial /l/ sounds is still often pronounced as a /w/ if Charlie is not concentrating): Charlie echoing is still exciting to me and especially when every sound is clear. It’s apparent from his face and his slightly troubled eyes that he is straining to coordinate something—in his brain—to get the words out and to speak his thoughts.
I wait; I try to make the connections, and give my best translation.
Jeff Stimpson
Jill Cornfield
Hmmmm…
Here is my question. Why is this gene changing/being disrupted/mutating in the first place? Something has to Cause it. If finding that isn’t the next step …………..
So they found the mutation in the Amish???? That’s perfect to contradict the biomed myth that the Amish don’t have autism because they “don’t vaccinate” (apparently this is another myth).
Not the **Amish** - an “extended Amish kindred.”
The study also notes “Second, mutations in CNTNAP2 itself were recently identified in an Amish family with seizures, language regression, and pervasive developmental disorder.”
To play devil’s advocate (since I live in Amish country)….. are we talking old order Amish? New order? Any one of the variants? Like the ones who have cell phones, go to doctors and don’t entirely live by the “old rules”?
It leaves a door open, that’s all I’m sayin’.
Best to keep it that way—-
I find this line of research fascinating. I have a son who has been delayed on his linguistic development and has also been in the same sort of Early Intervention for about six months (he’s about to turn two). I know that feeling of being able to translate what your child is saying; he recently said something that sounded very much like “I did!” in a situation where his speech therapist was increasing the type of tasks (putting two shapes into a shape sorter). It was remarkable how exciting it was just to hear that.
By the way, thank you for your blogging here; our son hasn’t been officially diagnosed, but his therapists have been hinting that he may be mildly autistic, and so I have taken a very personal interest in the subject as of late. Keep it up - your voice needs to be heard.
“Why is this gene changing/being disrupted/mutating in the first place?”
Well if you think back to the high school biology lessons on meiosis and mitosis changes in DNA are an inherent part of the replication process. Genetic information is not static. It is always being replicated and rearranged. Sometimes stuff gets rearranged in what turns out to be perhaps not an optimal fashion. These changes are a way of insuring that the species remains genetically diverse, that we don’t get too inbreed.
To put it another way, have you ever seen a photocopy of a photocopy of a photocopy of a photocopy of a photocopy…..
It’s a little bit messy but most of the information is still legible.
Gene mutations arise through many causes. One of the most obvious is crossing-over errors during meiosis, or replication errors during either process of cell division (meiosis or mitosis). Whenever a cell divides, it must first copy the millions and millions of building blocks of DNA so that it has a second set of DNA to put into the new cell. There are OFTEN errors in this process, at a rate that would probably surprise some people. The cell does have a few checkpoints to catch some of these errors, but…some do get missed. When they’re missed, if they’re not catastrophic to cellular function or housekeeping, they’ll be retained and passed on to other cells…viola–a mutation. If it is catastrophic, the cell will probably set off its suicide mechanism and die.
Thus, these mutations can happen without external inputs (i.e., “environmental” factors). If they’re not catastrophic to the development of the organism’s development, they can persist. If they’re not catastrophic or in combination with other genes catastrophic to the organism carrying it, that organism may survive and reproduce and pass along that mutation to its offspring.
Samantha - I don’t remember a class I had 35 years ago.
But I have to say, the Amish are fairly inbred. Old order, new order, whatever… lol.
But isn’t it an odd coincidence that this is all happening - that all these kids are being dx’ed - “lately”? There was nowhere near the number of kids on the spectrum when I was a kid, let alone 20 years ago. And that’s not because they weren’t being dx’ed. They weren’t *there.* These issues weren’t *there.* I know, I’ve been teaching that long.
“I don’t remember a class I had 35 years ago.”
I google the information a couple times a year just to keep it fresh in my memory. It makes reading these types of studies a lot easier.
They weren’t *there.* These issues weren’t *there.* I know, I’ve been teaching that long.
Just how many kids did you teach to be able to make this claim?
If you were in high school 35 years ago then I have relatives who are older than you who have these issues. I know that one anecdotal observation from one random individual doesn’t really carry much weight in this kind of discussion but a survey of the 50+ would likely turn up just as many individuals with these issues as a survey of the 5 and under crowd. Does anyone know if such a study has been done?
@Samantha, I think the CDC put out an RFA recently to do a prevalence study on autistic adults but they only received one application and it was not fundable.
@The Christian Cynic, thank you for sharing that “I did” that your son said. Throughout his life, my son has, from time to time, said random phrases very clearly and seemingly almost by accident (I swear he said “I wuv voo” when he almost two years old). But when he is trying to say things, it is sometimes harder. Hope he is doing well.
I can say unequivocally that I had significant “problems” as a child in elementary and secondary school (as long as 35 years ago), and no one ever thought of considering “autism” or PDD-NOS or ADHD, even though that would be obvious to consider these days. I have taught thousands of people of all ages, and I have seen autism and other disorders that are undiagnosed often through the years.
I’ve said it before–just because we didn’t realize it was there doesn’t mean it wasn’t there. My oldest son was born with autism, something I can see quite clearly in hindsight. However, I did not become fully aware of it until he was almost four years old, although my suspicions began much earlier.
I’m reminded, actually, of a child of George V of England who had a son with what was probably some sort of autism disorder–many think Asperger’s. That child was born over 100 years ago, well before Kanner or Asperger identified autism as a grouping. My own father did not speak until he was over two years old, and I’ll just say the fruit hasn’t fallen far from the tree since, but he was never diagnosed with anything…born too soon. I recognize even characters in classic literature who have traits that are very familiar to me. Things we have recognized as a “type” over the centuries (absent-minded professor, the “odd” woman, the eccentric child, marching to the beat of your own drummer, Albert Einstein) we now call by the names of disorders. They were there all along, we just hadn’t categorized and classified and codified.
I could write a book about autistic qualities of my relatives. My mother, for example, is an almost comically textbook case of Asperger’s. She and her siblings went to private schools because they would not have fit in in public ones, and my grandparents (at least one of whom was also, we all now understand, autistic) realized that. No one had a name for it back then, but it was there.
My child’s diagnosis with autism has allowed me to re-examine my entire life, and to accept and love people whom I had formerly written off as “mean” or “weird.”
I am grateful for this.
I very much think that my maternal grandfather was on the spectrum; one literary character for whom a possible autism diagnosis has been suggested is Bartleby—-here is an analysis.
I have a close friend who just yesterday told me that she’s learned that her husband probably has Asperger’s (something I’ve suspected for a long time). She says that it’s given her a new perspective on her interactions with him, and she’s changed her personal expectations in her dealings with him, which has helped her a lot with some frustrations she was experiencing within their marriage. Saber es poder, as we say in Spanish (knowledge is power). I almost shudder when I think of how frustrated and unhappy we and our children might be if we didn’t have a grasp of what makes them tick. My parents were *always* mystified by me and my circumstances at school; they just couldn’t *understand* why I couldn’t just behave like I was supposed to and do what I was supposed to do like everyone else.
Hi Emily,
I think you are referring to Prince John? This child was very loved and died young of epilepsy, which was his main dx.
Stephen Poliakoff directed a PBS drama, The Lost Prince, which is very worthwhile viewing. The scene where King George comes to fully appreciate his son, soon to die from a seizure at age 13, is splendid acting. The series does portray Prince John as having some Aspergers characteristics but from memoirs of contemporaries it does not appear that way.
He wasn’t actually that well loved by his parents, who generally kept him hidden and didn’t spend time with him or include him much in family portraits, and yes, he started having what they termed “epilepsy” when he was about four, but he also exhibited notable symptoms of being on the spectrum. He is widely reported now as having had autism or something like it, in addition to epilepsy.
And I realize that not being around one’s children…especially one’s seizing children…was the “style at the time” for the upper crust. I think the portrayal of Mary is probably off…from what I’ve read, she had more genuine sympathy and love for John than people give her credit for. It reminds me of the Kennedy family, though, shuffling away the “embarrassing” offspring from public view.
His interest in plants reminds me of my son’s interests.
There was something with that child…the rapid growth, seizures, behavior, gardening…
From the January 14th Science Daily, some background about a link between CNTNAP2 and autism: