It’s the countdown to the end of 2008 and here is some of what was going on at the beginning of the year:

The trial of Dr. Karen McCarron began on January 7th. On January 16th, McCarron was ruled guilty on all counts. On April 1st, she was sentenced to 36 years in prison for the May 13th suffocation of her then 3-year-old daughter, Katherine “Katie” McCarron.

January also saw the publication of further evidence refuting a link between vaccines and autism, with the publication in the Archives of General Psychiatry on the decline in thimerosal exposure and the continue increase of autism rates. A study in Pediatrics offered further proof that the vaccine-autism hypothesis is a hypothesis. The study showed that ethyl mercury is expelled faster from babies’ bodies than thought, and that there is “…..little chance for a progressive building up of the toxic metal.”

Nonetheless, a new legal drama, Eli Stone, based its first episode around a (highly fictional) case involving a child becoming autistic due to a vaccine. (And what celebrities have to say about science was a constant irritant throughout the year.)

Also, new research on genetics (on chromosome 16 and a test for autism) appeared in January, and throughout the year, with one scientist proposing a unified theory of autism.

“Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities”—-these are noted in one of the DSM-IV criteria for Autism Spectrum Disorder. A study published in the December 10th Neuron has found that reducing the activity of the gene FKBP12 in the brains of mice affected their synapses, and increased obsessive behavior and “fearful memory.” As noted in today’s Science Daily:

The protein FKBP12 regulates several important cell signaling pathways, and decreasing its activity enhances long-term potentiation in the hippocampus, said Dr. Susan Hamilton, chair of molecular physiology and biophysics at [Baylow College of Medicine] and a senior author of the report. (Long-term potentiation means the enhancement of the synapse or communication between neurons.)

It accomplishes this by fine-tuning a particular pathway called mTOR signaling (mammalian target of rapamycin). The mice in whose brains the activity of the gene was reduced had longer memories and were more likely to exhibit repetitive behaviors than normal mice.

Researchers suggest that their findings might lead to the develop of drugs for autism and also for obsessive compulsive disorders.

Although—-what about the use of such repetitive actions to calm and self-soothe?

MARBLES stands for Markers of Autism Risk in Babies—Learning Early Signs. The study investigates “biological and environmental triggers that children are exposed to prenatally and post-partum”: Some 100 women who have a biological autistic child and who are pregnant, or who are planning on becoming pregnant, are participating in MARBLES, which began in 2006. Researchers from the UC Davis-M.I.N.D. Institute are collecting blood, urine, hair, saliva, and breast milk (if the mother is breast feeding), as well as dust from participants’ houses, and mothers are interviewed and medical records examined. It’s noted that MARBLES is “unique” because

follows mothers before, during, and after their pregnancies, allowing us to obtain information about the pre-natal and post-natal environment to which the baby is exposed.? By gathering information in real-time we increase the accuracy of the information collected and will be able to better understand and observe the biological and behavioral changes that may occur in the mother and/or baby throughout the pregnancy and early childhood period.

The November 22nd InsideBayArea opens by suggesting that people’s homes “might reveal clues for solving one of the biggest mysteries of modern medicine: the cause of a rapid rise in autistic children.” Besides collecting dust with a “special vaccuum,” researchers are also noting what household cleaners soaps, beauty products, electronics, and types of paint, each family uses. And, when Danielle Bell of Danville—whose almost 4-year-old son Jake is autistic—had her now 8-month-old daughter, Layla, researchers were present and “took for laboratory analysis the umbilical cord, a portion of the placenta and what is known as meconium, or the baby’s first bowel movement.”

In the search for a cause, for some of us, it could be said that our homes indeed contain “clues” about autism, in our very selves, in our genes, and not so much is to be revealed by analyzin the dust or the types household cleaning products.

Aside from discovering our housekeeping habits……..

A gene linked to susceptibility to autism, CNTNAP2, has also been connected to specific language impairment, the most common childhood language disorder, as reported yesterday in Reuters. The study, A Functional Genetic Link between Distinct Developmental Language Disorders, is published in the New England Journal of Medicine.

Specific language impairment involves difficulties with language and, in particular, the repetition of nonsense words. Researchers analyzed CNTNAP2 function in 184 families with common language impairments; children with certain forms of the gene had certain difficulties with language, such as the repetition of nonsense words. It was found that FOXP2, which is mutated in people with a rare speech and language disorder, “directly regulates expression” of CNTNAP2. CNTNAP2 has also been linked to epilepsy, schizophrenia, and Tourette’s Syndrome and may not be specific only for language, but may also play a role in the early development of cognitive function. As noted in the Washington Post

“What skill in language-impaired children is this gene affecting?” said Dr. Karin Stromswold, author of an editorial accompanying the paper in the Nov. 6 issue of the New England Journal of Medicine. “There are a lot of reasons you can be language-impaired, excluding hearing loss and mental retardation.”

Many children with common language impairment also have motor impairment, so the gene could actually be affecting either core language or motor involvement, said Stromswold, a professor of psychology and member of the Rutgers University Center for Cognitive Science, in New Brunswick, N.J.

In their paper, the researchers suggest that “different components of autistic-spectrum disorders (communication deficits, impaired social interaction, and rigid or repetitive behaviors) may be under different genetic influences.”

Another study about autism genetics appears in the Journal of Medical Genetics and (as noted in the November 5th Vancouver Sun) suggests that disruptions in the gene, Contactin 4, stop the gene’s proper functioning and prevent the brain from making proper networks through the development of axons; the mutations are present from birth. 92 patients from 81 families with autism spectrum disorder participated and a whole genome analysis performed, and the results compared them to 560 people without autism. Three of the patients were found to have deletions or duplications of DNA that disrupted Contactin 4. In all the cases, these disruptions were inherited from fathers without a history of autism.

Researchers from the Seaver and NY Autism Center of Excellence at New York’s Mount Sinai School of Medicine have developed a new method to detect copy number variants associated with autism spectrum disorders and have also found new chromosomal duplications that can be linked to autism.The study is published in the October 16th BMC Medical Genomics.

279 child with ASDs were screened for micro-duplications and -deletions in regions of the genome that have been connected to other cognitive conditions. The researchers detected several previously known duplications associated with autism, but also some that had not previously been recognized. The approach that psychiatry researcher Joseph Buxbaum and his colleagues used is multiplex ligation-dependent probe amplification, or MLPA which, it’s underlined, is an inexpensive and “efficient method to screen or chromosomal abnormalities,” whether these are large or small duplications.

Here’s a summary of the study from Genome Web:

The researchers screened 279 unrelated children with ASD using four different MLPA panels targeted parts of the genome previously linked to cognitive impairment. The subjects, who were around 8 years old, were not pre-selected based on dysmorphism or cognitive defects, Buxbaum said.

After weeding out copy number variants that were found in healthy controls and validating micro-deletions or -duplications using fluorescence in situ hybridization, quantitative PCR, or direct sequencing, the researchers found that about one to two percent of those with ASD also had a chromosomal abnormality associated with cognitive impairment.

For instance, they found subjects with duplications in a chromosome 15 region known to be involved in Prader-Willi/Angelman syndrome, a region of chromosome 22 that’s linked to DiGeorge syndrome, and a region of the X-chromosome that’s associated with X-linked non-specific mental retardation. The team also detected subjects with a partial duplication in the ASMT gene, which is found in the pseudoautosomal region 1 of sex chromosomes and has been previously linked to ASD.

Although the approach is quick and easy, Buxbaum cautioned, MLPA can’t be used to find new, unknown mutations — a situation that may occur in autism. That means it could miss private mutations that could be caught using array CGH with a dense chip.

In contrast, array CGH is “very expensive and time consuming.”

Buxbaum notes that these findings are mostly significant for an etiological understanding of autism and to starting a child on therapy as soon as possible:

………he emphasized, it would be unrealistic and undesirable to think of applying this sort of test in a prenatal setting, particularly because the individual mutations associated with autism are often incredibly rare, often with a vast range of expressivity. In cases where there is a family-member with a known genetic condition, Buxbaum noted, genetic testing for that specific condition can sometimes be desirable.

“Every time you say genetic testing, some people automatically think of pre-natal testing,” Buxbaum said. “This is more about giving an etiological diagnosis to children with autism.”

Multiplex ligation-dependent probe amplification for genetic screening in autism
spectrum disorders: Efficient identification of known microduplications and
identification of a novel microduplication in ASMT can be read as a PDF file.

Currently, there’s no prenatal genetic test for autism. Long ago (as in “around the time I first started writing this blog”) I referred to such testing as “fighting word“: While some would welcome the notion of knowing that a child-to-be would have a disability, others have been quick to point out the possibility of people choosing to abort a fetus if a disability were detected.

In the October 13th Babble, an online web community for a “new generation of parents,” Karen Dempsey writes about Choosing (a) Life: They said our baby would have Down’s; we said we understood. We had no idea. Having conceived her second child after a year of infertility treatments, Dempsey was concerned that the “risks of amniocentesis outweighed the chances it would detect a problem.” During an ultrasound, the radiologist detected other possible signs of Down Syndrome (echogenic intracardiac focus, or EIF; the size of the baby’s nose). Dempsey and her husband knew they were going to have their baby, no matter what. The article depicts Dempsey’s emotional state and thoughts while awaiting her daughter’s birth:

One sleepless night near the end of my pregnancy, I lay in bed with my heart racing, remembering that tiny star from the ultrasound. Were we kidding ourselves, pretending we could just take things as they came? I couldn’t calm myself, though I was desperate to sleep. I tried relaxing by tightening and releasing the muscles of my body one by one, beginning at my toes. I should pray, I thought. I should pray for her. But what did that mean? She was there, fully formed inside of me. I could feel her knees and elbows, her stubborn round head. I didn’t believe in a prayer that would change her genetic makeup; she had Down syndrome, or she didn’t. And so what would I be asking for, a different baby? I’d already chosen to have this one. I finally found peace, and sleep, with the thought, She is who she is. Already, she is who she is, and she is mine.

Liddy does not have Down’s Syndrome, but she has a number of medical conditions: a heart murmur caused by a congenital heart defect, swollen kidneys, an elevated white blood cell count, severe gastroesophogeal reflux disease. Dempsey writes of what testing could have told her and what it could not have:

An amniocentesis would not have predicted Liddy’s complications, or prepared me for the realities of having a sick child. Caring for Liddy challenged my marriage, my family relationships, my friendships and my mental health — my very way of being in the world. John and I were naïve. We would learn, through Liddy, the awe-inspiring breadth of medicine’s understanding, as well as the frustration and grief of its limitations — and of our own.

There’s no question in my mind that we were going to have Charlie when I was expecting, “whatever” he might have. Dempsey’s experience seems to me a potential harbinger of questions that parents may find themselves facing should more prenatal tests be developed, including these tough questions:

Will medicine suggest that any and every variation from absolute normalcy is pathological?

How can we draw lines between disabling diseases such as severe autism and more mild differences such as Asperger’s, which may give society some of its greatest achievers?

Will parents have complete say over the kind of children they want to bear?

And what sorts of messages will doctors and genetic counselors convey when talking about risks, probabilities and choices that involve not life and death but personality and sociability, genius and geekiness?

Tough questions and big questions. Here’s two perspectives, one from a scientist and another from the father of an autistic daughter.

For myself, I would to some extent have appreciated knowing Charlie’s diagnosis as early as possible. Perhaps it’s from the memory of all my wondering, worries, and confusion during Charlie’s babyhood, when subtle things said “things are different,” but nothing stood too much out, and no one wanted to say “maybe he needs to be evaluated by a specialist.” On the other hand, before there might be such a test, it seems all the more imperative to—like parents of children with Down Syndrome—present a hopeful message out there about autism, with an emphasis on how it’s not a dreadful death sentence, and that we know a lot more and can help a child greatly.

When I tally up all the things that have happened to Jim and Charlie and me since Charlie was diagnosed, it’s a rich harvest of experience, with some really tough and awful times (because society and communities did not know what supports and services to provide him with to thrive) and some so good, you can’t imagine life without them.

Following up on the harvest theme, today is “harvest theme day” at the b5media Health and Wellness channel. Wishing you a day of plenty and of sunshine, and of good times with those who walk with you.

A study of autism among 378 Cambridge University students has found that autism is up to seven times more common among mathematicians than among students in other disciplines, and that it was also five times more common in the siblings of mathematicians, according to the October 5th Times. The genes that are thought to cause autism may also give mathematical, musical and other skills to those without autism. The study was led by Simon Baron-Cohen, director of the Autism Research Centre, who is quoted as saying:

“It seems clear that genes play a significant role in the causes of autism and that those genes are also linked to certain intellectual skills.”

Seven of the students in the Cambridge study were found to have autism, while only one in a control group of 414 had autism.

Baron-Cohen also notes other studies, one which found that the fathers and grandfathers of children with autism are twice as likely to work in engineering, and that science students also have more autistic relatives with autism than students in the humanities—-two findings that don’t quite adhere with Charlie’s situation. My mother’s father was a civil engineer and many of my relatives on my father’s side are engineers. Jim and I are not scientists, but definitely in the humanities, Jim being a historian and me teaching and writing about literature. Charlie is still working through very basic arithmetic.

He’s always been musical. He’s taken quite easily to learning piano and cello and is able to read music much better than words. I often understand something he’s trying to tell me when he sings part of a song or melody, or just by the tone of his voice, and he’s very attentive to the sounds, tones, and rhythms of our voices. He has no savant abilities though, in the past few months, after watching him swim in the ocean and ride his bike for many, many miles today (”’cause he’s fast,” Jim explained), he’s definitely got some athletic abilities.

Or maybe just some pretty good genes.

An article in the September 10th New England Journal of Medicine entitled Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes describes the associations between a microdeletion at 1q21.1 and impairments including mental retardation associated with microcephaly, cardiac abnormalities, or cataracts. A microdeletion at 16p11.2 is associated with susceptibility to mental retardation or autism and was discussed in the NEJM in February. In an editorial accompanying the new NEJM study, David H. Ledbetter, Ph.D., of the Department of Human Genetics, Emory University, Atlanta, notes that a “technologic revolution in human cytogenetics” has made these discoveries possible, thanks to “genomewide assessment of copy-number alterations (deletions and duplications)” that are performed “by means of high-density array technologies, hereafter referred to as cytogenetic arrays.”

That is, new technologies are enabling us to discover “new syndromes caused by deletion of genomic segments of 500 kb to 2 Mb in size” and Ledbetter concludes that pediatricians and clinicians “like researchers, can now shift to a ‘genotype first’ model of diagnosis for children with unexplained developmental abnormalities”—-doctors now have more tools at their hands to help make and/or confirm a diagnosis in a child with developmental delays.

The study’s authors note that 1q21.1 rearrangements are associated with a “broad spectrum of disorders” and further they “dispel the notion that such rearrangements will necessarily follow the one-gene, one-disease model.” As PhysOrg notes,

The authors recognize that the diversity of disorders and the lack of a distinct syndrome accompanying 1q21.1 rearrangements will complicate genetic diagnosing and counseling. They suggest that clinicians caring for patients who have unexplained developmental abnormalities consider the identification of a 1q21.1 rearrangement in a patient a significant clinical finding and probably an influential genetic factor contributing to the patient’s disorder. Evaluating the patient’s family members may reveal apparently unaffected or mildly affected relatives carrying the same rearrangement. Keeping in mind the many possible repercussions of having this rearrangement in the chromosome, the authors suggest that young carriers should be monitored over the long term for the emergence of learning disabilities, autism, schizophrenia, or other neuropsychiatric disorders.

This study, the authors said, adds 1q21.1 as a chromosomal locus to the growing list of structural variants that might eventually be included in genetic screening panels for people with developmental delays or neuropsychiatric diagnoses.

“Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype,” as the study’s authors conclude. The study both shows the “importance of rare structural variants in human disease” and also reveals some of the challenges, namely:

First, large samples of patients and controls are required to show that a specific variant is pathogenic. Although there have been several reports of patients with 1q21.1 deletions in studies of specific diseases, our study shows that recurrent 1q21.1 microdeletions are significantly associated with pediatric disease, through systematic comparison of the frequency of rearrangements in affected and unaffected persons. Second, detailed clinical evaluations of affected persons disclosed a much broader spectrum of phenotypes than anticipated, dispelling any notion of syndromic disease. While this article was being reviewed before publication, two groups reported enrichment of 1q21.1 deletions in persons with schizophrenia; they report deletions in 0.26% of patients with schizophrenia, as compared with our finding of deletions in 0.5% of persons with developmental abnormalities. These results confirm the association of 1q21.1 rearrangements with a broad spectrum of phenotypes but also further dispel the notion that rare copy-number variants will necessarily follow the one gene (or one rearrangement)–one disease model.

Researchers hope that such findings will lead to more accurate diagnosis (via genetic testing), and also “‘more effective treatments,’” as Professor Ledbetter is quoted (in HealthScout).

The new study further attests to the complexity of autism genetics, and to deep-running variance from individual to individual—there’s no one “autism gene” to be found.

In the ongoing chicken and egg type debate over what the causes of autism might be, how often have you it said that it’s believed that a child may have a “genetic predisposition” to autism, but that it’s an “environmental trigger”—-it’s something in the environment—-that leads to a child “having autism”?

An August 13th post on Mind Hacks on a letter to Nature on psychiatric genetics offers something to reflect on. From the letter:

Your News Feature ‘The brains of the family’ (Nature 454, 154–157; 2008) and accompanying Editorial ‘An unnecessary battle’ (Nature 454, 137–138; 2008) highlight the need to adopt a more integrated perspective when trying to unravel the biological complexity of neuropsychiatric disorders such as schizophrenia and depression. But the ‘battle’ between genetics and neuroscience, despite being well funded, may be missing the point.

The full version is only available via subscription; Mind Hacks quotes more:

Napoleon Bonaparte advised: “Never interrupt your enemy when he is making a mistake.” Those of us who assess the contribution of non-heritable risk factors to neuropsychiatric illness would like to politely interrupt this battle to remind opponents that environmental risk factors have now overtaken genetic factors with respect to both effect size and the proportion of the population that is affected.

For schizophrenia, for example, factors relating to urban birth, cannabis use and migrant status are well replicated and have relatively large effects — in contrast to the scant evidence that remains after decades of genetics research. Although the ‘heritability index’ for schizophrenia is large (about 85%), this metric encompasses the neglected contribution of gene–environment interactions, as well as the high-profile genetic component. This key point is largely forgotten in the heat of the battle.

Mind Hacks explains” gene-environment interactions” as “where exactly the same genes can produce different heritability depending on the environment.” So, if we all lived in a “virtually identical environment” and had “almost exactly the same life experiences,” genetics alone would have to account for our differences; whereas, if “environment was widely different for everyone, much more of the difference would come from experience.” It’s been noted that studies into the genetics of autism only relate to a small number of cases: If (as suggested in a recent study), different (and many different) genetic mutations lead to autism in different individuals, what other factors might be coming into play, it’s wondered?

Granted, when people talk about “environmental factors” that might “trigger” autism, factors such as “urban birth, cannabis use and migrant status”aren’t what they mean, but rather something more like pollution and vaccines or something in vaccines…….

As a parent, when I see the phrase “nature-nurture,” I get a bit stuck on the “nurture” word, as any suggestion that we didn’t provide the right emotional, social, and so forth “environment” for Charlie and did not provide enough “nurture” can lead a parent to think of the discredited “refrigerator mother” theory of autism. Neuroscientists at MIT’s Picower Institute for Learning and Memory are using the phrase “nature-nurture” to describe new findings about genes, the brain’s development, and autism. The researchers have found a set of genes—calcium sensor called cardiac Troponin C, or cTropC—that are

…..particularly sensitive to a critical period of development. The lack of proteins from these genes during a key phase of development could be one of the culprits in developing autism.

The study shows how autism “can be genetic and yet be dependent on the environment,” as co-author Mriganka Sur, Sherman Fairchild Professor of Neuroscience at the Picower Institute and chair of MIT’s brain and cognitive sciences department, says in Science Daily:

“Many genes require activity to be expressed and make their assigned proteins. They alter their expression when activity is altered. Thus, we reveal an important mechanism of brain development that should open up a window into the mechanisms and treatment of brain disorders such as autism.”

In the brain, some genes are only expressed, or turned on, in response to stimulus from the outside world. Like a panel of switches that turn lights on and off, genes that don’t receive electricity don’t “turn on” and express their particular proteins.

Scientists are trying to figure out the correlation between “nature”—the genes—-and “nurture”—the external environment. By identifying “which genes are particularly apt to switch their expression patterns in response to ‘nurture,’” they hope to detect the genes that are implicated in developmental disorders.

The study is published in the July 8th Proceedings of the National Academy of Sciences.