A breakthrough in understanding the genetics of schizophrenia -- and perhaps of autism too

A major publication in Science on the genetics of schizophrenia is summarized in Gordon's Notes

Gordon's Notes: What is schizophrenia? Not what we thought.

... note only 15% percent of "schizophrenics" fit this pattern. I'll summarize the key implications:

• Schizophrenia is not a disease. It's the name given a fairly large number of unique disorders of brain development that have, among their endpoints, social withdrawal, hallucinations, and fixed beliefs.
• A good number of cases of "autism" and "schizophrenia" are different manifestations of overlapping sets of mutations.
• There may be"no genes for most instances autism and schizophrenia". There are sets of large scale mutations that are similar between close genetic relatives, but similar appearances are resulting from disorders of quite different components of brain development.
• One in twenty seemingly normal people have big, ugly looking mutations that ought to be messing up their brain development. Yet they seem "normal". Seventeen in twenty persons with "schizophrenia" do NOT have these nasty scattered "sledgehammer" mutations. (So called because it's as though something took a sledgehammer to the genome.)
• The age onset of schizophrenia is determined by when the disordered developmental genes are activated. There's a lot of this going on in late teen years. The implication is that the same thing explains why "autism" presents around ages 2-3, and why it can seem to appear fairly suddenly. This may also explain why some conditions seem to improve at other ages. Schizophrenia syndromes often improves in middle age, for example.
• If every person with autism has a somewhat unique disorder, then treatments and prognosis are also unique. This validates the age old practice of asking someone with a cognitive/psychiatric disorder what treatments have worked for relatives.

I'm seeing a growing consensus that "autism" will turn out to have a similar picture. The trend is clear, autism is also going to turn out to be a diverse collection of disorders of brain development and injury response with diverse genetic causes. These as yet unnamed disorders will turn out to have different prognoses and different therapies.

Wanted: A new profession of neurotherapy

I don't ask for much.

So I won't ask for any miracle cures. I would, however, like to see a new profession.

I'd call it cognitive therapy, but that name's taken. So I'll call it neurotherapy for now.

A neurotherapist is a cross between a coach, teacher, occupational therapist, speech therapist, trainer, psychiatrist and neurologist.

A neurotherapist studies a child or adult with cognitive disorders and creates a profile of abilities, talents, disabilities and traits.

The neurotherapist then establishes up an empirical program of training, and studies the response across aspects of the individualized cognitive profile.

Some aspects respond to training. These receive special attention. Others respond poorly, they may be approached through different modalities. Over time a repeated failure of one aspect to respond to training means time and energy shift to other aspects.

A neurotherapist looks for collections of traits that may support employment or important skills. The neurotherapist designs training interventions that combine areas of relative strength that can compensate for areas of weakness.

Of course there's a wee problem with insurance payments and professional certification, but if we can squeak by that little detail I'm sure we could make progress. The first neurotherapists would likely be privately employed speech and occupational therapists looking to do much more than they're currently able to do.

Are you a speech or occupational therapist based in the Twin City region and looking to be one of the world's first neurotherapists? Send me a note: jfaughnan@spamcop.net.

Guanfacine and lessons about off-label drug use

Guanfacine, marketed as Tenex, was once used to treat hypertension. These days it's also used, off-label, for the management of behavioral disorders in children.

Very off-label. You won't find this mentioned in most drug references. You also won't find mention that guanfacine alters the course of neuronal development in mice, or that Guanfacine ... Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans:

Neuropsychopharmacology (1999) 20 119-130.10.1038/sj.npp.1395238...

... The present study compares the effects of two alpha2-agonists, clonidine (0.5, 2, and 5 g/kg, PO) and guanfacine (7 and 29 g/kg, PO) in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests.

In the PAL test, clonidine 2 and guanfacine 29 g/kg improved the subjects' performance.

In the DMTS test, clonidine at 5 g/kg delay-dependently impaired performance accuracy, and at 2 and 5 g/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 g/kg equally increased subjective feelings of sedation and reduced blood pressure.

The results suggest that both clonidine and guanfacine facilitated PAL learning by improving "frontal strategies," but only clonidine disrupted "mnemonic processing" decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha2A-adrenoceptor subtype may explain the different profile of action of the drugs.

This isn't a new study by the way, it's nine years old. It turns out there's an extensive literature on Guanfacine and cognition, much of it based on animal studies done in the 199os.

More recently, guanfacine is being studied for the treatment of schizotypal personality disorder because "there is evidence that guanfacine enhances cognition and diminishes impulsivity". In fact, today there are 19 Clinical Trials that reference guanfacine, one of which was completed and resulted in a publication in January 2008 -- "Guanfacine extended release met the primary and secondary efficacy end points. It was well tolerated and effective compared with placebo." (Clinicaltrials.gov, by the way, is impressive.)

Phew. I thought I was relatively clued into this world, but I'd have bet real money there wouldn't be any studies of Guanfacine in children -- it's off-patent. I'd have been very wrong.

So what lessons can I draw about off-label med use from this experience:

1. We didn't learn much from the responsible clinicians. I suspect that's typical.
2. You won't learn about off-label medication use by reading medication references -- they tend to avoid these topics.
3. Clinicaltrials.gov is very impressive. Enter your off-label drug there and learn.
4. scholar.google.com and PubMed cover the publication field, though I've found odd bugs in the former (links pointing to the wrong article).
5. Animal studies are particularly interesting.

Does this mean we're more comfortable with use of the drug? Yes, somewhat -- particularly because of the Jan 2008 publication in Pediatrics. I really hadn't expected to see real trials in children. On the other hand, guanfacine seems to be a relatively powerful medication, and we really don't know what the effects of longterm use are on the developing brain. It could be helpful in the short term and harmful in the long term (see: estrogen).

I've created an RSS feed in PubMed for guanfacine, so I'll be notified of new publications.

Google for Non-Profits

Google for Non-Profits doesn't have a lot of new things, but Google is putting them all in one place. Great stuff for special needs related organizations. The big three are:

1. Free online advertising (Google grants)
2. Google Apps for non-profits (a terrific infrastructure, see Minnesota Special Hockey).
3. Checkout: Google processes credit card donations - for free!
   

Applying lessons from the rehabilitation of traumatic brain injury to the care of special needs children

I've been frustrated by the thunderous silence on how to manage a special need's child whose brain has areas of profound weakness. Subsequently it has occurred to me that there has been quite a bit of research on the topic of optimizing the function of injured brains -- but the work has been done in the context of trauma, not of congenital or developmental injury.

Traumatic brain injury rehabilitation has always had much more funding than the rehabilitation of congenitally injured minds, but terrible rates of brain injury in modern warfare have greatly increased research funding for young adults as well.

A quick PubMed search suggests there may be fruitful ideas in this domain: "brain injuries"[MeSH Major Topic] AND ("rehabilitation"[Subheading] OR "rehabilitation"[MeSH Terms] OR rehabilitation[Text Word]) has 3537 hits, of which 534 show up in the review tab. A Google search using "rehabilitation" and "traumatic brain injury" has 812,000 hits today, though they are, of course, highly repetitive.

I'll look into this a bit more.

Interactive Autism Network Research: Johns Hopkins and the Kennedy Krieger Institute

I came across this one at a scientific meeting I was attending.

The Kennedy Krieger Institute claims to be America's largest facility for the care and study of children with autism and other developmental disorders. Together with Autism Speaks they're sponsoring the IAN Project, a national project to study the natural history and characteristics of the the complex array of syndromes and disabilities now awkwardly lumped together as "autism":

Interactive Autism Network Research

...IAN Research allows parents of children diagnosed with an Autism Spectrum Disorder (ASD) to participate in research over the Internet. Parents provide information about their child's diagnosis, behavior, family, environment, and services received. Parents may also report on their child's progress over time.

Who can participate in IAN Research?

To register and answer research questions in IAN Research, you must live in the United States and be a biological or adoptive parent of a child under the age of 18 who is diagnosed professionally with one of the following disorders:

• Autism Spectrum Disorder (ASD)
• Autism
• Asperger Syndrome
• Autistic Disorder
• Pervasive Developmental Disorder (PDD)
• Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS)
• Childhood Disintegrative Disorder (CDD)

The child should not have a diagnosis of Rett Syndrome.

What are the benefits of joining?

You will be able to participate in important research on ASDs. IAN will provide tools that help you monitor your child's progress over time and explore how your child is similar to (or different than) other children affected by this disorder.

I suspect there's some work involved and that the benefits will not accrue to this generation of autistic children, but we will consider entering the study.

The IAN Project has a related community component to recruit study participants and connect interested persons to their research developments (though they're not going to reveal anything interesting prior to publication - that's just the way academia works). It includes discussion groups and articles like this one:

What are the behaviors and ways of taking in the outside world that distinguish a person with an ASD from his or her “typical” peers? Although these will vary according to the severity of a person’s autism and where they are in the lifespan, there are core issues that impact most people with an Autism Spectrum Disorder. In this section we explore each of these overlapping topics...

The Community component is very much secondary to the research component. The articles all end on the same note "we don't know much, please join our study". A bit disappointing but also true -- we really don't know much about cognitive disorders.

The Discussion Groups are focused on the IAN research project. It will be tough to keep them on topic -- they'd need heavy moderation to survive. I'll take a look at them later and comment on how well that's working out.

Vaccine payment for a mitochondrial disorder?

It's a weird story. The feds paid out a vaccine injury claim for a child with a mitochondrial disorder.

Deal in an Autism Case Fuels Debate on Vaccine - New York Times

...Hannah’s father, Dr. Jon Poling, was a neurology resident at Johns Hopkins Hospital at the time, and she underwent an intensive series of tests that found a disorder in her mitochondria, the energy factories of the cells...

Since the formal definition of autism doesn't exclude brain injury from other causes Hannah does technically have autism, but she'd be excluded from any research study of the disorder. She apparently has a well defined and extremely rare disorder of her mitochondria...

...symptoms of mitochondrial myopathies include muscle weakness or exercise intolerance, heart failure or rhythm disturbances, dementia, movement disorders, stroke-like episodes, deafness, blindness, droopy eyelids, limited mobility of the eyes, vomiting, and seizures. The prognosis for these disorders ranges in severity from progressive weakness to death. Most mitochondrial myopathies occur before the age of 20, and often begin with exercise intolerance or muscle weakness. During physical activity, muscles may become easily fatigued or weak. Muscle cramping is rare, but may occur. Nausea, headache, and breathlessness are also associated with these disorders....

I wonder what the legal basis of the claim was? Are vaccines known to precipitate a crisis in mitochondrial disorders? They are thought to be exceedingly rare, so I suppose that's possible.

I hope this gets covered in more detail in a major medical or science journal. Based on what I've read so far I think this has no relevance to 99.99% of the children and adults who have some form of idiopathic autism. I think this does emphasize that the definition of autism is impossibly broad.

Update 3/18/2008: Dr Rahul Parikh, writing for Salon, is the only writer on this topic I've read who bothered to include the Judge's statement:

the court "concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations CHILD received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder. Therefore, respondent recommends that compensation be awarded to petitioners."

The vaccine court is predisposed to pay if there's any chance of injury. So they paid out, even though the expected course of some mitochondrial disorders includes, tragically, regressive encephalopathy.

The confusion in this case arises because the technical (DSM IV) definition of autism is exceedingly broad, and says nothing about the underlying cause. This story is yet another indicator that we need better ways to describe disorders of cognition.

BigScreen Live: XP software for elders and special needs

In general, what works for elders also works for persons with cognitive disabilities. I speak here as someone who is closer to elder than younger.

So I was intrigued to find this product in one of my routine searches for adaptive software solutions:

BigScreen Live: Software and Accessories

Create an account for yourself or for a relative or friend. After the 30-day trial a membership will be available to you for the price of only $14.99 per month.

You do not need an email address to get a BigScreenLive membership. We will provide you will an email address, and free download of the software. Currently BigScreenLive works with Windows XP and Vista and will be available for Macs soon.

Once you purchase a membership, we will also send you a BigScreenLive USB 2.0 Flash Drive, which will allow you to use BigScreenLive on public computers without having to download the software.

"Available for Macs soon" usually means -- we'll start work on an OS X version when heck freezes over. If my mother were using an XP solution I'd look at this more closely, but I'm pleased to see that there are vendors exploring this growing market. The USB 2.0 Flash Drive option is interesting.

There's no information on the site to suggest what the product actually is, but of course they're not selling directly to people like me.