Epilepsy and Genetics

[Bernard]

Researchers identify new childhood-onset epilepsy disorder and its genetic cause

Finding may also shed light on cause of autism

Researchers from the Translational Genomics Research Institute (TGen) and the Clinic for Special Children (CSC) in Strasburg, PA, have described a new childhood-onset disorder characterized by severe epilepsy and autistic traits, and identified its genetic basis.

Epilepsies are a biologically complex group of disorders comprising many discrete genetic entities, and the majority of recurrent seizure syndromes remain unexplained. Most, if not all, epileptic disorders can be traced to abnormalities of brain structure or chemistry that alter the electrical activity of nerve cell networks. The children in this study have autistic traits, also thought to be caused by disrupted nerve cell networks.

The finding, which is published in the March 30th issue of the New England Journal of Medicine, describes the newly discovered disorder called cortical dysplasia-focal epilepsy syndrome (CDFE) in a group of closely related Old Order Amish children from Pennsylvania.

All affected children had relatively normal development until the onset of frequent intractable seizures in early childhood. Thereafter, they developed language regression and additional features of autism, possibly implicating this gene as a cause of autism in the general population. Physicians at the CSC isolated DNA from four of the affected children and their six parents and, in collaboration with TGen, identified a mutation in the gene that codes for a protein called CASPR2.

New GeneChip technologies for scanning the human genetic blueprint are powerful tools for rapidly identifying causes of disorders such as epilepsy in carefully selected families.

"The ability to rapidly decipher the genetic underpinnings of brain disorders through genetic technologies will allow the medical community to better understand disorders such as autism and epilepsy, and this understanding is the first step in developing effective treatments" said Dr. Dietrich Stephan, Director of the Neurogenomics Division at TGen, Scientific Director of the TGen/Southwest Autism Research and Resource Center's (SARRC) autism research program, and a senior author on the study.

The protein has a well-known role in maintaining physical contacts between neurons and neighboring glial cells in the mature nervous system, but this is the first evidence that CASPR2 is also important for early human brain development.

According to Dr. Erik Puffenberger, laboratory director at the CSC, "We were able to unequivocally map the disease gene to chromosome 7 and identify a pathogenic sequence variant in the gene CNTNAP2, which codes for the CASPR2 protein. Although these patients were from an isolated population, we anticipate that CASPR2 mutations will be found in children from other populations with mental retardation, seizures, and autism."

"Previous studies on CASPR2 in isolated cell cultures and genetic 'knockout' mice did not predict its fundamental role in human brain development or cortical electrical activity. The present findings are compelling evidence for such roles, and open new directions for epilepsy and autism research beyond the index population," said Dr. Kevin Strauss, a pediatrician at the CSC.

According to Dr. Holmes Morton, co-founder and medical director of the CSC, "The identification of the mutation in CASPR2 in our Amish patients has already allowed us to recognize affected newborns before they become symptomatic. Our hope is that early treatment and prevention of prolonged seizures in these infants will lessen the effects of the disorder upon the lives of children and their families."

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Stacy has mentioned that there is a long history of epilepsy in her maternal family tree - mother, uncle, great grandmother and so on (it skipped her grandmother - she had diabetes). Maybe one day it will be easy for anyone to be tested for genetic mutations suspected to cause epilepsy.

[Bernard]

This just in from Forbes magazine:

Medicine's vaunted genomic era has yielded more murk than miracles. Of the hundreds of genes unearthed as purported links to either diseases or behavioral quirks, precious few have ever had that link confirmed. Joel Hirschhorn, a pediatric endocrinologist at Harvard's Children's Hospital, started looking into the matter after becoming worried that the whole field was in danger of losing credibility. "Just about everything that hit the papers up until a few years ago, all those were wrong," he says. Adds University of Oxford neurologist George Ebers: "It's a real issue. No one wants to say it publicly."

In a recent survey Hirschhorn found that only one of 50 proposed human obesity genes was confirmed to have that role. A 2005 study by Duke University researcher David Goldstein was unable to confirm any of 7 genes for temporal-lobe epilepsy. Celera Diagnostics and collaborators at the University of Texas at Houston could validate only one of 21 previously proposed heart disease genes when it scanned them against thousands of DNAsamples.

Attempts to use DNA chips to spot "genetic signatures" that predict cancer prognosis or survival have also come under question. A 2005 Lancet study rigorously reanalyzed data from several such studies and found that only two of seven proposed genetic signatures held up better than a coin flip in predicting cancer outcome. For some cancers, "I am really not convinced a unique signature exists," says study lead author Stefan Michiels.

One problem is the changing nature of medical discovery, says Greek clinical epidemiologist John Ioannidis, who studies how poorly many medical research findings hold up over time. Researchers have traditionally considered a study statistically valid if pure chance would create a similar finding less than 5% of the time. This worked well when scientists were examining a few well-understood risk factors, such as high cholesterol.

But these days researchers use computers to scan through thousands of little-known genes simultaneously in search of subtle contributors to disease. The huge number of comparisons virtually guarantees that false positives will be found. It's like rolling a pair of dice 1,000 times and rejoicing when dumb luck gives you three sevens in a row. "It is almost too easy to make a discovery," Ioannidis says. Compounding the problem are technical difficulties finding a properly matched control group; competing researchers who don't share data; and publication bias, the tendency of scientists to rush out positive results but sit on negative ones that won't bring them fame or tenure.

The Giant Genome Fizzle

[RobinN]

Some fascinating and exciting research:

It’s not often that words such as “rescue of neurological deficits” “therapy for cognitive impairment” and “reversal of neurological defects” are used in the titles of papers studying genetic disorders like Angelman, Down, and Rett syndromes – but a recent trio of papers does just that, offering hope for all those with complex neurodevelopmental disorders.

http://www.fpwr.org/node/352

[Belinda5000]

epilepsy is genetic in my family on one side.
I had an uncle not blood related who had epilepsy.
He had two children sons the son only had one seizure in the military.
The daughter is still not controlled she's probably in her 60's now.
She had two kids, one one child out had epilepsy he out grew it.
I don't know if he ever had any children.


Belinda

[Meetz1064]

my family, but we're not sure.

It's said that one of my great-great-(great?) uncles had something called St.Vitus' Dance. And possibly another one also. Several family members do have problems with migraines. HOWEVER, I am the ONLY one actually diagnosed with E.

[Belinda5000]

I have quite a few family members that have migraines including myself,mother few other aunts.

I also have a cousin with E her son my grandmother had seizures till she had her first child. my cousins son out grew E though.

Belinda

[Bernard]

Even with a genetic basis, all hope is not necessarily lost. See Healthy lifestyle triggers genetic changes.

[Lisa B]

Hi I found your thread really interesting, my little girl Rosie is currently being tested for autism and also undergoing tests for something called fragile x I was wondering if anyone else has heard of this particular syndrome. Rosie does present with many of the symptoms ie delayed speech and language, over sensitive hearing and developmental delay pretty scary place to be as a mum.
Best wishes to all x

[skillefer]

Hi Lisa! Welcome to CWE. As for fragile X syndrome, yes, I've heard of it. I'm a teacher, and one of my students had it. The student had some developmental delays, but was able to learn and make progress academically.

[Lisa B]

Thanks for your reply, we are waiting on an appt to have the relevant tests to confirm but it is looking highly likely that this is what Rosie has, still I am pleased to hear that academically she may well still achieve at the end of the day she is the most gorgeous little girl and I will hold her hand every step of the way.