rare disorder in Amish children - link to autism

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http://www.sciencedaily.com/releases/2010/05/

100511111933.htm

Rare Disease in Amish Children Sheds Light on Common Neurological Disorders

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PMSE brain exhibits abnormal brain architecture. Left, region of the cerebral

cortex obtained post-mortem from PMSE patient. Inset depicts neurons trapped in

the white matter that have failed to move into the cortex during brain

development. Right, three examples of abnormally large neurons in the cerebral

cortex in PMSE. (Credit: B. Crino, MD, PhD, University of Pennsylvania

School of Medicine)

ScienceDaily (May 12, 2010) — So often the rare informs the common. Penn

researchers investigating a regulatory protein involved in a rare genetic

disease have shown that it may be related to epileptic and autistic symptoms in

other more common neurological disorders.

A team of researchers from the University of Pennsylvania School of Medicine,

led by B. Crino, MD, PhD, associate professor of Neurology and director of

the Penn Epilepsy Center, demonstrate how mutations in the STRAD-alpha gene can

cause a disease called PMSE (polyhydramnios, megalencephaly, and symptomatic

epilepsy) syndrome, found in a handful of Amish children. PMSE is characterized

by an abnormally large brain, cognitive disability, and severe,

treatment-resistant epilepsy.

Specifically, in an animal model, they found that the lack of the STRAD-alpha

protein due to genetic mutations causes activation of the signaling pathway

involving another protein called mTOR. In humans, this in turn may promote

abnormal cell growth and cognitive problems in the developing brains of

children. STRAD-alpha and mTOR proteins are part of a complex molecular network

implicated in other, more common neurological disorders, many of which have

autism-like symptoms as a component.

" The identification of a new gene that regulates mTOR provides fascinating

insights into how mTOR pathway dysfunction may be associated with neurological

disorders, " says Crino. " Each new mTOR regulatory protein that is identified

provides a new possible therapeutic target for drug development and treatment. "

The research on PMSE -- published in the Journal of Clinical Investigation --

reveals clues about more common neurological disorders characterized by benign

tumors and malformations of the brain, the most common of which is tuberous

sclerosis complex (TSC). The root cause of TSC also lies in mutations in

proteins along the mTOR pathway, however a different protein is affected

compared to PMSE.

" It is quite compelling that TSC, a relatively common disorder, and PMSE, a rare

disorder, are linked by a common cellular pathway, and exhibit similar severe

neurological features, " notes Crino. " In our study, we found that we could

reverse some of the cellular features that result from STRAD-alpha deficiency in

cell culture models of PMSE. This provides important conceptual support for more

widespread treatment approaches that modify mTOR signaling in neurological

disorders associated with epilepsy, autism, and cognitive disability. "

Current estimates place tuberous sclerosis complex-affected births at one in

6,000. Nearly 1 million people worldwide are known to have TSC, with

approximately 50,000 in the United States.

PMSE, on the other had, has only been described in 25 people in Lancaster

County, PA. It's incidence among other Amish populations, let alone the rest of

the country, is unknown. PMSE is also known as pretzel syndrome in the Amish

community, because the lax joints of patients fold over easily. PMSE was

identified in an Amish, or Old Order Mennonite pediatric population in 2007 by

researchers from Penn and the Clinic for Special Children in Lancaster, PA, a

genetic clinic devoted to the needs of the Amish.

The mTOR pathway normally controls cell growth, but in PMSE uncontrolled mTOR

signaling leads to increases in brain size and areas in which the cerebral

cortex is malformed. To prove this, the researchers knocked down the activity of

the STRAD-alpha protein in a mouse model and caused malformations of the

developing brain. The structure of these malformations was similar to what is

seen in human PMSE and TSC and supports the conclusion that normal brain

development in part depends on normal STRAD-alpha function. Localized brain

malformations are among the most common causes of epilepsy and neurological

disability in children.

This research was funded by the National Institute of Neurological Diseases and

Stroke.

Ksenia Orlova, PhD, a graduate student in the Crino lab and Strauss, MD,

Medical Director at the Clinic for Special Children, were also co-authors on the

JCI paper.