Tests Can Predict Hereditary Mental Retardation

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Media contact: Beckie Smith American Neurological Association (612) 545-6284 theresagutoski@compuserve.com

TESTS CAN PREDICT HEREDITARY MENTAL RETARDATION

Physicians now have the tools to determine the risk for certain hereditary brain disorders that cause severe mental retardation, according to an editorial in this month's issue of the Annals of Neurology, the scientific journal of the American Neurological Association and the Child Neurology Society.

The editorial hails advances in the understanding of the genetic basis of brain development disorders, citing two articles in the February issue of the journal, one from a group in the United States and one from a group in Italy, that have further clarified the relationship between two specific gene mutations and lissencephaly and double cortex, two malformations of the cerebral cortex.

"As neurologists, we now have to look at brain malformations on MRI scans and recognize that they may have specific genetic causes. In any family where there's one child with one of these malformations, there is a defined risk for another occurrence," said Gary Clark, a pediatric neurologist in the Cain Foundation Laboratories at Baylor College of Medicine in Houston, Texas, and one of the authors of the editorial. "We can now do the genetic testing to help that family decide if there's a high risk that they will have another child with this disorder."

The cerebral cortex, the outer layer located on the top of the human brain, is essential for the functions that contribute to learning and intelligence (e.g., vision and other senses, attention, perception, thinking).

It is essentially a thin, convoluted sheet of 6 layers of nerve cells. Spread out, it would be as wide as a sheet of newsprint. In order for such a wide, flat object to fit into the much smaller hollow space of the human skull, it has to be folded.

This happens during the development of the brain in the fetus and infant: nerve cells born deep within the brain migrate to the surface to form the ever-expanding thin layer of the cerebral cortex. Convolutions form in the cortex, allowing it to retain its six-layer structure.

In lissencephaly, nerve cells appear to lose their sense of direction and purpose and do not migrate to form the six layers. Instead they form a disorganized mass of cells and the resulting brain is smooth on the surface.

Such disorganization usually leads to severe mental retardation and other problems (e.g., epilepsy or problems in breathing, temperature regulation, or accepting nourishment) that conspire to drastically shorten the lives of those affected.

In double cortex syndrome, on the other hand, many neurons migrate appropriately, but a subgroup gets stuck below the normal cortex. There these cells disrupt normal brain function, and may cause mental retardation or epilepsy.

One message of recent research into these disorders is that defects in either of two different genes, called LIS-1 and DCX-XLIS, can cause lissencephaly. Furthermore, the DCX-XLIS mutation will cause lissencephaly only in boys; most girls with the mutation will develop double cortex syndrome.

One of the studies in this month's Annals of Neurology, from a group led by Christopher A. Walsh, M.D., Ph.D., of Harvard University in Boston, shows that the DCX-XLIS gene is always defective in families with several occurrences of lissencephaly or double cortex syndrome.

The other study, from a group led Romeo Carrozzo, M.D., of the San Raffaele Hospital in Milan, Italy, demonstrates that different mutations of the LIS-1 gene can cause different manifestations of lissencephaly, broadening the clinical spectrum of the LIS-1 gene disorders.

Tests for mutations of LIS-1 and DCX-XLIS can thus help a family with one severely mentally retarded child determine the likelihood of another occurrence.

Further from clinical medicine, but equally important to the understanding of brain development disorders, these studies demonstrate that a single gene defect can be at the root of several different disorders. This raises the question of whether these genes are also involved in subtler forms of mental retardation, where brain scans typically show no obvious malformations.

"Up to now, we've selected children with very obvious brain malformations and tested them for abnormalities of these genes. Could there be patients out there who have no obvious malformations on their brain scans but have one of these genetic defects? We haven't even begun to look at that possibility. This work could lead to a broadening of the clinical spectrum associated with abnormalities of these particular genes." said Clark.

The other author of the editorial is Jeffrey L. Noebels, M.D., Ph.D., also of Baylor College of Medicine.

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