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Stanford Report, April 17, 2002

Medical center scientists close in on mysterious fetal brain disorder


Researchers and clinicians at Lucile Packard Children’s Hospital and the School of Medicine are joining forces to learn more about a fetal brain defect believed to cause the vast majority of miscarriages — and which has serious impacts on children who live with milder forms of the ailment.

Holoprosencephaly, a condition where the two halves of the brain are fused together rather than separated during early development, affects one in every 5,000 to 10,000 newborns. Scientists from around the world gathered last week in Bethesda, Md., for the second conference on this birth defect.

Although several genetic and environmental factors have been identified as likely causes of holoprosencephaly, clinicians still puzzle over the variety of malformations ranging from mild cases with reasonably separated hemispheres to severe ones with no apparent separation.

"We don’t know why there is this wide variation," said Jin Hahn, MD, medical director of the Carter Center at Packard Children’s Hospital and professor of neurology and pediatrics. "Even in the familial form where a gene has been identified, there may be variations in the family. Obviously environmental factors may play a role."

The Carter Center is one of only three centers nationwide dedicated to the study of holoprosencephaly. The center’s purpose is to create a comprehensive list of patients and to support and conduct basic research. One effort of Hahn and his team is aimed at developing a better system of categorizing the clinical and the radiological spectrum of patients with the disorder. The classification they have come up with may help clinicians improve their predictions on outcome and severity of their patient’s symptoms.

Hahn spoke on April 9 at the Bethesda conference, which was co-sponsored by the Carter Center, the National Human Genome Research Institute and the National Institutes of Health. The conference brought parents, professionals involved with patient care and researchers together to share experiences, ideas and the latest scientific developments.

Whereas newborns with no separation of their brain into two hemispheres often die after several days or weeks, mildly affected children may live a normal life span. They often have learning disabilities and motor impairments. They may also suffer from seizure disorders or diabetes.

"The diagnosis carries such an ominous meaning for a lot of physicians who think it is a fatal disorder," Hahn said. "But we want to emphasize that there are these milder forms where the children can survive many decades."

Through the planned collaboration with basic scientists, which is scheduled to begin in June, Hahn now hopes to learn more about what goes wrong during the cleavage of the fetus’ brain and which genes are governing that delicate process.

One of the scientists involved is Susan McConnell, PhD, professor of neuroscience at Stanford.

"Most of the genes that are known to be mutated [in holoprosencephaly] actually act in the ventral part of the brain," McConnell said. "Yet in holoprosencephaly there are striking problems with the formation of dorsal structures."

Medical center scientists are now trying to identify the genes responsible for shaping the dorsal, or upper, part of the fetal brain. (The ventral part of the brain is the bottom part.) "We have some leads on genes that might actually be playing the important role in the dorsal division of the brain into two hemispheres," McConnell said.

The goal of the collaboration is to create an animal model in which various new treatments and therapies can be tested. Today, scientists work with mouse models that display the most severe features of holoprosencephaly.

"We hope that by all teaming up together we are going to make progress not only in understanding the basic biology, but create a mouse model of the kind of features that patients with milder forms of holoprosencephaly present to the clinic," McConnell said. "We hope that understanding basic biological mechanisms can open up new avenues toward treatments."

Research intensifies with changing attitudes about rare brain deformity (4/19/00)

The Carter Centers for Brain Research

Lucile Packard Children’s Hospital