The roof plate is a well known signaling center in CNS development, but its roles in the developing telencephalon and the common holoprosencephaly (HPE) malformation have been uncertain. Using cellular ablations in mice, we show that roof plate cell loss causes failed midline induction and HPE in the dorsal telencephalon. This morphologic phenotype is accompanied by selective deficits in midline gene expression and a reduced activity gradient for bone morphogenetic proteins (Bmps), the major signals produced by the roof plate. In dissociated cells and mutant explants, exogenous Bmp4 is sufficient to mimic roof plate selectivity in midline gene regulation and to rescue roof plate-dependent midline patterning. Previously unrecognized neuroanatomical defects predicted by the mouse model are then confirmed in human HPE patients. These findings establish selective roles for roof plate-dependent Bmp signaling in dorsal telencephalic patterning and HPE and define novel candidate genes for the human disorder.

MR scans of 87 pediatric patients with brain stem gliomas were retrospectively reviewed to develop a new classification scheme based on MR imaging. The scheme that has been developed utilizes primarily T2-weighted images, as these most accurately show tumor extent. Tumors are characterized as to location of origin, focality, direction and extent of tumor growth, degree of brain stem enlargement, degree of exophytic growth, and presence or absence of cysts, necrosis, hemorrhage, and hydrocephalus. The use of this classification allowed identification of differences in a population of patients who were selected to be as similar as possible. This system will aid in the assessment of new protocols for treatment of brain stem tumors.

The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.

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