Pontine malformation, undecussated pyramidal tracts, and regional polymicrogyria: a new syndrome.

BACKGROUND: Horizontal gaze palsy and progressive scoliosis is caused by mutations in the ROBO3 gene, which plays a role in axonal guidance during brain development. Horizontal gaze palsy and progressive scoliosis is characterized by the congenital absence of conjugate lateral eye movements with preserved vertical gaze and progressive scoliosis as well as dysgenesis of brainstem structures and ipsilateral projection of the pyramidal tract. PATIENT: A 4-year, 11-month, girl presented with psychomotor retardation and autistic traits. Magnetic resonance imaging revealed hypoplasia and malformation of the ventral portion of the pons and medulla oblongata. Diffusion tensor imaging revealed the absence of decussation of the bilateral pyramidal tracts. These findings were similar to the typical findings for horizontal gaze palsy and progressive scoliosis. However, restriction of horizontal eye movement was minimal, and bilateral polymicrogyria were also noted in the occipitotemporal cortex in the present patient. These findings have not been previously reported in patients with horizontal gaze palsy and progressive scoliosis. No mutations in the ROBO3, SLIT1, SLIT2, NTN1, SEMA3 A, or SEMA3 F genes were identified. CONCLUSION: This child may have a disorder caused by an unidentified factor, other than a mutation in the genes analyzed, involved in corticogenesis, axonal guidance, and brainstem morphogenesis.

Hyperthermia induces translocation of apoptosis-inducing factor (AIF) and apoptosis in human glioma cell lines.

In the hyperthermal treatment, the wild type (wt) p53 plays an important role in apoptosis induction in the tumor cells. In human gliomas, p53 frequently has some form of mutation. The mutant type (mt) p53 does not work properly as a tumor suppressor and this may result in poor responses during treatment. We investigated the relationship between apoptosis-inducing factor (AIF) and apoptosis under various thermal conditions (43, 45, and 47 degrees C for 1 h) using four p53-wild or -mutant human glioma cell lines (A172, T98G, U251MG, and YKG-1). AIF translocation from the mitochondria to the nucleus under hyperthermal conditions was demonstrated by confocal laser microscopy. The percentage of AIF-positive nuclei increased significantly in comparison with the control in all cell lines and in all temperature groups except for YKG-1 at 47 degrees C. Immunoblot analyses of the nuclear fraction of each cell line revealed temperature-dependent increases in AIF. A simultaneous release of cytochrome c from the mitochondria to the cytosol was noted. A flow cytometric analysis showed that apoptosis induction occurred more often in a temperature-dependent manner in the 45 and 47 degrees C groups than in the control group. These findings indicate that the hyperthermal conditions can lead to AIF translocation and apoptotic cell death in the p53-mutant human glioma cells. The present report is the first description of AIF-induced apoptosis in hyperthermia.

Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas.

Although the expression O6-methylguanine-DNA methyltransferase (MGMT) is an important hallmark for decision of nitrosourea chemotherapy for glioma patients, no immunohistochemical method for analysis of MGMT has been standardized yet. Gliomas usually contain non-neoplastic cells even deep in the tumor. It is not known which of these components expresses MGMT. To clarify this point, we investigated MGMT expression in the non-neoplastic cells in autopsy and surgical specimens by immunohistochemistry. High grade gliomas were also studied to find a cut-off point for treatment decision. MGMT immunohistochemistry in the normal brain or brain with non-neoplastic disease revealed nuclear staining in some endothelial cells, inflammatory cells, ependymal cells, astrocytes and oligodendroglias. Some cells were double stained with CD68 (macrophages or microglias). The neurons were consistently MGMT-negative. High grade gliomas always contained an MGMT-positive non-neoplastic component. Although, the endothelial cells were easily distinguished from the neoplastic cells, other cells were often mistaken for tumor cells. The population of MGMT-positive non-neoplastic cells was usually less than 10%. We set a cut off-point at 10% between the positive and negative groups because the statistical difference in the overall survival was most distinct at this value. In 51 high grade glioma patients, who received both radiotherapy and chemotherapy with nimustine (ACNU), the median overall survival of the MGMT-negative group (23 months) was significantly longer than that of the MGMT-positive group (14 months) (P < 0.009). Multivariate analysis revealed that the negative MGMT expression was a significant prognostic variable next to the degree of surgical removal for the overall survival. In the MGMT-positive group, addition of platinum-based chemotherapy did not improve the survival.