Genetics and Hydrocephalus
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1 Genetics and Hydrocephalus James P. (Pat) McAllister II, PhD 1,2,4 1 Pediatric Neurosurgery, Primary Children s Medical Center & University of Utah, Salt Lake City, UT 2 Bioengineering and 3 Physiology, University of Utah, Salt Lake City, UT 1. Underscore multi-genetic aspects of hydrocephalus 2. Ilustrate how genetic changes cause hydrocephalus Hydrocephalus ex vacuo effects of cell birth and development Closure/narrowing of the cerebral aqueduct
2 Gene Defects in H-Tx rats with Aqueductal Stenosis 1. Chromosome Chromosome Chromosome 9 4. Chromosome 19 Open Aqueduct Blocked Aqueduct Although none of the four loci was essential for the hydrocephalic phenotype, the additive effects of two, three, or four loci increased the penetrance in a linear fashion. It is concluded that hydrocephalus in the H-Tx rat is associated with two, possibly four genetic loci Jones HC et al. Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat. Mamm.Genome 12: 22-26, 2001
3 Consequences of Genetic Defects in the Ventricular Walls Normal Lining Absent wild type Hyh (a-snap) Immature Neurons Exposed Progression E12.5 E13.5 E14.5 E15.5 Hydrocephalus Gaps WM
4 Ependymal Denudation Occurs at the Beginning of Neurogenesis Gap junctio ns Adherens junctions Tight junctions Denudation Apical E10.5 E12.5 E14.5 E16.5< VZ (neuroepithelium) Ventricular zone (VZ) Neuroepithelial cells Radial glia cells Ependymal cells Modified from Mori et al. (2005)Curr Top Dev Biol; 69:
5 Migration of Immature Neurons
6 Fewer Neurons Hydrocephalus Ex Vacuo Functional changes not caused by enlarged ventricles
7 Ependymal Denudation Observed in Human Fetuses Sival DA, Guerra M, den Dunnen WF, Bátiz LF, Alvial G, Castañeyra-Perdomo A, Rodríguez EM. Neuroependymal denudation 20 week human is in progress fetus in full-term human foetal spina bifida aperta. Brain Pathol Mar;21(2): Dominguez-Pinos MD, Paez P, Jimenez AJ. Ependymal denudation and alterations of the subventricular zone occur in human fetuses with a moderate communicating hydrocephalus. J Neuropathol Exp Neurol 2005;64: Guerra M, Sival D, Jimenez A, Dominguez Pinos MD, den Dunnen W, Bátiz LF, Pérez-Figares JM, Rodríguez E. Defects in cell-cell junctions lead to neuroepithelial-ependymal denudation in the telencephalon of human hydrocephalic foetuses. From 54th Annual Meeting of the Society for Research into Hydrocephalus and Spina Bifida Vancouver, Canada July 2010 CA PN5
8 Ependymal Denudation May Also Play a Role in Aqueductal Stenosis Normal H-Tx E21 Hydrocephalic H-Tx E21
9 Aqueductal Ependymal Denudation Observed in Human Fetuses De Wit et al. Pathogenesis of cerebral malformations in human fetuses with meningomyelocele. CSF Research 5:4, 2008 Guerra et al. Defects in cell-cell junctions lead to neuroepithelialependymal denudation in the telencephalon of human hydrocephalic foetuses. 2010
10 Case report 34 week Gestation MRI 3º C ph 4 th V SA PN2, Tomography The early detection of hydrocephalus and of SA stenosis stimulated a close follow up that lead to discover the SA obliteration at PN5. A ventriculostomy was performed at PN8 SA SA 4º Ce IV 3rd V LV E PN5, NMR F LV
11 Summary 1. Multiple genes can be involved in hydrocephalus 2. Genetic effects on ventricular walls can cause brain tissue atrophy that allows the ventricles to expand in a vacuum Closure/narrowing of the cerebral aqueduct
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