Genetics and Hydrocephalus - Hydrocephalus Association · Genetics and Hydrocephalus James P. (Pat)...
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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 Hydrocephalus Association 12 th National Conference; 6/30/2012 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
Transcript of Genetics and Hydrocephalus - Hydrocephalus Association · Genetics and Hydrocephalus James P. (Pat)...
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
Hydrocephalus Association 12th National Conference; 6/30/2012
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
Hydrocephalus Association 12th National Conference; 6/30/2012
1. Chromosome 11
2. Chromosome 17
3. Chromosome 9
4. Chromosome 19
Gene Defects in H-Tx rats with Aqueductal Stenosis
Jones HC et al. Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat.
Mamm.Genome 12: 22-26, 2001
“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…”
Open Aqueduct Blocked Aqueduct
WM
Consequences of Genetic Defects in the Ventricular Walls
Gaps
Normal Lining Absent
Immature Neurons Exposed
Hyh (a-SNAP) wild type
E12.5
E13.5
E14.5
E15.5 Hydrocephalus
Progression
Gap junctio ns
Adherens junctions
Tight junctions
Modified from Mori et al. (2005)Curr Top Dev Biol; 69: 67-99.
E10.5
E12.5 E14.5 E16.5<
Apical
VZ
(neuroepithelium)
Neuroepithelial cells Radial glia cells Ependymal cells
Ventricular zone (VZ)
Denudation
Ependymal Denudation
Occurs at the Beginning of
Neurogenesis
Hydrocephalus Association 12th National Conference; 6/30/2012
Migration of Immature Neurons
Hydrocephalus Association 12th National Conference; 6/30/2012
Hydrocephalus Association 12th National Conference; 6/30/2012
Fewer Neurons Hydrocephalus Ex Vacuo
Functional changes not caused
by enlarged ventricles
20 week human fetus
Ependymal Denudation Observed in Human Fetuses
Sival DA, Guerra M, den Dunnen WF, Bátiz LF, Alvial G,
Castañeyra-Perdomo A, Rodríguez EM. Neuroependymal
denudation is in progress in full-term human foetal spina
bifida aperta. Brain Pathol. 2011 Mar;21(2):163-79
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;64:595-604.
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. 7-10 July 2010
CA
PN5
Hydrocephalus Association 12th National Conference; 6/30/2012
Ependymal Denudation
May Also Play a Role in Aqueductal Stenosis
Normal H-Tx E21 Hydrocephalic H-Tx E21
Hydrocephalus Association 12th National Conference; 6/30/2012
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 neuroepithelial-
ependymal denudation in the
telencephalon of human hydrocephalic
foetuses. 2010
Aqueductal
Ependymal Denudation
Observed
in Human Fetuses
Hydrocephalus Association 12th National Conference; 6/30/2012
E
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
C
SA
4th V
3º
ph
34 week Gestation MRI
PN2, Tomography
3rd V
LV
LV
Case report
Ce
IV
SA SA
F PN5, NMR
4º
Hydrocephalus Association 12th National Conference; 6/30/2012
Summary
Hydrocephalus Association 12th National Conference; 6/30/2012
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
