Genetics and Hydrocephalus - Hydrocephalus Association · Genetics and Hydrocephalus James P. (Pat)...
Transcript of 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 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
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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
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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
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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
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Migration of Immature Neurons
Hydrocephalus Association 12th National Conference; 6/30/2012
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Hydrocephalus Association 12th National Conference; 6/30/2012
Fewer Neurons Hydrocephalus Ex Vacuo
Functional changes not caused
by enlarged ventricles
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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
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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
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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
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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
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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