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26 Cards in this Set
- Front
- Back
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Percent of genome expressed in developing brain and consequence
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25% of the 20,000+ genes
brain is sensitive to genetic alterations morphological, functionally, specifically and non-specifically |
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2 common genetic morphologic malformations in brain and 3 acquired malformations
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Genetic - Holoprosencephaly, Lissencephaly
Acquired - Porencephaly, Schzencephaly, Hydrancephaly |
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Holoprosencephaly Pathophysiology, Epidmiology, Types, Signs
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Pathophysiology: midline developmental brain anomaly due to FAILURE of cerebral cortex to develop into SEPARATE Hemispheres (from holosphere) due to incomplete 'cleavage' (NOT a true cleavage event) of developing forebrain (around weeks 3-7). Insult to PRECHORDAL MESODERM. Leads to facial anomalies
Epidemiology: Very common (1/16,000 births, 1/250 conceptuses) Causes: VERY heterogeneous based on genes, environment, multigene, 50% CHROMOSOMAL IMBALANCE Types: Lobar - complete separation of spheres but a few absent midline structures and connection of anterior lateral ventricles Semi-lobar - complete fusion of lateral ventricles, some separation of hemispheres Alobar - all ventricles same, no divisions, most severe Signs: facial anomalies (cyclopian in most severe alobar, flat nose, narrow set eyes (lobar or maybe semilobar), cleft lip and palate WITHOUT premaxillary process, loss of nasal bridge, rudimentary nostril Extra-cranial features means more likely chromosome imbalance, genetic syndromes, teratogen underlying |
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HPE vs typical cleft lip and palate
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Typical - hard tissue premaxillary process between ridges of upper lip
HPE - absent premaxillary process, drooping cleft |
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Teratogen factors leading to HPE
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Maternal Diabetes - 1% risk
Alcohol - FAS is a mild form of HPE maybe Estrogen/progesterone Salicylates Veratum californicum (100% if ingested) |
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Genetic causes of HPE and pathophysiology
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50% is Chromosomal anomalies: aneuploidies, trisomies 13,18,21, balanced translocations (HAVE EXTRACRANIAL STUFF)
Single gene disorders: AD, AR, syndromic, X linked Complex, multigene, multifactorial Most common is TRISOMY 13. some trisomy 18, then duplications and deletions on 13 and 18 that interrupt HPE gene Pathophysiology: trisomies cause HPE by prolonging cell cycle, less divisions, smaller number of cells, less signaling molecules, decreased inductive effect on neural plate |
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Trisomy 13 associated with?
Patau Syndrome |
most common genetic cause of HPE. Still not near a majority of cases (only 33%)
Patau Syndrome Trisomy 13. 1/8000. nondisjunction event associated with advanced maternal age early lethality in 1st month, only 5% live more than 6 months Normal maternal serum Signs: small-normal at birth size, microcephaly, holoprosencephaly (85%), cleft lip and palate, microopthalmia , postaxial polydactyly (extra fingers), cutis aplasia congenita (hole in skull) Also get heart defects |
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Syndromes associated with HPE
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Meckel Gruber
Smith Lemli Opitz Down syndrome Fetal Alcohol Syndrome looks like HPE not the typical facies seen (FAS has small eye openings, smooth philitrum, thin upper lip) |
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HPE genetic causes with normal karyotype
How to look for |
NOT trisomy 13, 18
Due to AD, reduced penetrant mutations all inter-related in Sonic Hedge Hog pathway (SHH) Include - SHH, GLI2, FAST1 All look similar (phenotype independent of etiology) |
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Sonic Hedgehog, haploinsufficiency
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Gene mutation associated with HPE (7q36 deletion),
Some mutation found in 30-40% AD HPE It's function is to be secreted and to serve as a polarity gene for DV axis. ventral somites secrete. patterning of ventral neural tube. In brain also stimulates mitogenesis. Post translation cholesterol modification. Cholesterol helps concentration. LOW cholesterol can lead to HPE b.c of this |
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HPE gene haplosufficiency
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Haploinsufficiency in MOST cases of HPE genes does not produce HPE because other factors involved (genes, mutations, environment for "second hit"
such as SHH plus TGIF, ZIC2, del18p hit OR cholesterol low in mother of HPE babies c/w paternal levels |
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Why is AD HPE underestimated
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Familial signs are microsigns
microcephaly, hypotelorism, cleft lip/palate, absent frenulum anosmia (no smell), hypopituitarism, single central incisor |
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Lissencephaly Pathophysiology, MRI, prognosis, Type 1, Type 2, Type 3,
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Very heterogeneous
Pathophysiology: disturbance of normal 6 layer cytoarchitecture of cerebral cortex including agyria (absence of gyral formation), pachygyria (later insult, decreased broad gyri POOR Px, associated with other CNS problems), polymicrogyria (excessive number of small & prominent convolutions, shallow sulci and lumpy cortex, several loci), heterotopias, ectopias, GYRIA DO NOT FORM OR ARE NOT VERY prominent. SMOOTH BRAIN MRI: figure 8 Poor prognosis: max developmental 3-5 months Recurrence risk - up to 25% if chromosomes normal, <1% if 17p13 deletion Lissencephaly Type 1: entirely smooth brain with relative preservation of cerebellum (only 4 cell layers); Genes: LIS1 (AD-always new), XLIS (X-linked) Type 2: Associated with other malformations/syndromes & cerebellar dysplasia & other CNS malformations, ACELLULAR ZONES POCKETS microscopic difference Type 3: Specific to Neu-Laxova Signs: MR, seizures |
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Normal morphogenesis of cortex
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Neurogenesis - (6-20 wks)
Migration - (7-25wks) Orientation |
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Recurrence risk of Lissencephaly
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Up to 25% if chromosomes normal
17p13 deletion: RR<1% |
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Miller Dieker syndrome
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Type 1 lissencephaly plus microcephaly, high forehead with vertical furrowing & bitemporal narrowing, small nose, upslanting palpebral fissures, thin upper lip
85% due to 17p13 deletion (LIS1) and rest of phenotype is additional genes lost |
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XLIS mutation; males vs females
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Lissencephaly Type 1 mutation in:
Males have lissencephaly/pachygyria with severe MR Females: subcortical laminar heterotopias ("double cortex") with mild MR and seizures Gene is doublecortin Males have much more severe disease |
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Heterotopias and Ectopias and Presentation
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Neuronal cell migration defects
Heterotopias - collection of neurons arrested along radial path in subcortical white matter (BIL periventricular nodular heterotopia, FLNA), LOOK LIKE BANDS or double cortex, nodules. Asymptomatic to seizures/MR Ectopias - collection of neurons that have migrated BEYOND normal limits, Asymptomatic to seizures/MR Presentation: seizures and MR |
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Porencephaly and Schizencephaly
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Porencephaly - usually acquired - vascular insult in gestation leading to cavity formation after resorption of destroyed cortical tissue. Smaller than schizencephaly and do not involve primary fissure
Schizencephaly - cleft in region of primary fissure (open or closed), Infolding of cerebral cortex, intact pia, Usually BIL, unilateral with ipsilateral heterotopias. Open communicates with CSF, closed does not. BIL suspect genetic. Unilateral environment or acquired |
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Hydrancephaly
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Extreme form of porencephaly due to CAROTID OCCLUSION
Loss of an entire hemisphere Cerebrum replaced by fluid-filled sac, normal skull, brain compartment, need to distinguish from extreme hydrocephalus and developmental anomaly BIL must distinguish from hydrocephalus (relieving CSF helps) in hydrancephaly relieving CSF does nothing |
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Primary microcephaly
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Structurally normal but small brain (OFC < 3SD)
Cryanosynostosis - premature fusion of skul bones AD, AR forms AD form can have normal intelligence MCPH (microcephalin) mutations |
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Amish-type microcephaly
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lethal, associated with extreme elevations of 2 - ketoglutaric acid
gene due to mitochondrial deoxynucleotide transportor |
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Hydrocephalus Pathology, Primary vs Secondary, Associations
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Increased volume of CSF relative to cerebral parenchyma, 3.5/1000
either due to making too much (VERY RARE) or blockage of reabsorption (tumor, blood, etc.) and more common. Primary - AQUEDUCTAL STENOSIS, communicating, Dandy-Walker malformation, Other. Secondary - hydrocephalus ex vacuo, normal pressure, loss of cerebral parenchyma (enclastic, atrophic) Associations: most have associated malformations, extracranial features, cytogenic anomaly, |
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Main cause of primary hydrocephalus
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Aqueductal stenosis - also only genetic cause
L1CAM association |
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X-linked hydrocephalus, Signs
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Most common form of hereditary hydrocephalus - 1/30k; 2-15% of primary idiopathic hydrocephalus
DUE TO AQUEDUCTAL STENOSIS usually evident after 20 weeks, Signs: MR, developmental delay, CNS malformations (ACC, fused thalami, hypoplastic corticospinal tract) L1CAM gene |
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Pachygyria and Polymicrogyria
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Pachygyria - mild version of lissencephaly, big gyri and sulci due to neuronal migration defects. Poor prognosis
Polymicrogyria lots of little gyri and sulci "lumpy cortex" , genetically and developmentally distinct from lissencephaly. |
