Embryology

Question 1

Periventricular Heterotopia (PH)

Answer 1

Caused by mutation in FLNA gene, which codes for an actin binding protein; inability of neurons to migrate past the ventricular zone results in inappropriate “pile up” of cells

X-linked dominant inheritance; affected males do not survive to term, females present with epilepsy

Question 2

Type 1 Lissencephaly

Answer 2

Caused by mutation in Lis1 gene, which encodes a protein that aides in microtubule polymerization; causes lack of layer specificity, neurons derail from radial glia at inappropriate positions

Affected individuals are heterozygous

Question 3

Double Cortex Syndrome

Answer 3

Caused by mutation in DCX gene (X-linked), which encodes a protein that aides in microtubule polymerization; causes lack of layer specificity, neurons derail from radial glia at inappropriate positions (defect of ongoing migration)

In females, characterized by mild mental retardation and epilepsy

Question 4

Cajal-Retzius Cells

Answer 4

Secrete reelin protein, which is the “stop” signal for neuronal migration; responsible for guiding the “inside-out” development of the cortical layers

Question 5

Lissencephaly with Cerebellar Hypoplasia (LCH)

Answer 5

Caused by mutations in reelin gene; results in inversion of the normal inside-out pattern of cortical development

Question 6

Radial migration

Answer 6

Describes the migration of cerebral cortex cells beginning from the ventricular zone and moving outward toward the superficial cortex along radial glia scaffold; gives rise to excitatory glutamatergic neurons

Question 7

Band heterotopia

Answer 7

Phenotype found in females with Double Cortex Syndrome (DCX gene mutation); neurons with the normal DCX gene are able to migrate normally (inside-out) but neurons with the mutated copy migrate inappropriately, forming a “band” of improperly developed cerebral cortex below the subcortical plate

Question 8

Chain migration

Answer 8

Neurons migrate from the ventricular zone to the olfactory bulb via chain migration

Question 9

Tangential migration

Answer 9

Cells from the lateral and medial ganglionic eminences (secondary zones) migrate tangentially into the cortex and disperse throughout the tissue; gives rise to inhibitory GABA-ergic neurons

Question 10

Neural crest cells

Answer 10

Arise from the border between neuroepithelium and ectoderm; during neurulation, neural crest cells constitute a mass of cells along the dorsal aspect of the neural tube; gives rise to PNS

Neural crest cells express integrin proteins that serve as receptors for ECM laminin and fibronectin proteins, which act as “permissive factors” for neuronal migration

Question 11

Neural crest migration - Dorsal (lateral) stream

Answer 11

Gives rise to pigment cells

Question 12

Neural crest migration - Medial (ventral) stream

Answer 12

Gives rise to PNS neurons and Schwann cells

Question 13

NGF - What’s the receptor?

Answer 13

TrKA

Question 14

BDNF - What’s the receptor?

Answer 14

TrkB

Question 15

NT-3 - What’s the receptor?

Answer 15

TrkC

Question 16

How do neurotrophic growth factors work?

Answer 16

Neurotrophic growth factors are secreted by target organs; they bind tropomyosin-related kinase (Trk) family receptors on growing axons; ligand-binding leads to receptor dimerization and generation of secondary, intracellular signaling molecules which promote axon growth

Question 17

Long range guidance molecules - Attractive

Answer 17

Netrins

Question 18

Long range guidance molecules - Repulsive

Answer 18

Semaphorins

Netrins

Question 19

Short range guidance molecules

Answer 19

Cell surface: Cadherins, CAMs

ECM: Collagen, laminin, fibronectin, proteoglycan

Question 20

Cranioraschisis Totalis

Answer 20

Most severe form of neural tube defect, caused by a complete failure of primary neurulation

Question 21

Anencephaly

Answer 21

Failure of the rostral neuropore to close; the forebrain neurectoderm fails to separate from the cutaneous ectoderm; a cerebrovasculosa is seen where the skull cap should have developed

Question 22

Encephalocele

Answer 22

Defect in the skull with protrusion of the meninges and/or brain; distinguished from anencephaly because there is an epidermal covering over the cranial neural tube closure defect

Question 23

Myelomeningocele

Answer 23

Failure of the posterior neuropore to close (80% in the lumbar area, which is the last area of the neural tube to close); spinal cord and meninges bulge through the vertebrae in the back

Question 24

Meningocele

Answer 24

A skin-covered, CSF-filled mass that is continuous with the CSF in the spinal canal; the meninges and CSF bulge through the vertebrae into the back

Question 25

Lipomyelocele / Lipomyelomingocele

Answer 25

Occurs when a lipoma extends from the subcutaneous tissues to the dorsal aspect of the cord, tethering the cord inferiorly; reflects premature separation of the cutaneous ectoderm during the process of neurulation which allows mesenchyme to enter the unclosed neural tube and differentiate into fat

Question 26

Dorsal dermal-sinus tract

Answer 26

An ectoderm-lined tract that can transgress the dura and allow communication between the skin and CSF; may also cause tethering of the spinal cord

Question 27

Spina bifida occulta

Answer 27

Failure of the bony laminar arch to completely envelop the meningeal sac; usually occurs at L5-S1 levels Usually asymptomatic, incidental clinical finding not requiring further work-up

Question 28

Chiari Type I malformation

Answer 28

Chronic herniation of cerebellar tonsils into the foramen magnum; blocks flow of CSF from central canal into subarachnoid space Mesodermal disorder of the development of occipital somites and bony posterior fossa; NOT related to NTD or folate deficiency Elongated cerebral tonsils are pushed downward through the foramen magnum, blocking the normal flow of CSF

Question 29

Hydromyelia

Answer 29

Accumulation of CSF within the central canal Common complication of Chiari Type I malformation

Question 30

Syringomyelia

Answer 30

Formation of a CSF-filled cyst that breaks out of the central canal and dissects into the substance of the cord Common complication of Chiari Type I malformation

Question 31

Type I Chiari Malformation - 3 complications

Answer 31

1. Hydromyelia - accumulation of CSF within the central canal, caused by blockage of the operature which allows CSF to exit the central canal into the sub-arachnoid space 2. Syringomyelia - formation and rupture of a CSF-filled cyst which can dissect into the substance of the spinal cord b 3. Hydrocephalus - accumulation of CSF within the 4th ventricle, caused by impeded flow of CSF from 4th ventricle to subarachnoid space

Question 32

With what other disorder is Chiari Type II malformation | always seen with? Why?

Answer 32

Failure of neural folds to completely close leaves a dorsal defect (Thoraco-lumbar myelomeningocele) through which CSF can leak out, causing collapse of the ventricular system and "sagging" of the cerebellar vermis through the foramen magnum

Question 33

Features of Chiari Type II malformation

Answer 33

Elongation of the cerebellar vermis causing cerebral tonsils to protrude through the foramen magnum and block CSF flow Abnormalities in the brainstem Abnormalities of the dural venous sinus

Question 34

What causes Chiari II malformation?

Answer 34

Failure of the neural folds to completely close, leaving a dorsal defect which permits CSF to leak through the central canal into the amniotic fluid; this creates collapse/underdevelopment of the ventricular system and posterior fossa, as well as a failure of neuronal migration

Question 35

Holoprosencephaly

Answer 35

Failure of differentiation of the prosencephalon into two telencephalic vesicles; usually occurs during 5th week of fetal development Due to sonic hedgehog mutation (Shh)

Question 36

Alobar holoprosencephaly

Answer 36

NO evidence of division of cerebral cortex; i.e. a single forebrain with a single ventricle

Question 37

Semilobar holoprosencephaly

Answer 37

Partial cleavage of the cerebral cortex; cerebral hemispheres are fused anteriorly and there is a single ventricle with a horse-shoe shaped appearance

Question 38

Lobar holoprosencephaly

Answer 38

Cerebral hemispheres are separated anteriorly and posteriorly; some degree of fusion of structures

Question 39

Dandy Walker Malformation

Answer 39

Cerebellar hypoplasia; characterized by partial or complete absence of formation of the cerebellar vermis, cystic dilation of the fourth ventricle that fills up an enlarged posterior fossa, and upward displacement of the tentorium Sporadic; NOT associated with NTD

Question 40

Where is the conus medullaris found at different stages of development?

Answer 40

In the newborn: L3 3 months: Not below the lower margin of L2 Adult: L1-L2

Question 41

Major causes of perinatal stroke - full term vs. pre term

Answer 41

Full term - birth trauma resulting in stretching of carotid arteries and subsequent vascular insufficiency Pre-term (<35 weeks): insufficient auto-regulation of blood flow leads to hemorrhage within the germinal matrix (GMH); most frequent cause of cerebral palsy

Question 42

Ulegyria

Answer 42

"Mushroom-shaped gyri"; occurs following perinatal stroke in the full-term infant, usually due to vascular insufficiency of the carotids; less-infarcted tissue in the crest of the gyri continues to grow and develop while more infarcted tissue within the sulci does not

Question 43

When do most neural tube defects occur?

Answer 43

Weeks 2-3 of gestation

Question 44

Folic acid guidelines

Answer 44

50% of NTDs are related to folate deficiency Recommended: 0.4mg/day for at least 4 weeks before coming pregnant, or 4.0mg/day for women with prior history of pregnancy with NTD

Question 45

How much does the normal brain weigh?

Answer 45

1,200-1,400g

Question 46

Clinical Presentation of Chiari Type I Malformation

Answer 46

Usually presents as headache - especially during Valsalva, in which venous return to chest is diminished causing increased dural venous pressure; CSF cannot be displaced into spinal cord to accomodate and so intracranial pressure increases, causing HA Likely a mesodermal disorder of underdevelopment of occipital somites and posterior fossa; NOT NTD

Question 47

Features of Chiari Type II Malformation

Answer 47

Elongation of the cerebellar vermis, which becomes pushed down through the foramen magnum blocking CSF flow; abnormalities of the brainstem including "beaking" and "kinking" of the midbrain and medulla

Question 48

Which morphogens promote caudal structure development? Where do they come from?

Answer 48

Wnts, FGFs, and Retinoic Acid secreted by the primitive node promote caudal structure development

Question 49

What are HOX genes?

Answer 49

Hox genes code for transcription factors that active the expression of downstream genes, which in turn active different programs of differentiation Hox gene expression varies along the AP axis (i.e. in the rhombomeres)

Question 50

What is the main "head organizer" morphogen?

Answer 50

Cerebrus

Question 51

What morphogens does the primitive streak secrete? What do they do?

Answer 51

The primitive streak secretes chordin, noggin, and follastatin; these morphogens inhibit BMPs and create a BMP gradient that is higher laterally (dorsally) than medially (ventrally)

Question 52

Sonic hedgehog

Answer 52

Secreted by the notocord; signals the thickening of embryonic ectoderm to form the neural plate

Question 53

Sulcus limitans

Answer 53

A crease in the neural tube that separates the ventral and dorsal cell populations

Question 54

Basal plate

Answer 54

Ventral population of cells in the neural tube

Question 55

Alar plate

Answer 55

Dorsal population of cells in the neural tube

Question 56

What are secondary zones of neurogenesis?

Answer 56

Specific regions of the brain that are hot spots of postnatal neurogenesis; i.e. the external granule layer of the cerebellum Cells that give rise to the external granule layer of the cerebellum are initially located near the rim of the 4th ventricle; before they are post-mitotic, they migrate to the external granule layer where they proliferate, exit the cell cycle, and migrate into the cerebellum

Question 57

Subventricular zone

Answer 57

Secondary zone of neurogenesis for olfactory neurons; neurons are initially located near the anterior wall of the lateral ventricles, then migrate to the subventricular zone where they proliferate, exit the cell cycle, and give rise to the olfactory bulb neurons

Question 58

Polyneuronal

Answer 58

The situation during embryonic and early postnatal life in which each muscle fiber is innervated by several motor neurons (prior to selective synapse elimination)

Question 59

Roles of neurotrophins

Answer 59

Axon growth and synapse formation Selective synapse elimination Activity-dependent modulation of synaptic transmission (LTP) Mediation of long-term consequences of abnormal brain function

Question 60

Brain abnormality seen in ASD

Answer 60

Abnormally large increases in size, especially in white matter areas, during the first few postnatal years Neuronal cell bodies are often smaller and dendrites branch less

Question 61

What mechanism underlies the greater seizure susceptibility of the neonatal brain?

Answer 61

During embryonic development, the presence of a Na/K/Cl co-transporter allows intracellular accumulation of Cl-, resulting in a more depolarized value for ECl; consequently, activation of GABA receptors leads to depolarization In the adult, a Cl- extruder protein is expressed; this shifts ECl to be near or negative to the resting membrane potential such that activation of GABA receptors leads to hyperpolarization

Question 62

What is meant by a cell's birthdate?

Answer 62

The time at which a cell underwent its last round of DNA synthesis; after this, the cell divides and exits the cell cycle

Question 63

Where do the 6 layers of the cerebral cortex arise?

Answer 63

From the marginal zone + cortical zone

Question 64

Where do radial glial cells live?

Answer 64

Intermediate zone of the pre-plate

Question 65

Nogo

Answer 65

A molecule expressed by CNS myelin that prevents axonal regeneration in the adult CNS

Question 66

How do pre- and post-synaptic terminals align during axon growth?

Answer 66

Neurexins interact with pre-synaptic Ca2+ channels and neuroligands interact with post-synaptic, intracellular synaptic organizing proteins (PSD95) to "bridge the gap" of the synapse

Question 67

What developmental change does the ACh undergo between embryonic and adult stages?

Answer 67

nAChR is formed by 5 subunits - 2 alpha (ACh binding), beta, delta, and either gamma (embryonic) or epsilon (adult); epsilon subunit increases AChR open time, allowing greater depolarization to occur