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Neurologic Development+

Organization of the Nervous System

Mary V. Andrianopoulos, Ph.D.Department of Communication Disorders

University of Massachusetts

Neuroembryology

• Objectives of this lecture:– To understand the orderly development of the

CNS and PNS

– To understand the pathogenesis of developmental neurologic abnormalities in neonates + pediatric individuals

Human Genome(comprised of 6-8 billion base pairs of DNA RNA)

What is a Gene:– a sequence of DNA chromosomes that

produces an RNA molecule (polypeptides)– each DNA molecule = a double helix– Range:

• 50,000,000 base pairs (chromosome 21) • 250,000,000 base pairs (chromosome 1)

What is a gene?

A specific sequence of nucleotides in DNA or RNA that is located usually on a chromosome and that is the functional unit of inheritance controlling the transmission and expression of one or more traits by specifying the structure of a particular polypeptide and especially a protein or controlling the function of other genetic material.

Webster’s Dictionary

Reproduction: Asexual

• Asexual reproduction is with mitosis only– new plant or root off-shoot from existing plant– identical off-shoot from parent plant (clone)– no diversity

Reproduction: Sexual

• Sexual: joining of gametes from different parents– female egg + male sperm– fertilize to form off-spring– combination of genetic information from two separate

cells that have one half the original genetic information • Both gametes are haploid, with a single set of

chromosomes • Off-spring is called a zygote, with two sets of

chromosomes (diploid). • Meiosis is a process to convert a diploid cell to a

haploid gamete, which causes change in the genetic information to increase diversity in the offspring

What is a Gamete?

A mature male or female germ cell usually possessing a haploid chromosome set and capable of initiating formation of a new diploid individual by fusion with a gamete of the opposite sex

Webster’s Dictionary

Cellular Division

Meiosis (I and II phases)vs

Mitosis

(Meiosis II is similar to Mitosis)

On-Going Meiosis in Humans(stem cells)

• Females:– Oogonia divide into oocytes (Meiosis I)

– Process Oogenesis• oocytes (eggs) remain dormant in follicles• non-fertulized eggs get arrested Menstrual Cycle• if egg meets sperm fertilization occurs (Meiosis II)

• Males:– Spermatogonia divide into sperm– Process spermatogenesis

• no arrest with sperm production continuous

Meiosis

Is a 4 phase process of cell division:• prophase:

– 1 chromosome per parent pair

• metaphase:– each pair move together form two chromatids

• anaphase:– double structured chromosomes pull apart

• telophase:– end phase of Meiosis (and Mitosis)

Chromosomal abnormalities

Nondisjunction:– abnormal separation of chromosomes– during Meiosis or Mitosis

Chromosomal abnormalities: wrong # chromosomes• Down Syndrome (Chr 21)• Patau Syndrome (Chr 13)• Edward Syndrome (Chr 18)• Kleinfelter Syndrome (extra X males)• Turner Syndrome (extra X females)• XYY Syndrome (extra Y males)

Embryonic Development: 1st week

Human development begins:– Spermatozoa + oocite unite Zygote

24 hrs. after ovulation Fertilization complete

– Sex is determined• Zygote divides multicellular form• Blastomere morula

– Blastocyte implanted in uterine lining (week 2)

– Undergoes mitotic division

Embryonic Development: 2nd week• Embryo starts to develop

• 2 layer disc: epiblasts + hypoblasts• Epiblasts give rise to endoderm+mesoderm• Hypoblasts give rise to yolk sac• Ectodermal cells become neuroectodermal layer

– Becomes CNS + PNS

• Various structures develop:• Amniotic cavity• Extraembryonic mesoderm• Prochordal plate mouth• Etc.,

Neural Tube Formation

• Occurs on the 18th day gestation• 2-layered embryo consisting of:

– ectoderm + endoderm– transforms into 3 layered structure

• mesoderm emerges from mid-two layers of primitive streak

Neuro-Evolution

Remember…..Epiblasts gives rise to ectoderm +

endodermEctoderm gives rise to Neuroectoderm

– Neuroectoderm• neural tube Brain + spinal cord + their nuclei (CNS)

• Neural crest Cranial + spinal nerves, etc.

Neuro-Evolution

3rd week of Embryonic Development– 1st missed menstrual cycle

Entoderm– GI tract (digestive), lungs, liver, respiratory systems

Mesoderm– Muscle, connective tissue, vascular system, bones,

kidney bonesEctoderm

– entire nervous system (CNS + PNS), epidermis

Cellular Differentiation

Neuron

Neuroblast

Oligodendroglia

Migratory spongioblast Astrocyte

Ependyma

Spongioblast

Neural Epitheluim

Origin of Neuroblasts

• Migrate (radial glial cells)• Guide formation of neuroblasts

– Bipolar unipolar multipolar

Types of macroglia

• glioblast (spongioblast)• astroblast + astrocytes• dendroblasts + oligiodendrocytes• microglia• What is a Teratoma?

– tumor of primitive streak– did not regress

Embryonic Development: 3rd week

• CNS + cardiovascular systems form• Neural plate neural folds neural tube

neural crest evolve

Neural Tube Cross-Section

Neural plate + Neural Tube

Neural plate Neural Tube Evolution

Neural Tube

Development of CNS ~ 3rd

week A critical period!• Neurologic structures laid down• Neuroectodermal layer CNS + PNS• Neural tube Brain + Spinal Cord• Neural Crest

– Sensory ganglia of Cranial + Spinal Nerves– Nerve sheaths, autonomic nerves– Etc..

~ 4th Week Embryonic Development

• Neural tube is open: Cranial + Caudal ends• Cranial end closes on day 25• Caudal end closes on day 27

• Cranial End 2/3rds of neural tube brain• Caudal End 1/3rd of neural tube spinal cord

Neural tube defects

Transformation of Neural Folds~ 4th week

Neural Folds fuse into 3 primary vessicles

Prosencephalon(forebrain)

Mesencehphalon(midbrain)

Rhombencephalon(hindbrain)

Neural Folds

Transformation of Neural Folds~ 5th week

The 3 primary vessicles transform into 5

diencephalon

telencephalon

Prosencephalon Mesencephalon

myelencephalon

metencephalon

Rhombencephalon

Neural Folds

Telencephalon• Transforms into:

– Eye structures

– Cerebral hemispheres– Sulci + Gyri (evident ~ 24 weeks gestation)

topographically mapped at birthlobes identified by 3rd trimester

Diencephalon• Transforms into:

– Thalamus– Medial + lateral geniculate bodies

• (vision + hearing)

– Hypothalamus– Epithalamus– Pineal Gland

Mesencephalon

• Superior colliculus visual impulses• Inferior colliculus auditory impulses• Basal laminae tegmentum

– Red nucleus– Substantia nigra– Reticular nuclei– Cranial III + IV nuclei

Rhombencephalon

• Transforms into:– Metencephalon:

• cerebellum, sensory Cranial 5 + 8, pons– Myelencephalon:

• medulla, cerebellar peduncles• Sensory Cranial 7, 9, 10

Between 4th + 8th weeks of Development

• All major organ systems are formed

• By end of 8th week, embryo resembles a human appearance

• Cranial nerves (12 pairs) develop between 5th + 6th weeks.

Embryologic developmental milestones

• Week 9-birth: Fetal Period– Differentiation of tissues + organs

• 9-12 weeks: head makes-up ½ length fetus– Upper limbs almost to relative length

• 13-16 weeks: body length doubled. Ossification of skeleton

• 17-20 weeks: somatic growth slows, length increases. Mother feels fetal movement.

More developmental milestones

• 21-25 weeks: weight gain, lungs produce active lipid that maintains alveoli, respiratory system still immature.

• 26-29 weeks: lungs function with some difficulty, control of body temperature, coordination between CNS + lungs, eyes begin to open.

More developmental milestones

• 30-34 weeks: pupillary light reflex present, white fat present (~8% body weight, feeding potential). Stable temp regulation

• 35-40 weeks: head + abdomen circumference equal. Full term, body weight ~16 %.

Myelinogenesis

Begins end of 1st trimester– 12th week extends till age 4 years– Look for: presence + suppression:

• developmental + physiological reflexes in children

Neurodevelopmental Problems

Etiologies• Developmental• Teratogenic• Chromosomal• Genetic

Teratogenesis

• Teras = Monster• Congenital problems that develop in gestation

• CNS abnormalities occur ~ 25 weeks gestation involving brain and spinal cord– CNS congenital malformations = 3/1000 births– 85% defects involving closure of neural tube

• Spina bifida• Anencephaly• Cerebral Palsy: prenatal or birth involvement (H2O)

Risks

• Survival is at risk 2° to prematurity and other complicating matters

• Survival is at risk with a birth weight less than 500 grams.

Some Developmental Abnormalities: Affecting the CNS

• Anencephaly• Cranium bifidum• Spina bifida• Hydrocephalus• Microcephalus• Teratomas

Anencephaly

• Missing cerebral hemispheres• Incidence 1:1000 deliveries• Female predominance• Survival: hours days• Optic nerves absent

Cranium Bifidum

• Protrusion of brain + spinal cord• Through midline of skull• Incomplete fusion of rostral neural tube

– ~ 25 days gestation

Spina Bifida

• Spina bifida cystica• Posterior vertebral arches fail to fuse• Lumbrosacral abnormalities• Caudal end does not fuse: ~ 27 days

• Spina bifida occulta• Posterior skin epithelialized• Skin, spinal cord, bone deformities

Spina Bifida, OccultaPediatric Database (PEDBASE, 1997)

A neural tube defect affecting the spine arising from the incomplete closure of the neural canal in the lumbosacral region. Pathogenesis: Not associated with abnormalities of the meninges, spinal cord, or nerve roots. Frequently only one vertebrae is affected. Represents a posterior defect in the vertebral bodies. May be associated with syringomyelia, diastematomyelia, or a tethered cord.

Spina Bifida, CysticaMedicineNet.com

A bony defect in the vertebral column that causes a cleft in that column. The meningeal membranes that cover the spinal cord protrude through this cleft, and are visible. The opening can be surgically repaired, usually shortly after birth. Some children will also need treatment for related problems, such as hydrocephalus

Video link: http://www.youtube.com/watch?v=E080qJ

uHWdQ

Spina Bifida

Hydrocephalus

• Enlarged cerebral ventricles• Too much CSF• Obstruction of CSF drainage• Brain atrophy

Microcephalus

• Small brain• Face normal• MR sometimes• Possible etiologies:

– environmental, genetic, radiation

Rostral Teratoma

First Gene Linked to Language

• FOXP2:– this gene releases a protein that allows brain’s

language circuitry to function– Dr. Toni Monaco studied the KE Family

Complex Trait Syndromes

• Autism:– possible FoxP2 downstream problem– multiple predisposing variants + environmental

factors– theory based on radial unit hypothesis.– CNS involvement– normal function requires columns to be laid

down properly and for connectivity to occur between them

Teratogens:Recreational + Environmental

• Fetal Alcohol Syndrome (FAS)– ETOH consumption (< 3 mos gestation)– microcephaly, ear malformations,– small eyes, poor optic nerve,– upturned nose, low bridge,– wide space between eyes– possible general intellectual impairment

Facial Appearance of FASSome, or all, of the following facial features are associated with FASMicrocephaly - leads to small head circumference Palpebral fissure - short opening of eye Epicanthal folds - fold of skin at inside of corner of eye Midface - flat Nasal Bridge - low Philtrum - Indistinct, vertical grooves between nose and mouth Upper Lip - thin Micrognathia - small jaw Ears - curve at top part of outer ear is underdeveloped and folded over parallel to curve beneath. Gives the appearance of a "railroad track"

FAS facial features(image modified from Wattendord, 2005)

Fetal Alcohol Syndrome

Teratogens:Environmental Mercury

• Mercury consumption or contact– inhibitory effect myelin production– neurological defects– blindness, seizures, incoordination– digestive system + kidney problems– speech problems– general intellectual impairment

Teratogens: Metabolic

• Congenital Rubella Syndrome– maternal infection of “rubella virus”– neurological defects 2° poor cell replication– tissue damage 2° to weakened immune system– eye + heart malformations– hearing loss, pulmonary artery stenosis– general intellectual impairment

Teratogens: Pharmaceutical

• Phenytoin Tx (Fetal Hydantoin Syndrome)– Delantin Tx seizures– growth problems, developmental delay– cleft palate, facial characteristincs– heart malformations– Abnormalities of fingers + nails

Chromosomal Problems I

• Down’s Syndrome (Trisomy 21)– 3 #21 chromosomes instead of 2– male vs. female pair of #21 chromosomes fail

to separate (faulty cellular division -95%)– Hypotonia, abnormal ears, macroglossia– flat facial profile, upward eye slant morphology

Down’s Syndrome

Chromosomal Problems II

• Klinefelter Syndrome (XXY Syndrome)– fertilized egg with extra X sex chromosome– only effects males– yields low production of male hormones– underdeveloped testicles infertility– taller height + feminine body morphology– low IQ, delays in speech + language

Kleinfelter Syndrome

Chromosomal Problems III• Turner Syndrome

– 1 of 2 “X” chromosomes found in females missing or partially missing

– only effects females– lack of ovarian development– spatial-temporal, non-verbal memory problems– learning disabilities– otitis media, conductive + sensorineural loss– hearing amplification candidates

Turner Syndrome

Turner Syndromehttp://www.nature.com/ncpendmet/journal/v4/n3/images/ncpendmet0747-f1.jpg

Genetic Problems I• Fragile “X” Syndrome

– a section of DNA sequence (FMR1 gene) has multiple repetitions

– speech delay, sensori-motor problems– oral weakness (dysarthria)– ear infections– general intellectual impairment– attention + behavioral issues– social - pragmatic issues

Fragile X Syndromehttp://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen09.gif

Chromosomal Genetic Problems II

• Angelman Syndrome– deletion or inactivation of specific genes that

regulate protein, ubuquitin of specific chromosomes

– movement disorder: jerkiness– protruding tongue, feeding issues– Microcephaly small brain– balance disorder walking + standing

Angelman SyndromeDevelopmental Delays

– Speech + language problems– Impaired cognitive levels– AAC may be used for communication– May benefit from oral sensory and motor

treatment• Can cause drooling, mouthing + biting behaviors

which are common in children with AS

– In rare cases, may coexist with Autism

Angelman Syndromehttp://www.youtube.com/watch?v=BjZA9GF

3_Kg

http://www.armyofangels.org/liam_school_1_sm.jpg

Stem Cell Research for Angelman Syndrome

• Child fails to inherit UBE3A gene from mother• AS Skin cells obtained, then cells converted to

stem cells form neurons• Stem Cell neurons have same characteristics as

AS• Scientists study how AS develops + ways to

intervene• Enables drug therapies to facilitate duplication of

father’s gene to replace absent maternal one (UBE3A)

Genetic Problems III

• Huntington’s Disease– heredito-familial mechanism– degeneration of neurons– movement disorder– dysarthria (speech problem)– dysphonia (loss of voice)– dysphagia (swallowing problems)

Genetic Problems IV

• Multiple Sclerosis– autoimmune disease– demylination– progressive multisystem failure– dysarthria (speech problem)– dysphonia (loss of voice)– dysphagia (swallowing problems)

Single Gene Syndromes, Examples

• Alport• Apert• Neurofribromatosis• Treacher Collins• Van Der Woude• Waardenburg

Polygenic-Multifactorial Syndromes, Examples

• Cleft lip + cleft palate• Pierre-Robin• Stuttering

Sporadic + Environmental Syndromes, Examples

• Sporadic:– Moebius– Prader-Willis

• Environmental:– Cytomegalovirus

Critical periods

• Pages124-127 Bhatnagar: Please review