Lecture 11; Brain development Lecture 3 Flashcards Preview

Medsci 317 > Lecture 11; Brain development Lecture 3 > Flashcards

Flashcards in Lecture 11; Brain development Lecture 3 Deck (68):

Define neuraldevelopmental disorders;

•Impairments in growth and development of the CNS
–Can occur in prenatal or postnatal life


What are some examples of NDD?

–Neural tube defects, neuronal migration/proliferation disorders, synaptic disorders (e.g. Autism), myelin disorders (Leukodystrophies)


What are some causes of disorders?

Multiple causes


What are genetic disorders?

•Variation or a mutation in a gene–Random gene mutations, environmental exposure, inherited

Neural tube defects
Neural migrational disorders
White matter myelin disorders


Whats the most common birth defect?

Neural tube defects 1;500-1000 births


What is a neural tube defect?

•Brain and/or spinal cord exposed at birth
–Defect in skull or vertebrae
–Incomplete closure of the neural tube


What are the types of disorders from neural tube defects?

•Anencephaly, Encephaloceles, Hydranencephaly, Spina bifida


What is a strong cause of neural tube closure failure?

•Folic acid (vitamin B9) deficiency


What is folate required for?

– Folate required for cell production and maintenance during neural tube development (neurulation)

–Folate prior to and during pregnancy


What is anencephaly?

No brain


What is Encephaloceles?

‐ protrusion of brain through skull in a sac like membrane. Surgery effec9ve. Intellectual disability


What is Hydranencephaly ?

missing cerebral hemispheres, replaced by sacs of fluid


What is spina bifida?

opening of the spinal cord. Meninges or spinal cord herination

Most common NTD (~50%)


What is a cruicial determinate of insut and outcome?

timing during development


When does majority of neural migration occur?

12-24 weeks


What does failure of migration usually cause?

•Failure of normal neuroblast migration often causes neurons to accumulate in unusual areas (heterotopias)


What are some types of heterotopias?

–Focal (nodular heterotopias), Basically ‘clumps’ of neurons located in the wrong part of the brain
•All levels of the migration pathway (VZ to CP)–Diffuse band heterotopias
•Band of neurons formed in the WM beneath the cortex


What are some examples of disorders from migration interruption?

Lissencephaly, polymicrogyria, focal cortical dysplasia, schizencephaly


What are some effects from neural migration interruption?

Epilepsy, intellectual disabilities


What does migration completion depend on?

Completion depends on GABAergic neurons


What is Lissencephaly?

Absent (agyria) or decreased (pachygyria) cortical folding


Describe type one l Lissencephaly?

E.g. Type 1 LIS
–Migratory defect occurs 12-16 weeks gestation
–Very thick 4-layered cortex
–Hypotonia (muscle weakness) at birth, develop progressive spasticity
–Seizures start within first few months of life


What do most Lissencephaly result from?

Most cases results from LIS1 gene disruption

–Encodes B-acetylhydrolase
–Degrades platelet activating factor (PAF)

•Accumulation of PAF impairs neuronal migration


What are the side effects of LIS?

•Early developmental delay, early diffuse hypotonia, spastic quadriplegia, seizures, severe intellectual disability


What are subcortical Band Heterotopia ?

Bands of neurons are located in the white matter between the cortex and the lateral ventricles


What causes majority ofsubcortical Band Heterotopia?

•Majority of cases due to mutations of the doublecortin (DCX) gene

–Encodes the DCX protein expressed in migrating neuroblasts
–Regulates cytoskeletal dynamics and neuroblast migration

DCX is important in growth cones and radial glial movement


What is focal cortical dysplasia?

Spectrum of abnormalities of the laminar structure of the cortex


What are some features of focal cortical dysplasia?

•Various cytopathological features
–Giant neurons
–Dysmorphic neurons
–Balloon cells (enlarged cell bodies but no dendrites/axons)


What are the causes of FCD?

•Abnormal migration, maturation, and cell death

–Causes unknown


side effects of FCD?

•Intractable epilepsy in children•Developmental delays


What are Leukodystrophies ?

•Group of disorders characterized by progressive white matter degeneration


What causes Leukodystrophies ??

•Mutations in genes that produce or maintain myelin–Oligodendrocyte death and myelin degeneration


When do Leukodystrophies occur?

•Manifest during childhood (incurable, premature death)
–Symptoms vary according to the specific type of leukodystrophy
–Progressive decline in motor, cognition, and language skills
–MRI pathology typically hypomyelination


What are some examples of leukodystrophies?

•Metachromatic leukodystrophy, Krabbé disease, Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with CNS Hypomyelination (Vanishing White Matter Disease)


What is Vanishing White Matter Disease pathology?

Pathology: Oligodendrocyte cell death, diffuse disappearance of white matter, loss of myelin


What causes vanishing WM disease?

Mutations in eIH2B1-5 genes (oligodendrocyte survival/apoptosis)


What are the symptoms of vanishing WM disease?

•Childhood ataxia (gait difficulties)
•Rapid cognitive decline (2-5 years)


What is Phenylketonuria ?

•Metabolic disorder (1:10,000)–Mutation in phenylalanine hydroxylase


What does PKU do?

•Baby cannot digest the dietary amino acid phenylalanine (e.g. in milk)

•Phenylalanine accumulates in brain
–Inhibits HMG-COA reductase to decrease cholesterol synthesis
–Oligodendrocytes do not produce myelin



What is the consequence of PKU and what can be done?

•Impaired brain development and intellectual disability

•Strict diet with no phenylalanine


Can infectious diseases cause neural development problems?

•Some infectious diseases can be transmitted congenitally or in early childhood, and can cause serious neurodevelopmental disorders including schizophrenia


Example one of infectious disease?

•Congenital toxoplasmosis (protozoa Toxoplasma gondii)
– domestic cat
–Can cause cyst formation in the brain; seizures; intellectual disability
–Most damaging in first trimester


example two of infectious diseases

•Congenital syphilis can progress to neurosyphilis and brain defects
–Most damaging in third trimester


example three of infectious diseases

•Measles can progress to subacute sclerosing panencephalitis
–Causes oligodendrocyte and neuronal cell death
–Mental deterioration and death within 3 years


Example four of infectious diseases

•Congenital rubella syndrome linked to schizophrenia
–Also, hearing impairment and visual impairment
–First few weeks of gestation is a critical period for negative effects


How can the immune system be damaging?

Immune reactions during pregnancy and in infant can produce neurodevelopmental disorders

–Sydenham’s Chorea

–Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)

Both are autoimmune reactions against brain tissue following Group A Streptococcus bacteria infection


What does inflammation against pandas and sydenhams chorea do?

•Kills neurons in the corpus striatum of the basal ganglia


What does inflammation against pandas and sydenhams chorea do in terms of side effects?

•Abnormal movements of the body, emotional disturbances, altered cognition, tics, and obsessive compulsive disorder symptoms


What is an example of an Perinatal Systemic Infection?

•Chorioamnionitis (maternal infection)

–Inflammation of fetal membranes due to bacterial infection
–Bacteria ascending into the uterus–Typically non-pathogenic (e.g., staph aureus


What is maternal Systemic Infection associated with?

–Associated with high rates of motor (e.g. cerebral palsy) and neurocognitive deficits
–Fetal/newborn inflammation (inflammatory response syndrome)

•Neonatal sepsis (bacterial infection spread via blood stream)


What is fetal inflammatory response syndrome?

•Chorioamnionitis associated with elevated levels of inflammatory molecules in fetus/neonate


What does fetal inflammatory response syndrome result in?

•CNS inflammation following systemic infection
•FIRS important cause of in utero/postnatalbrain injury


How is fetal metabolism altered?

•Fetal metabolism altered by:
–Maternal nutrition (e.g., folate deficiency)
–Maternal neurotoxins/teratogens (nicotine, alcohol etc.) exposure, diabetes



What are some inherited metabolic disorders?

–In-born errors of metabolism (IEM)
– single gene defects in biochemical pathways (Phenylketonuria)
–Lysosomal storage disorders (intracellular structures responsible for break down of metabolic waste products)



How can diabetes mallitus affect children?

In children, diabetes can produce impaired neurodevelopment/cognition


How does gestational diabetes effect babe?

In utero, a non-diabetic fetus can also be subjected to glucose effects if its mother has undetected gestational diabetes (~6% of all pregnancies)

–~10-fold increase in congenital abnormalities if during 1st trimester
–CNS defects including anencephaly and spina bifida
–Delays in motor and cognitive function in childhood


What did the dutch study show regarding nutrition deficits?

hildren who were affected in the second trimester of their mother's pregnancy had 10X increased incidence of Schizophrenia as adults

At 56-59 years of age, showed impaired cognitive ability due to accelerated brain aging


What are tertogens?

Exogenous agents that causes birth defects


When is each organ system most vulnerable?

Each organ system is most vulnerable to disruption at the time when it is developing most rapidly


How is retinoic acid a teratogen?

Accutane (13-cis-retinoic acid) produced as treatment for acne
–>2,000 women using this during pregnancy had high rates of children born with birth defects
–Hearing and visual impairment, intellectual disability


How many women drink when pregnanat?

•2% of women drink significantly during pregnancy (binge), 10% drink some


When does fetal brain damage occur with alcohol

Fetal brain damage occurs at regular doses of 1-2 oz/da


Describe the consequences to the child from perinatal drinking;

•Infant: Problems with sleep, feeding, milestones, muscle tone, sensory information processing

•Child: Hyperactive, poorly coordinated, learning delays

•Adolescent/Adult: poor judgment, attention, problems with arithmetic, memory, abstraction, frustration/anger


How does alcohol influence brain development?

Alcohol inhibits all stages of brain development, except neuronal death, which it promotes


Describe the action of nicotine on the fetal brain

•Nicotine is a fetal neuroteratogen
–Targets nicotinic acetylcholine receptors in the fetal brain
–Impairs cell proliferation and differentiation, synaptogenesis, and induced neuronal apoptosis
–Constricts placental blood vessels, to reduced blood flow/nutrients to fetus


What are the babies outcomes from mother smoking?

Decreased IQ, depression, criminal behavior


How does mercury effect the brain?

Spectrum of nervous system damage including neurodevelopmental behavioral disorders in children, visual impairment, impaired coordination, hallucinations, intellectual disability, depression, and death


How does lead effect the brain?

•Neuronal, astrocyte, and oligodendrocyte apoptosis
•Altered neurotransmitter storage/release