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?
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?
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?
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
–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
–Balloon cells (enlarged cell bodies but no dendrites/axons)
What are the causes of FCD?
•Abnormal migration, maturation, and cell death
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
–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