Module A

Question 1

Main Types of Neurodevelopmental Disorders

Answer 1

Genetic disorders, Infectious diseases, Immune Dysfunction, Metabolic Disorders, Nutrition, Toxic and environment factors

Question 2

Neurodevelopmental Disorders - Definition

Answer 2

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

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Question 3

Genetic disorders

Answer 3

Variation or a mutation in a gene
- Random gene mutations, environmental exposure, inherited
* Neural tube defects
* Neuronal migration disorders - Lissencephaly, subcortical band heteropia, focal cortical dysplasia
* White matter myelin disorders - leukodystrophies, phenylketonuria

Question 4

Neural Tube Defects

Answer 4

• Most common birth defect
  *Brain and/or spinal cord exposed at birth
• defect in skull or verterbrae
  -incomplete closure of the neural tube
  *folate (B9) is required for cell production and maintenance during neural tube development (neuralation). Folate prior to and during pregnancy

Question 5

Anencephaly

Answer 5

Without brain, do not survive hours past birth

Question 6

Encephaloceles

Answer 6

Protrusion of brain through skull in a sac like membrane. Surgery effective. Intellectual disability

Question 7

Hydranencephaly

Answer 7

Missing cerebral hemispheres, replaced by sacs of fluid

Question 8

Spina bifida

Answer 8

Opening of the spinal cord. Meninges or spinal cord herniation. Most common NTD ~ 50%.

Question 9

Neuronal Migration Disorders: General information

Answer 9

*Majority of neuronal migration between 12-24 weeks
*Failure of normal neuroblast migration often causes neurons to accumulate in unusual areas (heterotopias)
- Focal (nodular heterotopias) - basically ‘clumps’ of neurons located in the wrong part of the brain
- Diffuse band heterotopias
*Lissencephaly, polymicrogyra, focal cortical dysplasia, shizencephaly

Question 10

Subcortical Band Heteropia

Answer 10

*Bands of neurons are located in the white matter between the cortex and the lateral ventricles
*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. Cytoskeletal = filopodia, growing dendrites and axons

Question 11

Lissencephaly

Answer 11

*Absent (agyria) or decreased (pachygyria) cortical folding
*E.g Type 1 LIS
- Migratory defect occurs in 12-16 weeks gestation
-Very think 4-layered cortex
-Hypotonia at birth, develop progressive spasticity
-Seizures start within first few months of life
*Most cases results from LIS1 gene disruption
- Encodes B-acetylhydrolase
- Degrades platelet activating factor (PAF)
*Accumulation of PAF impairs neuronal migration
*Early developmental delay, early diffuse hypotonia, spastic quadriplegia, seizures, severe intellectual disability

Question 12

Focal Cortical Dysplasia

Answer 12

*Spectrum of abnormalities of the laminar structure of the cortex
*Various cytopathological features
- Giant neurons
- Dysmorphic neurons
- Balloon cells (enlarged cell bodies but no dendrites/axons)
*Abnormal migration, maturation and cell death
- Causes unknown
*Intractable epilepsy in children
*Developmental delays

Question 13

Myelin Disorders: Leukodystrophies

Answer 13

*Group of disorders characterized by progressive white matter generation
*Mutation in genes that produce or maintain myelin
- Oligodendrocyte death and myelin degeneration
*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

Question 14

Vanishing White Matter Disease

Answer 14

*Pathology: Oligodendrocyte cell death, diffuse disappearance of white matter, loss of myelin
*Mutations in elH2B1-5 genes (oligodendrocyte survival / apoptosis)
*Childhood ataxia (gait difficulties)
*Rapid cognitive decline (2-5 years)

Question 15

Phenylketonuria (PKU)

Answer 15

*Metabolic disorder (1:10,000)
- Mutation in phenylalanine hydroxylase
*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
*Hypomyelination/demyelination
*Impaired brain development and intellectual disability
*Strict diet with no phenyalanine

Question 16

Infection Disease: General Information

Answer 16

*Transmitted congenitally or in early childhood - can cause serious neurodevelopment disorders including schizophrenia.
*E.g Congenital toxoplasmosis (protozoa Toxoplasma gondii) - domestic cat
- Can cause cyst formation in the brain; seizures; intellectual disability
- Most damaging in first trimester, not damaging after first trimester

Question 17

Infectious Diseases: Pathology

Answer 17

*Congenital rubella syndrome
*Outcome relates to gestation age
- <10 weeks ~ 90% injury
- >16 weeks, 10 - 20% damage
- >20 weeks, no damage
*Pathology
- Diffuse white matter injury, atrophy, (oligodendrocyte death)
- Moderate neuronal loss
*Mental and motor retardation, hearing difficulty, schizophrenia

Question 18

Infectious Diseases: Zika

Answer 18

*Congenital Zika syndrome (Brazil, 2015)
* ~50% of mothers infected during pregnancy experience adverse outcomes
- Miscarriage, microencephaly, haemorrhage
*Mechanisms
- Halts stem cells proliferation of neuroepithelial cells, early neuronal migration and neuronal apoptosis

Question 19

Immune Dysfunction: General Information

Answer 19

*Immune reactions during pregnancy and in infant can produce neurodevelopmental disorders
*E.g Chorioamnionitis (maternal bacterial infection) - abnormal cytokines, abnormal inflammation response.
*Fetal inflammation
*Associated with high rates of motor (e.g cerebral palsy) and neurocognitive deficits)

Question 20

Metabolic Disorders: General Information

Answer 20

*Fetal metabolism altered by:
- Maternal nutrition (e.g folate deficiency)
- Maternal neurotoxins/teratogens (nicotine, alcohol) exposure, gestational diabetes
*Many inherited metabolic disorders
- In-born errors of metabolism (IEM) - single gene defects in biochemical pathways (Phenylketonuria)
- Lyososomal storage disorders (intracellular structures responsible for breakdown of metabolic waste products)
*Cause neurodevelopmental disorders
- Major effects during gestation

Question 21

Diabetes Mellitus

Answer 21

*Metabolic disorder involving high blood sugar due to failure to produce insulin (type-1) or cell-insensitivity to insulin (type-2)
*In children, diabetes can produce impaired neurodevelopment/cognition
*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 increaese in congenital abnormalities if during 1st trimester
- CNS defects including anencephaly and spina bifida
- Seizures
- Delays in motor and cognitive function in childhood

Question 22

Nutrition: General Information

Answer 22

1944 Dutch Famine
*End of World war II, German-occupied parts of Netherlands were cut off from food supply to punish for supporting Allies
- Severe 5 months of undernutrition - consumed tulip bulbs and sugar beets (<400 calories per day)
- Famine unique as occurred in modern, developed and literate country)
- Excellent records (Dutch Famine Birth Cohort Study)
Children 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.

Question 23

Toxic and environmental factors (Teratogens)

Answer 23

*Exposure to teratogens can alter organ development
- Exogenous agents that causes birth defects
*Each organ system is most vulnerable to disruption at the time when it is developing most rapidly
*Alcohol, drugs, nicotine, heavy metals, (mercury, lead), x-ray irradiation, PCBs, anesthetic gases, solvents, pesticides
*Thalidomide (~10,000 infants)

Question 23

Retinoic Acid

Answer 23

*Retinoids include the alcohol, aldehyde and acid forms of vitamin A (retinol, retinal, and retinoic acid, respectively)
*Experimental studies (1930) found that metabolic precursors or derivatives of vitamin A (retinoids) are teratogenic (cause gross malformations in brain development)
*1980s - 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.

Question 24

Fetal Alcohol Spectrum Disorders

Answer 24

Experimentally: Fetal brain damage occurs at regular doses of 1-2 oz/day (2-4 drinks)
Infant: Problems with sleep, feeding, milestones, muscle tone, sensory information processing
Child: Hyperactive, poorly coordinated, learning delays
Adolescent/Adult: poor judgement, attention, problems with arithmetic, memory, abstraction, frustration/anger

Question 25

Maternal Smoking - Nicotine

Answer 25

*Maternal smoking increases risk of low birth weigght
- ~20-30% of all LBW infants due to maternal smoking (as little as 1 cigarette per day)
*Nicotine is a fetal neuroteratogen
- Targets nicotinic acetylcholine receptors in the fetal brain
- Impairs cell proliferation and diffrentiation, synaptogenesis, and induced neuronal apoptosis
- Constricts placental blood vessels, to reduced blood flow/nutrients to fetus
*Decrease IQ, depression, criminal behavior

Question 26

Heavy Metal Poisoning - Mercury

Answer 26

*Heavy metal poisoning prominent in the 20th century
- Even very low doses in utero are dangerous
*Developmental mercury poisoning
- Industry, dentists/technicians, semiconductor manufacturing facilities / high fish diet, (high levels of mercury due to industrial pollution)
*Spectrum of nervous system damage including neurodevelopmental behavioural disorders in children, visual impairment, impaired coordination, hallucinations, intellectual disability, depression and death

Question 27

Cord Blood Lead and Mental Developmental Index

Answer 27

*Lead accumualates and stored in bones for decades
- Paint, pipes (water)
*Women exposed to lead can cause elevated fetal lead even well after exposure
*Neuronal, astrocyte and oligodendrocyte apoptosis
*Altered neurotransmitter storage/release.