Down Syndrome: Genetic Causes & Characteristics

• NEUR 1203 Lecture 4-7 Notes

Stages of Human Neurodevelopment

• Day 1: Fertilization occurs forming a zygote with half of the mother's DNA and half of the father's DNA.
• Day 2: Cells start dividing and this continues throughout life.
• Day 15: The embryonic disc forms with several layers of cells, visible only under a microscope.
• Days 18-21: Neural plate and groove formation occurs; this process is known as neuralation.
• Days 22-24: The neural tube forms from the neural plate.
• Around 3 weeks rapid changes occur, creating a hole in the brain for the ventricles, and the neural tube forms the spine.
• Day 49 (7 weeks): The embryo begins to resemble a human and can be seen on an ultrasound at 6 weeks.
• Day 100 (14 weeks): The brain starts to resemble a human brain.
• 7 Months: Gyri and sulci form but are not complex, only small grooves and bumps are present.
• 9 Months: The brain is fully formed but the cellular structure is still developing and complex.

Formation of the Neural Tube

• Formation is also known as neuralation.
• The embryo consists of 3 layers including the endoderm, ectoderm, and mesoderm layers.
• Around day 18, the ectoderm thickens and folds due to cells growing and pushing.
• Around day 21, due to growing and pushing a hollow cylinder shape, known as the neural tube, is formed.

How Neurons and Glia are Formed

• Stem cells make one of itself and one progenitor cell, and does not self-renew.
• Progenitor cells are precursor cells that can divide into nondividing cells such as neuroblasts or glioblasts.
• Neuroblasts are cells that will form into a neuron, either an interneuron or pyramidal neuron.
• Glioblasts are cells that will form into a glial cell, such as an oligodendroglia or astrocyte.

Chemicals that Influence Stem Cell Production

• Prolactin: A hormone that increases to very high levels during pregnancy, increasing fetal neural stem cell production.
• Gene transcription: Genes get turned "on" through transcription, influencing stem cell fate towards neurons rather than skin cells.
• Epigenetics: Controls which genes are turned off and on; different cells require different genes and proteins, occurring a lot during development. It typically occurs in response to signals from the environment like hormones and stress.
• DNA methylation: The addition of a methyl group that turns the gene off.

Neurotrophic Factors

• Neurotrophic factors go from stem cell to progenitor to glial neuron
• Help nourish (trophic) cells by supporting growth and differentiation; these are usually produced by epithelial cells, not neurons.
• Epidermal growth factor: Stimulates neural stem cells to turn into progenitor cells.
• Basic fibroblast growth factor: Stimulates progenitors into neuroblasts or young neurons but does not affect stem cell production.

Stages of Neural/Glial Growth

• Cell birth, also known as neurogenesis and gliogenesis, is largely complete by 5 months prenatally.
• During this time, the brain is resilient to injury from teratogens or trauma, and the embryo will have all the neurons it needs.
• Cell Migration: Traveling to the final destination after neurogenesis lasts for 6 weeks and moves away from the ventricular zone.
• Cell differentiation: Cells develop specific tools or skills, beginning during migration and completing after migration, ending at birth.
• Cells differentiate to become neurons such as dopamine or GABA neurons.
• Cell Maturation: Includes dendritic development and axonal growth, occurring for years into adulthood; this allows for chemical transmission.
• Synaptogenesis: The formation of synapses occurs as each neuron begins forming its own networks, with synapses numbering in the hundreds of thousands with other neurons.
• Cell Death: Apoptosis occurs where unused cells are lost.
• Myelogenesis: The formation of the myelin sheath is how neuronal networks become more efficient in their communication, a sign of neurodevelopmental maturity that continues into adulthood, helping axons communicate more efficiently, mature = complete genesis.

Cell Migration

• Begins around 6 weeks' gestation.
• The cortex is highly organized into layers numbered I to VI, built from the inside out; layer VI is on the inside and builds from there.
• Subventricular zone: Contains a primitive map - cells from specific regions migrate to specific areas of the cortex.
• Cells follow set paths along radial glia; glial cells create paths from the SVZ to the top of the cortex.
• Progenitor cells follow the path, contributing to the extremely ordered cortical formation.

Cell Differentiation

• Intracellular signals restrict cell types.
• Emergence of a cell type depends on 3 factors:
  • Genetic expression: progenitor > neuroblast > inhibitory/excitatory > pyramidal cell.
  • Timing: Genes are not always active thus they can turn on and off.
  • Signals in the local environment, such as neurotrophic factors.

Cell Maturation

• Immediately after differentiation cells are still small in structures.
• Young neurons require growth in 2 parts to function.
• Dendrites: Provide a surface area for synapse formation through
  • arborization - branching like a tree; and
  • spine formation - components making contact with axon terminals where synapses occur.
• Axons: Extend to a target area to contact other neurons and influence the post-synaptic cell type.
• Axons are guided towards targets by chemicals that attract or repel them.
• Growth cones are extensions of developing axons.
• Filopods are shoots coming off the growth cones; if they reach the target, the rest of the growth cone follows and establishes a complete axon.

Growth Cone

• Movement of the growth cones depends on:
  • Cell adhesion molecules: Found on the cell surface, guides the growth cone to a specific cell, or provides something for growth cones to attach to in the intracellular space.
  • Tropic molecules: Secreted from target cells that either attract or repel, guiding neurons Netrin: Brings the cone towards a cell. Semaphorins: Repels growth cones and forces the axon to move out.
• After the growth cone attaches, it forms a synapse.
• It is estimated that the human brain contains 10^14 synapses.
• Organization of synapses is guided by local environmental cues and signals.
• 5 months: Simple synaptic contacts
• 7 months: Deep cortical layers develop intense synaptic organization within layers IV and V.
• After birth: The amount of synapses increases drastically, doubling between 2-4 months, peaking after 1 year.

Synaptic Pruning

• Starts with many more synapses than needed, decreases over time.
• Influenced by many factors like genetic signals, life Experiences, hormones, stress, etc.
• 40% of synapses are lost from childhood to adulthood if not integrated into a circuit.
• Neural Darwinism: Competition for finite resources leads to those best suited for the environment. Neurons depend on forming synapses so that their connection allows them to absorb neurotrophic factors.

Myelination

• Nerve growth factor is produced by cells that help you regulate neuron survival, made by cortical cells and absorbed by cholinergic cells in the basal forebrain.

• Only so much nerve growth factor (NGF) is produced; neurons that do not receive enough will express genes that lead to apoptosis.

• It is mostly complete by age 20, although there are exceptions

• Language areas actually increase in grey matter density as an individual ages; neurons do not die off, instead becoming more complex as learning occurs, such as learning a new language.

• Language is fundamental to human cognition and learning. This is thought to occur due to the unique timeline of language acquisition and its role in learning throughout life.

• Last process to occur during development.

• Myelin in the CNS is formed by oligodendrocytes and continues to develop throughout life.

• Myelination rates vary in different areas of the cortex; whatever is more important is myelinated first.

• Myelination can be a marker for neuronal maturity.

• Regions that are myelinated early control simple movements like the visual cortex.

• Regions myelinated later control higher mental functions like the frontal cortex.

Neuroplasticity

• Process by which the brain is modeled by experience, such as culture, language, relationships, values, and behavior.
• An individual's culture is an important aspect of the environment that can shape the brain; different cultures can lead to structural differences causing differences in behavior.

Donald Hebb Experiment

• A test of how early life experiences affect brain development and test learning.
• Two group were compared:
  • Lab Rats: Raised in standard cages with minimal stimulation.
  • Home-Raised Rats: Allowed to explore and interact with a normal home environment.
• Home-raised rats performed better in the maze, solving it quicker with less mistakes.
• Early enriched environments improve brain function and learning abilities, supporting the impact of experience on shaping brain development

Environmental Influence on the Brain

• Tactile stimulation - speeds up growth of premature infants (e.g., skin to skin, breastfeeding, petting).
• Lab Setting - Brushing rats for 15 mins 3x a day for the first 3 weeks speeds up their development.
• Leads to neurons that are larger and richer in synapses in the cortex of adults, more dendrites, more axons, and overall more dense.
• Abnormal experiments in brain development:
• Dogs put in the dark with no stimulation caused no reactions to people or other dogs, loss of all pain sensation, unable to do a maze task and overall poor brain development due to lack of stimulation/stimulation.
• Monkeys removed from parents after birth were unable to form relationships, abnormal intellectual and social behaviors
• Orphans who were not in school or with families, were malnourished and had severe motor and cognitive deficits, luckily due to neuroplasticity the brain can develop more neurons in the future with proper stimulation.

Fragile X Syndrome

• Most common inherited neurodevelopmental disorder, also known as martin-bell syndrome.
• Causes developmental delays and intellectual disability, ranging from mild to severe.
• The disorder is caused by mutations on the fragile X ribonucleoprotein 1 (FMR1) gene.
• The mutation makes the X chromosome look fragile or broken.
• Biological males and females are affected.
• Males are more severe in symptoms or susceptible to having the disorder as they only have one X chromosome.
• For a female to have a severe case of fragile X both chromosomes would need to be affected which is very rare. Average age of diagnosis:
  • Males: 35-37 months.
  • Females: 42 months, the diagnosis is usually detected later because symptoms are less severe.
• It is typically noticed by parents in the first 12-16 months that typical milestones are not reached.
• Has a strong comorbidity with ASD.
• Ranges from mild to severe including:
  • learning disorders to intellectual disability.
  • females typically only have a mild deficit or normal intelligence. Low IQ worsens with age, possibly due to attentional issues, comorbidity including ADHD.
• Delays in certain intellectual milestones. Physical characteristics:
  • Long face.
  • Prominent jaw.
  • Macro-orchidism (abnormally large testicles).
  • Joint hypermobility.
  • Flat feet.
  • Not visible until puberty. Behavioural Features:
  • Anxious in new situations which may lead to lashing out, and is overly common due to abnormal circuitry.
  • Difficulty making eye contact leads to difficulty in social relationships.
  • Males typically have attentional issues and/or aggression and women especially tend to have social anxiety.
  • Flapping or biting hands in social situations to relieve anxiety which can be physically damaging.
• Speech and language includes:
  • Significant delays in word acquisition which is one of the first signs of intellectual disability as these individuals won’t speak until ages 3-5.

Sensory and other Issues Associated with Fragile X

• Impaired reading skills where a grade 4 child can only read at the grade 1 level.
• The use of repetitive language; usually because the speaker is trying to understand the words.
• Difficulty in communicating informative details, such as giving directions.
• Sensory:
• Heightened senses and hypersensitivity is common.
• Can be auditory, tactile, or visual, where auditory is most common.
  • Impaired sound habituation and reduced auditory attention where noises can’t be tuned out and it is hard to listen for extended time.
  • Some show significant visuospatial impairments where one cannot move around in space correctly, and cannot judge distances.
• What causes FMR1 mutations:
• Fragile X Messenger Ribonucleoprotein 1 gene is silenced/loss of function, becoming a non-functional protein.
• FMR protein is necessary for neurodevelopment as it regulates protein translation, especially in synapses.
• Caused by the addition of CGG repeats to the promoter region of the FMR1 gene:
  • Number of repeats correlates with severity.
    • Normal range: < 45.
    • Intermediate/grey zone: 45-54.
    • Pre-mutation show specific issues later in life, and a higher risk of giving full mutation to offspring: 55-200.
    • Full mutation: > 200.

Chromosome Structure

• All cells contain DNA, which are instructions to make proteins that allow them to survive and carry out function.

• DNA gets stored in chromosomes inside the nucleus.

• Humans have 23 pairs.

• The 23rd pair are the sex chromosomes, female XX and male XY.

• Basis of chromosomal inheritance:

  • Reproductive cells contain only one copy of a chromosome, only take on pair, mom gives X and dad gives X or Y.
  • During fertilization, the chromosome from the parents join to form a new chromosomal pair in the offspring.

• Mutations in FMR1 are passed down depending on which parent possesses it, these genes do not follow mandelian genetics.

• Mothers that are carriers of the premutation have increased risk of children with full mutation

  • CGG repeats are unstable and tend to grow with maternal transmission; they can pass the mutation to either son or daughter.

• Fathers only have one X chromosome; therefore, can only pass on the mutation to their daughters. DNA Structure and transcription in Fragile X include:

  • Genes are highly structured and depend on the presence of a promoter for transcription to occur.
  • Transcription: Creation of mRNA, based on codons made from the nucleotides.
    • A promoter allows for the binding of RNA polymerase to the DNA chain and subsequent formation of mRNA.

• Too many CGGs prevents the binding of RNA polymers.

• FMR1 CGG mutation includes:

  • CGG repeats are found in the 5' region of the DNA, part of the promoter that helps regulate the binding of RNA polymerase
  • Inherently unstable and polymorphic.
  • Causes DNA methylation (silencing of a gene).

• For a full mutation (> 200 repeats) gene is entirely silenced and the protein is no longer produced.

• Premutation can still produce proteins.

  • If females have Fragile X association it is known as fragile X ovarian association.

FMRP Importance

• Regulates protein translation, acts as a break and slows down protein production.
• Protein translation is essential for synaptic function, circuit formation, dendritic spine numbers, morphology, and neurogenesis.
• Needs proteins to get through path and FMRP regulates this and increasing protein translation is detrimental.

Neuroanatomical Changes in Fragile X Syndrome

• The brain is similar to the immature brain before fine-tuned networks, such as underdeveloped brains.

• A smaller cerebral vermis; loss of this can lead to motor dysfunction and mental retardation.

• Larger 4th ventricle; large ventricles push the brains and takes up space for further development.

• Increased caudate nucleus and HC.

• There is increased spine density.

• Malformed spines often look immature and more like filopodia.

• Neurophysiological changes in Fragile X include:

• Long term depression is increased which leads to impaired synaptic functioning.

• Constant low frequency stimulation of neurons leads to weakened synapses through internalization of receptors.

• Characterized by smaller excitatory neurons in the post synaptic cell, less stimulation means there are less receptors and less ions.

• LTD plays a role in protein synthesis, malformed spines occur since there is an increase in LTD where more LTD means more protein synthesis which is bad.

• FXS shows hyperexcitability in some brain regions, oversensitivity to stimuli.

• Counterintuitive of how LTD leads to reduced stimulation.

• Taken together there is an ESPS and ISPS imbalance that influence the symptoms.

Synaptic and Neurotransmitter Changes in FXS

• Amygdala: Lower inhibitory synapse number, GABA release, and GABA vesicular content (less inhibition = more GO).
• Cortex: reduced inhibitory function by reduced excitatory transmission onto GABA neurons (less GO and less STOP).
• Striatum: increased GABA, more STOP.
• Hippocampus: increased endocannabinoid activity that reduces GABA function (more STOP).
• Diagnosis for FXS:
• It requires DNA testing from the child, sequenced for the specific region.
• Typically occurs between 35 to 37 months for males and 42 months for females.
• Parents that carry the premutation may get their child tested during gestation (amniocentesis - taking amniotic fluid, or chronic villus sampling - cell sample from the placenta.)

Current Treatment for FXS

• There is no cure for FXS, cannot force protein to be made and reverse structural changes that occurred during development.
• Can treat comorbid features such as ADHD, seizures, aggression/OCD, and sleep issues.
• Theraputic things that can help are speech and language therapy, occupational therapy, and other interventions early on to develop a normalized timeline.

Down Syndrome

• Genetic disorder causing delays in neural and physical development.
• It is the most common chromosomal condition.
• Occurs due to extra or partial copy of chromosome 21. Epidemiology of Down syndrome:
  • The highest risk factor is maternal age -> thought to occur due to higher ratio of eggs with extra chromosome
  • Rate seems to be increasing up by 30%
  • Life expectancy of 47 years, many issues during development that increase risk of death early

Physical Changes in Down Syndrome

• Flattened face, especially bridge of the nose.
• Almond eyes that slant up.
• Short neck.
• Small ears, overall short in height.
• Tongue tends to stick out.
• Small hands and feet.
• Poor muscle tone or loose joints.

Physiological Problems in Down Syndrome

• Ear infections or hearing loss.
• Vision problems or eye disease.
• Dental problems.
• Prone to infections or illnesses.
• Obstructive sleep apnea.
• Congenital heart disease.

Cognitive Issues in Down Syndrome

• Usually mild, moderate, rarely severe.
• Short attention span and slow learning
• Delayed language and speech development.
• Delayed motor skills.
• Mental health issues and early dementia.
• Typically noticeable early in life and still able to develop proper communication skills.

Behavioral Changes in Down Syndrome

• Impulsive behavior and OCD.
• Poor judgement and temper tantrums.
• Self-talking and unique talents.
• Strong social skills and is highly empathetic.

Causes Involved with Down Syndrome

• During normal egg/sperm production, cells undergo meiosis.
• During fertilization, the 23 chromosomes from the mother and father come together to form 46 pairs.
• All chromosomes are duplicated forming sister chromatids.
• Meiosis I separates the homologous chromosomes and forms 2 cells.
• Meiosis II separates the sister chromatids in both cells so when those divide and form 2 new cells.
• In Down syndrome, there can be an extra copy of chromosome 21, either in portions of cells known as mosaicism, or in all cells known as trisomy 21.
• This is where there is an error in the steps of cell division and replication.
• Translocation: Where an additional/partial copy of 21 binds to another chromosome, usually 14 which is least common.
• Trisomy 21 error in cell division causing an egg or sperm cell to have an extra chromosome 21 - this the most common.
• Mosaicism: Normal egg/sperm occurs.
• Error is found during early embryonic days leading to some cells having an extra chromosome 21.

Neuroanatomy in Down Syndrome

• Smaller adult brain volume is found.
• Volume decreases between ages 10-20 related to synaptic pruning which leads to too many cells are getting pruned.
• Brachycephalic: results in a small cerebellum, simplified gyri, and smaller head causing smaller structures and less growth. The cortex: -reduced number of neurons.
  • decreased neuronal density. -abnormal neuronal distribution in Layers II/IV. -abnormal synaptic length and density.
• Less neurons are being born at 17 weeks.
• Frontal lobe: Reduced volume with fewer cells.
• Temporal lobe: Reduced volume, reduced number of granule cells.
• Brainstem: Altered serotonergic, noradrenergic, and cholinergic systems.
• Basal ganglia: Normal

Down Syndrome Diagnosis and Treatment

• Pre-screening involves less invasive methods being done in the 1st/2nd trimester.
• Diagnostic testing involves invasive methods that can pose complications due to taking blood from the embryo. Pre-Screening usually involves:
• blood test and ultrasound from the mother in the first trimester.
• or a blood test in the second trimester. If there are positive results, there is an option for diagnostic testing to confirm.
• Diagnostic testing includes. -Amniocentesis: Sample of amniotic fluid and karyotyping done at 14-18 weeks.
• Chronic villus sampling: Cells are taken from the placenta done at 9-11 weeks. -Precutaneous umbilical blood sampling: Blood sample from the umbilical cord done at 18-22 weeks (most accurate).
• Down syndrome has no available cure and cannot come up with a drug that undoes all the developmental changes.
• Therapy options include:
  • physical therapy. -speech therapy. -occupational therapy. -behavioural therapy.
• severity and person varies.

Explore the genetic origins, risk factors, and neuroanatomical aspects of Down syndrome. This lesson covers prenatal screening, diagnostic procedures, and cognitive characteristics. Also, learn about the impact of environmental enrichment and tactile stimulation for individuals with Down syndrome.