Midterm 2 Flashcards
What is the most common inherited cause of intellectual disability?
Fragile X syndrome - an X-linked genetic disorder
What are the 2 types of FXS?
Full mutation FXS
Pre mutation FXS
What causes FXS?
Caused by mutations to the Fragile X Mental Retardation (FMR) gene
This causes decreased levels of FMR protein (FMRP)
Normally people have 6-50 CGG repeats. however CGG repeats between 50-200 is considered FXS permutation FXS and over 200 is full FXS
Why are X chromosomes unique?
You would assume that a female who has two X chromosomes would have double the amount of proteins and mRNA that are on the X chromosome
But in females the body works to silence one of the X chromosomes so both men and women have one functional X chromosome
Is FXS more common in males or females? Why?
Males because they only have 1 X chromosome so they must express it
Whereas women have 2 so they have a backup copy and tend to exhibit milder symptoms
If a father has a mutated X-linked chromosome which children will become affected?
What about when the mother has the mutated x chromosome?
Only the daughters because they get 1 X from their father and 1 X from their mother (genes will decide whether to exhibit the mutated or unmutated X). The sons cannot get it because they only get the Y chromosome from their father
Both sons and daughters get their X chromosomes from their mother it just depends which one they express. So both could be affected but they could also express the unmutated X chromosome
If you have permutation FXS can you have children?
When have children you CGG repeats may expand causing more repeats and therefore your children may develop full mutation FXS
What is the role of DNA methylation in FXS?
It turns off gene expression off
Elongation of CGG repeats allows hypermethlation of FMR1 gene at CpG islands - When this gene is silenced FMRP is not produced which has a major impact on the severity of FXS phenotype
Where is the highest concentration of the FMR protein? What is the function in the body?
In the brain and testes - It appears to be critical for cognitive functioning and reproductive function
It functions to bind mRNA and transports it out of the cell nucleus to the synapse - suppressing mRNA
The lack of FMRP reduced mRNA suppression with impairs neuroplasticity
How does FXS clinically present differently in men and women?
Males with the full mutation are severely impacted; the degree depends on the amount of CGG repeats
Degree of impairment varies in women depending on the ratio of normal:mutated FMR gene
Women with permutation do not show the phenotype
What are some physical features of FXS?
- long, narrow face with prominent forehead and chin
- large ears
- testicular enlargement with normal function
- macrocephaly
- hypotonia
What causes macrocephaly in people with FXS?
Increased caudate nucleus, fourth ventricles and hippocampal volume
This causes a decrease in lateral ventricle
The more abnormal the size of the caudate nucleus and lateral ventricle the more severe IQ impairment
What are the cognitive symptoms of FXS?
Developmental delays
Intellectual disability
Learning disability
Boys typically have delayed language development and expression - poor articulation, repetitive
FXS has different symptoms at different ages.
True or False
True
The symptoms reflect impairment in age-approbate brain development
Ex. in infancy poor such and in childhood impulsivity or aggression
Is FXS difficult to diagnose?
YEs because in absence of family history the diagnosis is based on cognitive, developmental, and/or behavioural concerns
The earlier caught the better so appropriate interventions can be initiated - a simple genetic test for FMR1 gene can confirm suspicion of FXS
What interventions can help FXS patients?
education plans, language therapy, behavioural therapy, pharmacotherapy to treat inattention, hyperactivity, anxiety, etc.
What is down syndrome?
A genetic disorder caused by 3 copies of chromosome 21, also known as trisomy 21
What is the most common chromosomal abnormality cause of intellectual disability?
Down syndrome
DS accounts for 1/3 of all intellectual disabilities worldwide
Fetuses with trisomy 21 are more likely to be born stillbirth
True or False
True
Most fetuses with trisomy 21 do not make it through pregnancy
What are the physical characteristics of DS?
It is regarded as a spectrum disorder as there is a variability of impairments
- small chin
- slanted eye
- hypotonia
- flat nasal bridge
- single crease of palm
- protruding tongue
- slowed growth in height
- flat & wide face, short neck, joint flexibility, extra space between big toe and second toe
What health conditions are common amongst people with DS?
They have poor immune function and generally hit developmental milestones much later in age
They have increased risk of:
- heart defect
- epilepsy (5-10% in children and up to 50% in adults)
- leukaemia
- thyroid disease
- mental illness (30%)
- autism (5-10%)
- depression/anxiety - dementia/alzheimer
What are the cognitive characteristics of people with DS?
- IQ ranges 35-69 but can be lower than 35 (normal is 100)
- Speech abnormalities : stutter, rapid or irregular speech, language comprehension is much more advanced than ability to speak
How is DS diagnosed?
Often made by prenatal screening confirmed with a genetic test:
- chorionic virus sampling (CVS): cells are taken from the placenta in the 1st trimester
- Amniocentesis: sample is taken of the amniotic fluid surrounding fetus through a needle into the mothers uterus during the 2nd trimester
- DS can also be recognized from phenotypic features after birth
What effect does maternal age have on DS?
Having birth later in life between 34-44 increase risk of DS
What occurs genetically when an individual has DS?
The extra chromosome happens by change and causes an over expression of each of the 300-500 genes carried on chromosome 21
It produces more mRNA which are translated into protein and whatever that protein does happens at a higher rate which throws off homeostasis
Your body doesn’t silence the 3rd chromosome as in the X chromosome in the females
What is mosaic down syndrome?
Some of the cells in the body are normal while others have trisomy 21
Rare but results in a mild or undetectable form of DS
What causes trisomy 21?
Failure of the 21st chromosome during egg or sperm development - producing an extra copy
88% of cases result from the mothers egg and 8% in the fathers sperm and 3% after the egg and sperm have merged
Which genes are over expressed during DS?
It is not entirely clear but research suggests:
Beta amyloid - this overproduction occurs also in Alzheimer’s disease
Superoxide dismutase (SOD)
What is beta amyloid
A protein derived from the amyloid precursor protein (APP) located on chromosome 21 which function is poorly understood
Possibly involved in activation of kinase enzymes, protection against oxidative stress, and regulation of cholesterol and iron transportation
It is the main component of amyloid plaques which are aggregates of misfolded proteins that are able to stick together and clog up the brain - the main cause of Alzheimer’s
What is Superoxide dismutase (SOD) ?
The gene for SOD is located on chromosome 21
Oxidative stress is the imbalance between production and removal of oxygen-derived free radicals which causes decreased immune function, premature aging, and impaired mental function
SOD produces hydrogen peroxide which are less toxic than -02 but in the presence of ferrous iron it forms the highly toxic hydroxyl radical (OH) which has profound cellular damage
What is the treatment for DS?
There is no cure or treatment
However education and proper care can drastically improve QoL
Supplementation with antioxidant nutrients to prevent cellular damage from oxidative stress is proposed as a potential therapy for DS
What is a concussion?
Concussions are a mild traumatic brain injury
It is a biomechanical induced transient (temporary) disturbance of neurological function (it is due to movement) that may be associated with:
- loss of consciousness
- temporary loss of brain function
- a variety of physical, cognitive and emotional symptoms
What causes a concussion?
Rapid acceleration or deceleration of the brain resulting in the brain colliding with the skull
- coupe (first impact of brain) and then contrecoup (second impact of brain on opposite side)
Bruising and swelling follows can can persist for up to 48 hours and can cause cerebral edema increasing intracranial pressure
Which direction of impact causes the most severe concussion? Why?
Rotational - may cause bridging veins/synuses or corpus callosum to be sheared
Can cause diffuse axonal injury (DAI): shearing force cause axons to detach from cell body which causes release of the excitatory NT of glutamate that cause excitotoxic lesions 24-48 hours post injury
Midbrain and diencephalon are most affected by rotational forces which disrupt normal cellular function thought to produce LOC
Axon shearing often leads to a subdural hematoma -> a collection of clotted blood that increase pressure on the brain
This shearing may cause cellular death
What is an epidural hematoma?
Collection of blood between the dura mater and the skill rather than under as in subdural
_________ are viewed as the hallmark of brain damage following a brain injury
Brain contusions
What is the aftermath of a concussion?
A concussion can lead to neuronal and vascular tissue damage leading to a distortion of cell membranes
- neuronal activity picks up Glutamate
- cerebral blood flow is interrupted due to hematoma
The indiscriminate release of Glutamate produces the events known as the metabolic facade leading the a cerebral energy crisis
Which NTs increase during the neurmetabolic cascade following a concussion/
- glutamate
- glucose
- and a longer increased release of potassium and calcium
What is glutamate?
The main excitatory Nt in the brain that is present in more synapses than any other NT
It can bind to 3 post-synaptic receptors:
- AMPA
- NMDA
- Kainate
Thse also care Na+ into the postsynaptic cell and cause depolarization and EPSP
What is glutamate excitoxicty?
Exictotoxicity can occur with overexposure of glutamate (or other excitatory NT) caused by a prolonged depolarization of the post synaptic neurons
When subjected to prolonged stimulation a large % of cells die by either:
- Necrosis: rapid lysis of cells due to osmotic swelling (more severe death)
- Apoptosis: delayed cascade of biochemical events that leads to DNA breakup and ultimately cell death
Glutamate activating NMDA receptors can allow entry of Ca2+ (a second messenger) into the cell that at high concentrations are extremely toxic
- interrupts function of mitochondria and ATP production is hindered and can initiate apoptosis
How does exitotoxicity lead to an energy crisis?
Glutamate increases entry of Ca2+ which hinders ATP production
ATP is required for entry and fueling Na-K pumps; Na-K are working in overdrive which requires a ton of ATP which results in an increase in glucose metabolism
This glucose demand comes at a time when verbal blood flow is reduced and mitochondria are dysfunctional
Hypoglycemia ensues, leading to cognitive deficits and an energy crisis that leads to secondary injuries
What are secondary injuries caused by concussions?
BBB permeability: anaerobic glucose metabolism (glycolysis) produces lactate followed by lactic acid - this overproduction results in acidosis which damages the BBB, leaving it vulnerable to toxins
Inflammation: microglia activation results in cellular damage leading to apoptosis
These secondary injures can take days, weeks, months, or months to develop and can persist for years
What are the symptoms of concussion?
Symptoms vary but can include:
- headache, pressure in the head -> vascular indies
- LOC -> brain stem
- Confusion -> corpus collosum
- amnesia surrounding event -> hippocampus, frontal lobes
- Ringing in ears -> temporal lobes
- Nausea/vomiting -> area postrema (good sign something is seriously wrong)
- changes in mood and emotional disturbances -> amygdala
How are concussions detected and diagnosed?
- Sport concussion assessment tool (SCAT-5)
- checklist of signs/symptoms of trauma, memory test, neurological screen
- Concussion Recommendation Tool or Immediate Post Concussion & Cognitive Testing (ImPACT)
- Computer tests aimed at detecting post-concussive symptoms, 20 min neurocognitive test
What is second impact syndrome (SIS?
SIS occurs when an individual suffers a concussion while still symptomatic from a pervious concussion
SIS carries a 50% mortality rate, 100% mobility rate (something wrong)
Repeated concussions have a cumulative effect on the human brain
What is chronic traumatic encephalopathy (CTE)?
CTE (aka demential pugilistic) is the result of multiple, sub-concussive blows to the head
CTE is a progressive degenerative disease found in individuals with repeated head trauma - characterized by neurofibrillary tangles, beta amyloid , amyloid plaques and neural death
This causes dementia and are all found in people with Alzheimer
The brain consumes ____% of the body’s blood supply
15-20
What are the two major arteries that supply blood to the brain?
The internal carotid arteries: branches into the anterior cerebral, and middle cerebral arteries
Vertebral arteries: branches into the posterior central artery
The species regions the arteries supply blood to can aide in diagnosing a stroke
ex. the posterior supplies the occipital lobe
The _____ is targherting during choke/sleeper holds
carotid artery
The middle cerebral artery stoke is most likely to affect the _____
Broca’s area - loss in speech
What is the Circle of Willis? What is its function?
A collection of arteries at the base of brain
The communicating arteries link the right and left sides of the circle allowing for anatomical redundancy
This means that if one artery is blocked, blood may be able to bypass it and still supply much of the brain
What is a stoke?
An abnormality of the vascular supply causes damage to the CNS
The blockage must occur long enough and cause damage that impairs the body beyond 24 hours+ to be considered a stroke
What are the two main types of strokes?
Ischemic (lack of blood flow)
Hemorrhagic (caused by bleeding)
What are the common symptoms of a stroke?
Symptoms usually occurs unilaterally
Common symptoms are:
- weakness in face and/or limbs
- numbness (loss of sensation)
- Aphasia or dysarthria
- vision loss
- headache (common in hemorrhagic stroke only)
Rare symptoms:
- LOC
- Pain
- Abnormal movement
Remember FAST: Facial droop, Arm weakness, Speech difficulty = Time to call 911
What is an ischemic stroke and what are the main causes?
An ischemic stroke is caused by a blockage of arterial blood vessels
The two main causes are:
- Thrombosis: obstruction of a blood vessel by local blood clot
- Embolism: obstruction due to an embolus from elsewhere in the body
What happens to brain tissue when it is deprived of oxygen?
Brain tissue ceases to function if deprived for more than 60-90sec and will suffer irreversible damage after ~3 hours of schema
The body is not very good at generating ATP in absence of oxygen (lactate -> lactic acid -> acidosis) leading the an energy crisis that causes apoptosis or necrosis (very similar to what occurs during concussions)
Infarction is the tissue death (necrosis) caused by lack of blood supply
What is a hemorrhagic stroke and what the the main types?
Hemorrhagic stoke refers to bleeding in our about the brain membrane usually caused by a rupture of blood vessel or abnormal vascular structure (aneurism)
4 main types are:
- *Epidural: between skull and dura matter
- *Subdural: between the dura matter and arachnoid space
- Sub-arachnoid: between arachnoid space and pia matter
- Intracerebral: bleeding within the brain itself. Either from the brain tissue (intraparenchymal hemorrhage) or from the brains ventricular system (intraventricular hemorrhage)
What are symptoms that are specific to hemorrhagic strokes?
- severe headache
- dizziness
- seizures
- vomiting
