Genetics Flashcards
What is an example of an X-linked recessive neuro disease?
Duchenne muscular dystrophy
What is an example of an AD neuro disease?
Huntington’s
What are some examples of neuro diseases displaying heterogeneity/are multifactorial?
Alzheimer’s
MS
What does DMD cause?
Delay in motor development
Wheelchair bound by 10-12y
Death from involvement of respiratory and cardiac muscle in 20s
Male incidence 1:3000
When and where does the onset of DMD occur?
~3-4 years in the pelvic and shoulder girdles
What feature occurs in DMD and Becker muscular dystrophy?
Calf hypertrophy
Why does DMD occur?
Deletion of dystrophin gene in 70% DMD boys
Point mutations, small insertions and deletion in remaining 30%
How is DMD diagnosed?
Developmental delay in boys Muscle weakness- Gower's, toe walking Raised CK EMG Muscle Biopsy Molecular genetic testing
What may be included in a DDx of DMD?
Autosomal recessive limb girdle muscular dystrophies-some caused by sarcoglycan deficiencies
What carrier testing occurs in DMD?
Identify mutation in affected boy
Test for mutation in female relatives wishing to know status
Female carriers of dystrophin mutations can be offered prenatal/pre-gestational testing
What histological findings are seen in DMD?
No spinal cord or nerve abnormality
Muscle tissue has extensive granulation and the sarcolemma is broken down and destroyed
What is Huntington’s disease?
AD progressive neurodegenerative disorder
Incidence 1:20000
What happens in Huntington’s disease?
Onset between 30-50
Involuntary movements
Dementia
Progression to severe dependency and death over 15-20 years
What is the penetrance of Huntington’s?
Age dependant (variable)
What are some early clinical signs of Huntington’s?
Clumsiness Agitation Irritability Apathy Anxiety Disinhibition Delusions/Hallucinations Abnormal eye movements Depression
What are the later clinical signs of Huntington’s?
Dystonia Involuntary movements Trouble with balance and walking Trouble with activities that require manual dexterity Slow voluntary movements Difficulty initiating movement Inability to control speed and force of movement Weight loss Speech difficulties Stubbornness
What are the late clinical signs of Huntington’s?
Rigidity Bradykinesa Severe chorea Serious wt loss Inability to walk Inability to speak Swallowing problems Inability to care for oneself
What atrophies in Huntington’s?
Caudate nucleus
Where is the genetic defect in HD?
CAG gene- codes for glutamine
What genetic principle does Alzheimer’s display?
Heterogeneity
What pathology occurs in Alzheimer’s?
Loss of cortical neurones Neurofibrillary tangles (intracellular) Senile plaques (extracellular)
What do the senile plaques in Alzheimer’s contain?
Amyloid Beta protein- a fragment of the product of the amyloid precursor protein (APP) gene
Where is the APP gene found?
Ch 21
What inheritance can early onset Alzheimer’s display?
AD in 5-10% cases
What condition can be considered a genetic cause for Alzheimer’s?
Down syndrome (onset in 3rd to 4th decade)
Where are the mutations present in AD Alzheimer’s?
APP (Ch 21)
Presenilin 1 (Ch 14)
Presenilin 2 (Ch 1)
Others
Presenilins are a component of what secretase?
Gamma-secretase
What polymorphism has been shown to cause Alzheimer’s?
Apolipoprotein E (ApoE)
What ApoE alleles cause Alzheimer’s and in how many of the population are they present ?
e4 17%
e3 72%
e2 11%
How many people will be affected by Alzheimer’s with an e4/e4 genotype?
55% by 80yo
How many people will be affected by Alzheimer’s with an e3/e4 genotype?
27% by 85yo
How many people will be affected by Alzheimer’s with a no e4 genotype?
9% by 85yo
What does the e4 allele predispose to?
Alzheimer’s with some clustering in families
What is the e2 allele associated with?
Longetivity
What genetic pattern does MS display?
Multifactorial- clustering in families.
First degree relative 3% risk, second degree 1%
