NeuroGenetics Flashcards
What inheritance pattern does Duchenne Muscular Dystrophy (DMD) follow?
X-linked recessive
=> females can be carriers, males will always be affected if they have the gene
What symptoms are usually present at onset of DMD, and at what age does this usually occur?
Delayed motor development
Weakness of pelvic and shoulder girdle muscles
Onset at age 3-4 years
Children with DMD usually take longer to learn to walk. TRUE/FALSE?
TRUE
If a child isn’t walking by 18 months, what serum marker should be checked to possibly diagnose DMD?
Creatinine kinase
this leaks out of damaged muscle
WHy does death occur so young in DMD?
Respiratory and cardiac muscles also develop weakness
=> incompatible with life
Describe the typical posture of a child with DMD?
Accentuated lumbar lordosis
- compensating for weak pelvic girdle
What muscle may actually show hypertrophy in DMD, rather than atrophy?
Calf muscles
The mutation in DMD codes for which protein?
Dystrophin
What does the dystrophin protein do?
Connects contractile filaments to the cell membrane
=> muscle cells fail to renew themselves properly without dystrophin
What findings would lead to a diagnosis of DMD?
- Developmental delay
- Positive Gower’s sign
- increased serum CK
- positive muscle biopsy
Describe Gower’s sign
If asked to jump up from a lying/sitting position
children with DMD will walk their hands up their legs in order to stand up
What other muscular dystrophies present similarly to DMD and how are they inherited?
Sarcoglycan and dystroglycan muscular dystrophies
These are autosomal recessive as these proteins are not found within the X chromosome
At what age to DMD patients usually end up wheelchair bound?
roughly by 10-12 years
What is Huntington’s and when does it usually present?
Progressive neurodegenerative disorder
• Onset usually between 30 and 50 years (this is variable e.g. from teens -> 70s)
What symptoms are usually present in Huntington’s?
- involuntary movements (chorea)
- dementia
How long does it take for Huntington’s patients to become severely dependent?
15-20 years
How is Huntington’s inherited?
Autosomal dominant
What is meant by age dependent penetrance?
As a patient gets to 50, their likelihood of developing the disease decreases.
This continues as they age, therefore when they are 70 they have an even smaller chance of having inherited the disease.
What early symptoms are often present in Huntington’s disease?
- Clumsiness
- Agitation
- Anxiety
- Disinhibited
- Delusions/Hallucinations
- Abnormal eye movements
- Depression
=> very NON-SPECIFIC
What later symptoms can be seen in Huntington’s?
- Involuntary movement
- Trouble with balance, walking, coordination of movement
- Weight loss
- Speech difficulties
- Swallowing problems
Give some examples of subtle chorea (involuntary) movements.
Raising eyebrows uncontrollably
Tilting head back
What evidence of Huntington’s can be seen in the brain?
Caudate atrophy around the lateral ventricles
What can strokes in the area of the caudate nucleus cause?
chorea-like symptoms
Describe the genetic component of huntingtons disease?
Mutation in the Huntington’s gene
CAG repeat expansion
36 repeats (Or more) rather than normal 20
What does the CAG repeat in Huntington’s cause pathophysiologically?
Excess glutamine production
- this is neurotoxic
What is predictive genetic testing?
Adults can be tested for their likelihood of the disease, before deciding to have children.
Huntington’s passed on to the next generation will have an earlier onset than that of the last generation. TRUE/FALSE?
TRUE
Having more repeats in the CAG sequence attributes to an earlier onset of Huntington’s. TRUE/FALSE?
TRUE
What genetic testing method is used for Huntington’s?
PCR
primers are directed at CAG sequence to determine how many repeats are present
What spinal muscular atrophy?
progressive loss of anterior horn cells
- Both in spinal cord and brain stem nuclei
How do patients usually present with spinal muscular atrophy and who usually is affected?
Infants normally affected Present with: – hypotonia – proximal muscle weakness – tongue fasiculation (rippling movement)
How is spinal muscular atrophy acquired?
Autosomal Recessive (=> affects males and females equally)
Deficiency of what gene is responsible for Spinal Muscular Atrophy?
SMN1 (on chromosome 5)
SMN1 protein produced by this gene betters survival of the lower motor neurones
Describe how a new drug has been produced in order to lessen the deificiency of SMN1?
SMN2 makes similar mRNA to SMN1 (excpt one exon is missing)
A drug has been made which alters the splicing of the SMN2 mRNA to keep this exon in
=> it functions more similarly to SMN1
How is the new drug for Spinal muscular atrophy delivered?
injected via lumbar puncture into the CSF
What does alzheimers disease cause and who does it usually affect?
Common cause of dementia (50-70% of cases)
Usually occurs in old age
Alzheimer’s disease tends to cluster in families. TRUE/FALSE?
TRUE
What pathological signs are indicative of Alzheimer’s disease?
- Loss of cortical neurones
- Neurofibrillary tangles (intracellular protein)
- Senile plaques (extracellular)
What protein do senile plaques deposit and why is this relevant to Alzheimer’s disease?
amyloid β protein
this is a product of the APP (amyloid precursor protein) gene on Chromosome 21, which is often mutated in Alzheimers
A small percentage of Alzheimer’s disease is inherited autosomal dominantly. TRUE/FALSE?
TRUE
around 5-10%
What particular group are more at risk of Alzheimer’s disease due to over-representation of chromosome 21?
Down Syndrome - Trisomy 21
=> more APP genes to create more amyloid β protein deposits
=> onset is EARLIER (3rd/4th decade)
Other than APP mutations, what genetic mutations can contribute to Alzheimer’s disease?
- Presenilin 1 (chromosome 14)
* Presenilin 2 (chromosome 1)
Old age Alzheimer disease cluster in families usually have what genetic component?
ApoE gene involvement
- if they have e4 variant then the predisposition to alzheimers is higher
First degree relatives of patients with Multiple Sclerosis (MS) are at high risk of developing the condition. TRUE/FALSE?
FALSE - multifactorial disease
Some families do have clusters but relative risk for 1st and 2nd degree relatives is LOW
