Neurogenetics

Question 1

what is Duchenne muscular dystrophy?

Answer 1

X linked recessive condition causing dystrophin deficiency

results in progressive delay in motor development

Question 2

life span of Duchenne muscular dystrophy?

Answer 2

onset of weakness around 3-4 years in girdles
wheelchair bound by 10-12
death from involvement of resp and carido muscles

Question 3

characteristic appearance of Duchenne muscular dystrophy?

Answer 3

characteristic posture = large lumbar lordosis
calf hypertrophy
gowers sign
toe walking

Question 4

how is DMD diagnosed?

Answer 4

characteristic signs
raised serum CK
electromyography
muscle biopsy
molecular genetic testing (screen for deletions)

Question 5

how are carriers tested for mutations?

Answer 5

identify mutation in affected boy
test for mutation in female relatives
female carriers of known DMD mutations can be offered pre-natal testing

Question 6

what is huntington disease?

Answer 6

autosomal dominant progressive neurological disorder causing involuntary movements, dementia and progression to severe dependency and death over 15-20 years
onset usually 30-50

Question 7

early clinical signs of huntingtons?

Answer 7

clumsiness
agitation
irritability
apathy
anxiety
disinhibition
delusions/hallucinations
abnormal eye movements
depression

Question 8

later clinical signs of huntingtons?

Answer 8

dystonia
involuntary movements
trouble balancing and walking
trouble with activities requiring dexterity
slow involuntary movements
difficulty initiating movement
inability to control speed and force of movement
weight loss
speech difficulty
stubbornness

Question 9

late clinical signs of huntingtons?

Answer 9

rigidity
bradykinesia
severe chorea
serious weight loss
inability to walk
inability to speak
swallowing problems
inability to care for self

Question 10

huntingtons causes atrophy of what?

Answer 10

caudate nucleus

- shows up on imaging

Question 11

what is the molecular genetic defect in Huntingtons?

Answer 11

too many repeats of CAG codon within the huntington gene

normal = up to 35, 36+ = huntington disease

Question 12

what does CAG codon code for?

Answer 12

glutamine

Question 13

huntington shows what type of penetrance?

Answer 13

age dependant

Question 14

how is predictive testing used in huntingtons?

Answer 14

informed consent due to implications of knowing that you have it (work, finances, emotional etc) despite there being no treatment
pre-natal and pre-gestational testing used for carriers who want to have children

Question 15

what is spinal muscular atrophy?

Answer 15

autosomal recessive disorder causing progressive loss of anterior horn cells in spinal cord and brain stem nuclei

Question 16

features of spinal muscular atrophy?

Answer 16

hypotonia
proximal muscle weakness
tongue fasciculation
variable age of onset and rate of progression

Question 17

deficiency of what causes symptoms in SMA?

Answer 17

SMN protein

Question 18

what is SMN protein?

Answer 18

protein made by SMN genes
usually 2 SMN1 genes and 2 SMN2 genes in each cell
spinal muscular atrophy = mutation/deletion of both SMN1 genes
(carrier = mutation/deletion of 1)

Question 19

how is SMN1 deficiency corrected?

Answer 19

altered splicing of mRNA translated from SMN2 gene
binding of synthetic oligonucleotide onto SMN2 mRNA results in retention of exon 7 in SMN2 mRNA
(only difference between SMN1 and SMN2 mRNA is the presence of exon 7, so altered splicing basically makes synthetic SMN1 mRNA and therefore SMN protein)

Question 20

what is Alzheimer disease?

Answer 20

most common cause of dementia
can also cause pre-senile dementia
genetic heterogeneity
shows clustering in some families

Question 21

what is the pathology in alzheimers?

Answer 21

loss of cortical neurones
neurofibrillary tangles (aggregates of hyperphosphorylated tau protein) (intracellular)
senile plaques (extracellular)

Question 22

what are senile plaques?

Answer 22

extra cellular protein deposits containing amyloid Beta protein

Question 23

is there any genetic component to alzheimers?

Answer 23

in some cases
autosomal dominant in 5-10% (generally only in early onset cases)
linked to down syndrome

Question 24

what causes autosomal dominant alzheimers?

Answer 24

APP mutations (chromosome 21)
presenilin 1 (chromosome 14)
presenilin 2 (chromosome 1)

Question 25

what is apolipoprotein E?

Answer 25

protein involved with fat metabolism
associated with Alzheimer disease
polymorphic (has 3 forms resulting from 3 alleles)
- e4 (55% get Alzheimers)
- e3
- e2
only e4 is considered to predispose to Alzheimer disease

Question 26

genetic link in MS?

Answer 26

multifactorial
no real definite link but clustering is seen in families
- higher concordance in monozygotic twins
more common in people with certain MHC haplotypes