Genetics of CNS Disease

Question 1

what type of inheritance is duchennes muscular dystrophy?

Answer 1

x linked recessive in gene which codes for dystrophin

Question 2

what is the progression of DMD?

Answer 2

onset of weakness = 3-4 yrs (pelvic and shoulder girdles)

wheelchair bound by 10-12 years

death from resp and cardiac muscles in 20s

Question 3

what is the tell tale signs of DMD?

Answer 3

classic posture

calf hypertrophy

gower’s sign

toe walking

Question 4

what type of mutation is DMD?

Answer 4

large scale deletions in 70%

point mutations, small insertions and deletion in remaining 30%

Question 5

what investigations take place in DMD?

Answer 5

raised CK
EMG
muscle biopsy
molecular genetic testing

Question 6

what is a differential diagnosis of DMD?

Answer 6

autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)

Question 7

what is huntington disease?

Answer 7

progressive neurodegenerative disorder

Question 8

what age does HD usually occur?

Answer 8

between 30 and 50

Question 9

what is progression of HD?

Answer 9

involuntary movements
dementia
progression to severe dependency and death

Question 10

what pattern of inheritance is HD and what does penetrance depend on?

Answer 10

autosomal dominant

depends on age

Question 11

what are early clinical signs of HD?

Answer 11

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

Question 12

what are the later clinical signs of HD?

Answer 12

dystonia
trouble with balance and dexterity 
slow voluntary movement 
weight loss 
speech difficulties 
bradykinesia 
chorea
inability to walk and speak 
swallowing problems 
inability to care for self

Question 13

what does HD classically look like pathologically / on imaging?

Answer 13

caudate atrophy

Question 14

what is the specific molecular genetic defect in HD?

Answer 14

normal = CAG which codes for glutamine repeated 20 times

HD = repeated 42 times

Question 15

how is HD diagnosed?

Answer 15

predictive testing using PCR

Question 16

does any treatment exist for HD?

Answer 16

no, just coping strategies

Question 17

what is spinal muscular atrophy?

Answer 17

progressive loss of anterior horn cells in spinal cord and brain stem nuclei

Question 18

what are symptoms of spinal muscular atrophy?

Answer 18

hypotonia
proximal muscle weakness
tongue fasciculation

Question 19

what age does SMA come on?

Answer 19

variable age and rate of progression (types 0, I, II, III and IV)

Question 20

what pattern of inheritance is SMA?

Answer 20

autosomal recessive

Question 21

what gene is affected in SMA?

Answer 21

SNM1

Question 22

who does SMA more commonly affect?

Answer 22

children (types 0 and I)

Question 23

how can SMA be treated?

Answer 23

by altering splicing of SMN2 mRNA by a synthetic oligonucleotide (Nusinersin)

Question 24

what is the most common cause of dementia?

Answer 24

alzheimers

Question 25

is family clustering seen in pre-senile alzheimers or old age?

Answer 25

both

Question 26

what is the pathology of alzheimers disease?

Answer 26

loss of cortical neurones

neurofibrillary tangles (intracellular)

senile plaques (extracellular)

Question 27

what are senile plaques?

Answer 27

extracellular protein deposits containing amyloid B protein

Question 28

what can be genetic cause of alzheimers?

Answer 28

autosomal dominant trait in 5-10% cases (early onset)

downs syndrome (onset in 3rd or 4th decade)

Question 29

what genes could be affected in autosomal dominant alzheimers?

Answer 29

APP mutations (chromosome 21)

presenilin 1 (chromosome 14)

presenilin 2 (chromosome 1)

Question 30

how does ApoE contribute to alzheimers?

Answer 30

e4 predisposes to alzheimers

e4/e4 = 55% affected by 80
e3/e4 = 27% affected by 85
no e4 = 9% affected by 85

Question 31

what causes multiple sclerosis?

Answer 31

multifactorial with some clustering in families