Genetics of CNS Disease Flashcards
what type of inheritance is duchennes muscular dystrophy?
x linked recessive in gene which codes for dystrophin
what is the progression of DMD?
onset of weakness = 3-4 yrs (pelvic and shoulder girdles)
wheelchair bound by 10-12 years
death from resp and cardiac muscles in 20s
what is the tell tale signs of DMD?
classic posture
calf hypertrophy
gower’s sign
toe walking
what type of mutation is DMD?
large scale deletions in 70%
point mutations, small insertions and deletion in remaining 30%
what investigations take place in DMD?
raised CK
EMG
muscle biopsy
molecular genetic testing
what is a differential diagnosis of DMD?
autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)
what is huntington disease?
progressive neurodegenerative disorder
what age does HD usually occur?
between 30 and 50
what is progression of HD?
involuntary movements
dementia
progression to severe dependency and death
what pattern of inheritance is HD and what does penetrance depend on?
autosomal dominant
depends on age
what are early clinical signs of HD?
clumsiness agitation / irritability apathy anxiety / depression delusions disinhibition abnormal eye movements
what are the later clinical signs of HD?
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
what does HD classically look like pathologically / on imaging?
caudate atrophy
what is the specific molecular genetic defect in HD?
normal = CAG which codes for glutamine repeated 20 times
HD = repeated 42 times
how is HD diagnosed?
predictive testing using PCR
does any treatment exist for HD?
no, just coping strategies
what is spinal muscular atrophy?
progressive loss of anterior horn cells in spinal cord and brain stem nuclei
what are symptoms of spinal muscular atrophy?
hypotonia
proximal muscle weakness
tongue fasciculation
what age does SMA come on?
variable age and rate of progression (types 0, I, II, III and IV)
what pattern of inheritance is SMA?
autosomal recessive
what gene is affected in SMA?
SNM1
who does SMA more commonly affect?
children (types 0 and I)
how can SMA be treated?
by altering splicing of SMN2 mRNA by a synthetic oligonucleotide (Nusinersin)
what is the most common cause of dementia?
alzheimers
is family clustering seen in pre-senile alzheimers or old age?
both
what is the pathology of alzheimers disease?
loss of cortical neurones
neurofibrillary tangles (intracellular)
senile plaques (extracellular)
what are senile plaques?
extracellular protein deposits containing amyloid B protein
what can be genetic cause of alzheimers?
autosomal dominant trait in 5-10% cases (early onset)
downs syndrome (onset in 3rd or 4th decade)
what genes could be affected in autosomal dominant alzheimers?
APP mutations (chromosome 21)
presenilin 1 (chromosome 14)
presenilin 2 (chromosome 1)
how does ApoE contribute to alzheimers?
e4 predisposes to alzheimers
e4/e4 = 55% affected by 80
e3/e4 = 27% affected by 85
no e4 = 9% affected by 85
what causes multiple sclerosis?
multifactorial with some clustering in families
