Neurogenetics Flashcards
what is Duchenne muscular dystrophy?
X linked recessive condition causing dystrophin deficiency
results in progressive delay in motor development
life span of Duchenne muscular dystrophy?
onset of weakness around 3-4 years in girdles
wheelchair bound by 10-12
death from involvement of resp and carido muscles
characteristic appearance of Duchenne muscular dystrophy?
characteristic posture = large lumbar lordosis
calf hypertrophy
gowers sign
toe walking
how is DMD diagnosed?
characteristic signs raised serum CK electromyography muscle biopsy molecular genetic testing (screen for deletions)
how are carriers tested for mutations?
identify mutation in affected boy
test for mutation in female relatives
female carriers of known DMD mutations can be offered pre-natal testing
what is huntington disease?
autosomal dominant progressive neurological disorder causing involuntary movements, dementia and progression to severe dependency and death over 15-20 years
onset usually 30-50
early clinical signs of huntingtons?
clumsiness agitation irritability apathy anxiety disinhibition delusions/hallucinations abnormal eye movements depression
later clinical signs of huntingtons?
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
late clinical signs of huntingtons?
rigidity bradykinesia severe chorea serious weight loss inability to walk inability to speak swallowing problems inability to care for self
huntingtons causes atrophy of what?
caudate nucleus
- shows up on imaging
what is the molecular genetic defect in Huntingtons?
too many repeats of CAG codon within the huntington gene
normal = up to 35, 36+ = huntington disease
what does CAG codon code for?
glutamine
huntington shows what type of penetrance?
age dependant
how is predictive testing used in huntingtons?
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
what is spinal muscular atrophy?
autosomal recessive disorder causing progressive loss of anterior horn cells in spinal cord and brain stem nuclei
features of spinal muscular atrophy?
hypotonia
proximal muscle weakness
tongue fasciculation
variable age of onset and rate of progression
deficiency of what causes symptoms in SMA?
SMN protein
what is SMN protein?
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)
how is SMN1 deficiency corrected?
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)
what is Alzheimer disease?
most common cause of dementia
can also cause pre-senile dementia
genetic heterogeneity
shows clustering in some families
what is the pathology in alzheimers?
loss of cortical neurones neurofibrillary tangles (aggregates of hyperphosphorylated tau protein) (intracellular) senile plaques (extracellular)
what are senile plaques?
extra cellular protein deposits containing amyloid Beta protein
is there any genetic component to alzheimers?
in some cases
autosomal dominant in 5-10% (generally only in early onset cases)
linked to down syndrome
what causes autosomal dominant alzheimers?
APP mutations (chromosome 21) presenilin 1 (chromosome 14) presenilin 2 (chromosome 1)
what is apolipoprotein E?
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
genetic link in MS?
multifactorial
no real definite link but clustering is seen in families
- higher concordance in monozygotic twins
more common in people with certain MHC haplotypes
