Neurogenetics Flashcards
What is the mode of inheritance of duchenne muscular dystrophy?
X-linked recessive
What is the progression of duchenne muscular dystrophy?
Delay in motor development
Pelvic and shoulder girdle weakness at 3-4 years
Wheelchair bound by 10-12 years
Death from involvement of resp and cardiac muscles in 20s
What is the characteristic posture in duchenne muscular dystrophy?
Accentuated lumbar lordosis due to weakness in pelvic girdle muscles
What will occur in the legs of boys with DMD?
Calf hypertrophy; no strength gained just hypertrophied
Which protein dysfunction is DMD due to?
Dystrophin
What is the mode of action of dystrophin?
Connects actin filaments to the proteins at the cell membrane
Muscle cells cannot renew themselves and so will degenerate
What mutations result in DMD?
Deletion of dystrophin gene in 70%
Point mutations, small insertions in remaining 30%
How is DMD diagnosed?
Motor developmental delay Gower's sign Toe walking Raised CK EMG Muscle biopsy Molecular genetic testing for deletions
What is the change of inheritance in a boy whose mother is a carrier?
1 in 2
Are all cases of DMD from familiar inheritance?
No - 30% of DMD are de novo mutations
What is the incidence of huntington’s disease?
1 in 20,000
At what age is huntington’s disease most likely to present?
Between 30 and 50
What are the characteristics of huntington’s disease?
Involuntary movements
Dementia
Progression to severe dependence and death over 15-20 years
What is the mode of inheritance in huntington’s disease?
Autosomal dominant
What is different about the inheritance of huntington’s disease?
Age dependent penetrance
Displays genetic anticipation
What are the early clinical signs of huntington’s disease?
Clumsiness Agitation Irritability Apathy Anxiety Disinhibition Delusions Hallucinations Abnormal eye movements Depression
What are the later clinical signs of huntington’s disease?
Dystonia Chorea Trouble with balance and walking Trouble with manual dexterity Slow voluntary movements Difficulty initiating movement Inability to control speed and force of movement Wt loss Speech difficulties Stubbornness
What are the end stage signs of huntington’s disease?
Rigidity Bradykinesia Severe chorea Serious wt loss Inability to walk Inability to speak Swallowing problems Inability to care for oneself
What is the basic pathogenesis of huntington’s disease?
Caudate atrophy
What is the genetic basis of huntington’s disease?
CAG repeats which codes for glutamine - this has a neurotoxic effect
What is the basic pathogenesis of /spinal muscular atrophy?
Progressive loss of anterior horn cells in the spinal cord and brain stem nuclei
What are the signs/symptoms of spinal muscular atrophy?
Hypotonia
Proximal muscle weakness
Tongue fasciculation
What is the inheritance of spinal muscular atrophy?
Autosomal recessive
Which gene is affected in spinal muscular atrophy?
SMN1 which is required for the survival of lower motor neurones
Is there a treatment for spinal muscular atrophy?
Yes - synthetic oligonucleotide
What is alzheimer’s disease?
Common cause of dementia; 50-70% of cases
Occurs in old age
What is the genetic basis of alzheimer’s disease?
Genetic heterogeneity
What is the basic pathology of alzheimer’s disease?
Loss of cortical neurones Neurofibrillary tangles (intracellular) Senile plaques (extracellular)
What are senile plaques?
Extracellular protein deposits containing amyloid beta protein which is a fragment of the product of the amyloid precursor protein gene on chromosome 21
What percentage of alzheimer’s is autosomal dominant?
5-10%
Commonly seen in early onset alzhemiers
Which genes have been identified to cause autosomal dominant alzheimer’s?
APP mutations on chromosome 21
Presenilin 1 on chromosome 14
Presenilin 2 on chromosome 1
Which apoprotein can predispose to alzheimer’s?
ApoE4
What is the genetic basis of MS?
Multifactorial
Mutations in MHC haplotypes which are key regulators in the immune system
