Genetics Flashcards
What mode of inheritance is DMD?
X-linked recessive
De novo in 1 in 3 boys
How does DMD present?
Delay in motor development, slower to sit and walk
Develop weakness in shoulders and pelvic girdle at the age of 3-4 years old
Describe the progression of DMD
Wheelchair by 10/12 years old
Death by 30 due to respiratory/cardiac muscle involvement
What type of mutation occurs in DMD?
70% are large scale deletions
30% are point mutations, small insertions or deletions
What is the function of dystrophin?
Connects actin to the cell membrane complex and extracellular matrix
Where does dystrophin localise to?
Cell membrane
What does distrophin disturbance lead to?
Muscle wasting and weakness
Name two classic signs of DMD
Gower’s sign and calf hypertrophy
What is another disease that causes calf hypertrophy but wasting of proximal muscles?
Becker Muscular Dystrophy - shorter dystrophin but it is still present, later onset and slower progression
How is DMD diagnosed?
Raised CK
Molecular genetic testing
EMG
Muscle biopsy
What is the mode of inheritance for huntington’s disease?
Autosomal dominant - age dependent penetrance
What is the most common age of onset in huntingtons?
Between 30 and 50 years old
How does Huntington’s initially present?
Involuntary movements of limbs, trunk, head, face
Dementia
How long between onset of symptoms and death?
15-20 years
What are the late signs of huntingtons?
Rigidity, bradykinesia, severe chorea, weight loss, inability to speak or walk, swallowing problems, requires care
Describe the pathogenesis of Huntington’s disease
Loss of cells from the basal ganglia specifically caudate nuclei as well as the cerebral cortex leads to flattening of the walls of the lateral ventricles
What is the genetic mutation in huntingtons?
CAG repeat expansion leads to a long string of glutamine residue which is toxic to cells in the brain
What can be used to measure the CAG repeat expansion and what can this help to predict?
PCR with a primer can measure the expansion, the larger the expansion the younger the onset of symptoms
What is the mode of inheritance of spinal muscular atrophy?
Autosomal recessive
SNM1 gene mutations on chromosome 5
What happens to the SNM1 gene in spinal muscular atrophy?
Loss of both functioning SNM1 genes
If SNM2 is identical why is losing SNM1 a problem?
Splicing is different and SNM2 splicing removes exon 7 which is vital for prevention of neuronal loss
Describe the pathogenesis of spinal muscular atrophy
Loss of anterior horn cells and lower motor nuclei leads to loss of function
How does spinal muscular atrophy present?
Hypotonia, muscle weakness and wasting of proximal skeletal muscles in addition to respiratory muscles
What can prevent future disability due to spinal muscular atrophy?
Treatment from birth
What is the commonest cause of dementia?
Alzheimer’s Disease
How many people are affected by Alzheimers?
1 in 5 over 80s
What is the inheritance of Alzheimers?
Polygenic multifactorial
State the name given to early onset alzheimers
Pre-senile dementia
Describe the pathology of alzheimers
Loss of cortical neurons, abnormal accumulation of proteins,
Intracellular - neurofibrillary tangles
Extracellular - senile plaques
What are senile plaques?
Deposits of protein containing amyloid beta protein
What disease prediposes to alzheimers ?
Down Syndrome, onset in 30s/40s
How is 10% of Alzheimer’s inherited?
Autosomal dominant
Which genes are responsible for the autosomal dominant inheritance pattern?
APP
Presenilin 1
Presenilin 2
Amyloid precursor protein is broken down by gamma-secretase that P1 and P2 are components of
What accounts for family clusters of alzeihmers?
ApoE4 gene mutations - the protein transports lipids
