Genetics

Question 1

What mode of inheritance is DMD?

Answer 1

X-linked recessive

De novo in 1 in 3 boys

Question 2

How does DMD present?

Answer 2

Delay in motor development, slower to sit and walk

Develop weakness in shoulders and pelvic girdle at the age of 3-4 years old

Question 3

Describe the progression of DMD

Answer 3

Wheelchair by 10/12 years old

Death by 30 due to respiratory/cardiac muscle involvement

Question 4

What type of mutation occurs in DMD?

Answer 4

70% are large scale deletions

30% are point mutations, small insertions or deletions

Question 5

What is the function of dystrophin?

Answer 5

Connects actin to the cell membrane complex and extracellular matrix

Question 6

Where does dystrophin localise to?

Answer 6

Cell membrane

Question 7

What does distrophin disturbance lead to?

Answer 7

Muscle wasting and weakness

Question 8

Name two classic signs of DMD

Answer 8

Gower’s sign and calf hypertrophy

Question 9

What is another disease that causes calf hypertrophy but wasting of proximal muscles?

Answer 9

Becker Muscular Dystrophy - shorter dystrophin but it is still present, later onset and slower progression

Question 10

How is DMD diagnosed?

Answer 10

Raised CK
Molecular genetic testing
EMG
Muscle biopsy

Question 11

What is the mode of inheritance for huntington’s disease?

Answer 11

Autosomal dominant - age dependent penetrance

Question 12

What is the most common age of onset in huntingtons?

Answer 12

Between 30 and 50 years old

Question 13

How does Huntington’s initially present?

Answer 13

Involuntary movements of limbs, trunk, head, face

Dementia

Question 14

How long between onset of symptoms and death?

Answer 14

15-20 years

Question 15

What are the late signs of huntingtons?

Answer 15

Rigidity, bradykinesia, severe chorea, weight loss, inability to speak or walk, swallowing problems, requires care

Question 16

Describe the pathogenesis of Huntington’s disease

Answer 16

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

Question 17

What is the genetic mutation in huntingtons?

Answer 17

CAG repeat expansion leads to a long string of glutamine residue which is toxic to cells in the brain

Question 18

What can be used to measure the CAG repeat expansion and what can this help to predict?

Answer 18

PCR with a primer can measure the expansion, the larger the expansion the younger the onset of symptoms

Question 19

What is the mode of inheritance of spinal muscular atrophy?

Answer 19

Autosomal recessive

SNM1 gene mutations on chromosome 5

Question 20

What happens to the SNM1 gene in spinal muscular atrophy?

Answer 20

Loss of both functioning SNM1 genes

Question 21

If SNM2 is identical why is losing SNM1 a problem?

Answer 21

Splicing is different and SNM2 splicing removes exon 7 which is vital for prevention of neuronal loss

Question 22

Describe the pathogenesis of spinal muscular atrophy

Answer 22

Loss of anterior horn cells and lower motor nuclei leads to loss of function

Question 23

How does spinal muscular atrophy present?

Answer 23

Hypotonia, muscle weakness and wasting of proximal skeletal muscles in addition to respiratory muscles

Question 24

What can prevent future disability due to spinal muscular atrophy?

Answer 24

Treatment from birth

Question 25

What is the commonest cause of dementia?

Answer 25

Alzheimer’s Disease

Question 26

How many people are affected by Alzheimers?

Answer 26

1 in 5 over 80s

Question 27

What is the inheritance of Alzheimers?

Answer 27

Polygenic multifactorial

Question 28

State the name given to early onset alzheimers

Answer 28

Pre-senile dementia

Question 29

Describe the pathology of alzheimers

Answer 29

Loss of cortical neurons, abnormal accumulation of proteins,
Intracellular - neurofibrillary tangles
Extracellular - senile plaques

Question 30

What are senile plaques?

Answer 30

Deposits of protein containing amyloid beta protein

Question 31

What disease prediposes to alzheimers ?

Answer 31

Down Syndrome, onset in 30s/40s

Question 32

How is 10% of Alzheimer’s inherited?

Answer 32

Autosomal dominant

Question 33

Which genes are responsible for the autosomal dominant inheritance pattern?

Answer 33

APP
Presenilin 1
Presenilin 2
Amyloid precursor protein is broken down by gamma-secretase that P1 and P2 are components of

Question 34

What accounts for family clusters of alzeihmers?

Answer 34

ApoE4 gene mutations - the protein transports lipids