Neurogenetics

Question 1

Epidemiology of Duchennes Muscular Dystrophy

Answer 1

X Linked Recessive
1/3000 boys
1/3 affected have a new mutation

Question 2

What are the general disease milestones for a child with duchenes muscular dystrophy

Answer 2

Hip and Shoulder girdle weakness - 3/4 years
Wheelchair bound - 10-12 years
Death in 20’s

Question 3

What are the common causes of death in a child with duchennes muscular dystrophy?

Answer 3

Respiratory and Cardiac muscles are affected so respiratory or cardiac failure.

Question 4

What gene is affected in Duchennes?

Answer 4

Dystrophin gene located on the X chromosome which encodes for the dystrophin protein.

Question 5

What are some clinical signs off Duchennes?

Answer 5

Tip toe walking
Lumbar lordosis
Calf hypertrophy
Gowers sign

Question 6

What is gowers sign

Answer 6

When getting up from lying down. The child shimmies his hands along the floor to his feet then uses his hand to push off of his legs like an old man in order to straighten up.
Think Jungle Book

Question 7

What is used to diagnose Duchennes?

Answer 7

Raised Serum Creatine Kinase - Not very specific
Eclectromyography
Muscle Biopsy
Molecular Genetic Testing

Question 8

What would be seen on muscle biopsy in Duchennes?

Answer 8

Small irregular muscle cells with no staining for dystrophin.

Question 9

Describe the types of mutations present in Duchennes?

Answer 9

70% are large scale deletion

30% are point mutations either small insertions or deletions

Question 10

LIst a rare differential diagnosis for Duchennes.

Answer 10

Autosomal Recessive Limb Girdle Muscular dystrophies.

Question 11

If a female presents with duchennes like symptoms what is it likely to be?

Answer 11

Autosomal Recessive Limb Girdle Muscular dystrophies.

Question 12

A mutation in what protein is likely to cause an Autosomal Recessive Limb Girdle Muscular dystrophy.

Answer 12

Sarcoglycan - protein in the same complex as dystrophin.

Question 13

When is carrier testing used in Duchennes muscular dystrophy?

Answer 13

In the female relatives of an affected male.

Can be offered prenatal testing.

Question 14

Epidemiology of Huntington’s Disease

Answer 14

Autosomal Dominant trait with an age dependant penetrance
1/10,000 affected
1:1 M:F

Question 15

What age range does Huntington’s present

Answer 15

30-50 years

Question 16

From onset of symptoms what is Huntington’s prognosis?

Answer 16

15-20 years

Question 17

What is the clinical presentation of someone with Huntington’s ?

Answer 17

Rigidity 
Bradykinesia (difficulty initiating/continuing movement)
Severe Chorea ( Uncontrolled movement)
Serious Weight loss
Inability to walk or speak
Swallowing problems - choking

Question 18

What does the brain of someone with Huntington’s look like?

Answer 18

Caudate Atrophy
Loss of cells from basal ganglia and cerebral cortex
Flattened convex curve of the basal ganglia.

Question 19

What is the genetic defect in HD?

Answer 19

CAG repeats over >40
CAG codes for Glutamate
Glutamine residues are toxic to cells in brain

Question 20

What genetic tests can someone undergo for HD?

Answer 20

Pre natal or gestational testing.

Question 21

What needs to be considered around testing for HD?

Answer 21

Fully inform the patient that a positive test will limit their insurance finances and what they can do for work despite being physically fine for years.
No licensed treatment so diagnosis doesn’t make a difference.
Living with the knowledge has severe impact on mental health.

Question 22

Spinal Muscular Atrophy Epidemiology.

Answer 22

1 in 50 Carriers
1 in 1000 incidence
Autosomal Recessive

Question 23

Clinical signs of someone with Spinal Muscular Atrophy

Answer 23

Proximal skeletal and respiratory muscle weakness.

Question 24

What is the pathology behind spinal Muscular Atrophy?

Answer 24

Loss of the anterior horn due to SMN1 deficiency

Loss of Exon 7 on the SMN1 gene.

Question 25

What is a treatment used from birth to prevent or delay the progression of Spinal Muscular Atrophy?

Answer 25

Addition of Exon 7 from SMN1 gene onto the SMN2 gene.

Question 26

Genetic links in Alzhiemers.

Answer 26

5-10% of cases are autosomal dominant
Presenilin 2
Presenilin 1
APP mutation (Linked to Down syndrome)

Question 27

Which variant of ApoE is linked to longevity?

Answer 27

e2

Question 28

Which variant of ApoE is linked to clusters of Alzhiemers in families?

Answer 28

e4