Neurogenetics

Question 1

What is the inheritance pattern of Duchenne muscular dystrophy?

Answer 1

X-linked recessive

Question 2

What is the presentation of Duchenne Muscular Dystrophy?

Answer 2

Delay in motor development Onset of weakness - 3-4 years Wheelchair bound by 10-12 years Death from involvement of respiratory and cardiac muscles in 20s

Question 3

What are some characteristic features of DMD?

Answer 3

Calf hypertrophy

Gowers sign

Toe walking

Question 4

What causes DMD?

Answer 4

Genetic abnormalities of the dystrophin gene

• large scale deletion in 70%
• point mutations, small insertion and deletion in remaining 30%

Question 5

How is DMD diagnosed?

Answer 5

• raised serum creatine kinase (CK)
• electromyography (EMG)
• muscle biopsy
• molecular genetic testing

> screen for deletions

Question 6

What is the differential diagnosis of DMD?

Answer 6

Autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)

Question 7

DMD is caused by de novo mutations in what proportion of boys?

Answer 7

1/3

Question 8

Describe carrier testing for DMD?

Answer 8

mutation testing

• identify mutation in affected boy
• test for mutation in female relatives wishing to know carrier status
• female carriers of known dystrophin mutations can be offered pre-natal testing

Question 9

What is the incidence of DMD and huntingtons?

Answer 9

DMD: 1/3000 males

Huntingtons disease: 1/20,000

Question 10

What is the presentation of huntingtons disease?

Answer 10

• onset usually between 30 and 50 years
• involuntary movements
• dementia
• progression to severe dependency and death over 15-20 years

Question 11

What is the inheritance pattern of huntingons disease?

Answer 11

Autosomal dominant trait

Age dependant penetrance

Question 12

What are the early clinical signs of huntingtons disease?

Answer 12

• clumsiness
• agitation
• irritability
• apathy
• anxiety
• disinhibition
• delusions
• hallucinations
• abnormal eye movements
• depression

Question 13

What are the later clinical signs of huntingtons disease?

Answer 13

• dystonia
• involuntary movements
• trouble with balance and walking
• trouble with activities that require manual dexterity
• slow voluntary movments
• difficult initiating movement
• inability to control speed and force of movement
• weight loss
• speech difficulties
• stubbornness

Question 14

What are the late clinical signs of huntingtons disease?

Answer 14

• ridigity
• bradykinesia
• severe chorea
• serious weight loss
• inability to walk
• inability to speak
• swallowing problems
• inability to care for onself

Question 15

What is the molecular defect in the huntington gene?

Answer 15

CAG repeats

Question 16

What testing can be offered to pregnant women for huntingtons disease?

Answer 16

Pre-natal testing

Pre-gestational testing

Question 17

What is spinal muscular atrophy?

Answer 17

Progressive loss of anterior horn cells in spinal cord and brainstem nuclei

Question 18

What is the presentation of SMA?

Answer 18

• hypotonia
• proximal muscle weakness
• tongue fasciculaiton

Question 19

What are the types of SMA?

What is the inheritance pattern of SMA?

Answer 19

• 0, I, II, III, IV
• autosomal recessive

Question 20

What causes SMA?

Answer 20

SMN1 deficiency

Question 21

How can SMA be treated?

Answer 21

BY synthetic oligonucleotide (nusinersin)

Binding of synthetic oligonucleotide results in retention of exon 7 in SMN2 mRNA

Question 22

What causes 50-70% of cases of dementia?

Answer 22

Alzheimers disease

Question 23

Describe the pathology of alzheimers disease?

Answer 23

• loss of cortical neurones
• neurofibrillary tangles (intracellular)
• senile plaques (Extracellular)

Question 24

What are senile plaques?

Answer 24

Extracellular protein deposits containing amyloid B protein

Question 25

Amyloid B protein is a fragment of which gene?

Answer 25

the APP (amyloid precursor protein) gene (chromosome 21)

Question 26

Describe the genetic aetiology of alzheimers disease

Answer 26

An autosomal dominant trait in 5-10% of cases (early onset) Down syndrome (trisomy 21) (onset in 3rd or 4th decade)

Question 27

What causes autosomal dominant alzheimers disease?

Answer 27

- APP mutations (chromosome 21) - Presenilin 1 (chromosome 14) - presenilin 2 (chromosome 1)

Question 28

e4 allele confers what prognosis?

Answer 28

Predisposes to alzheimers disease with some clustering in families

Question 29

e2 allele confers what prognosis?

Answer 29

Associated with longevity

Question 30

e4/e4 genotype means \_\_% are affected by alzheimers at 80 years

Answer 30

e4/e4 genotype means 55% are affected by alzheimers 80 years

Question 31

e3/e4 genotype means \_\_% are affected by alzheimers at 85 years

Answer 31

e3/e4 genotype means 27% are affected by alzheimers at 85 years

Question 32

no e4 genotype means \_% are affected by alzheimers at 85 years

Answer 32

no e4 genotype means 9% are affected by alzheimers at 85 years

Question 33

Alzheimers disease is \_\_\_\_\_genous with rare ______ \_\_\_\_\_\_ forms and common _______ forms

Answer 33

Alzheimers disease is heterogenous with rare autosomal dominant forms and common multifactorial forms

Question 34

Multiple scleosis is ______ with some clustering in families

Answer 34

Multiple scleosis is multifactorial with some clustering in families

Question 35

Multiple sclerosis risk is; \_% in first degree relatives \_% in second degree relatives \_% population risk

Answer 35

Multiple sclerosis risk is; 3% in first degree relatives 1% in second degree relatives 0.2% population risk

Question 36

MS is more common in individuals with certain ___ haplotypes

Answer 36

MS is more common in individuals with certain MHC haplotypes