L4 - Neurogenetic Disorders

Question 1

Briefly state different modes of inheritance?

Answer 1

1. Autosomal dominant AD
2. Autosomal recessive AR
3. X-Linked recessive (manifesting female carrier)
4. Mitochondrial diseases
5. Triplet repeat diseases (anticipation)

Question 2

What is a triple repeat expansion?

Answer 2

Expansion of a DNA segment that contains a repeat of 3 nucleotides, such as CAGCAGCAG

Question 3

Describe what genetic anticipation is in the context of triple repeat expansion?

Answer 3

• Trinucleotide regions are unstable in meiosis and may expand.
• As gene passed on from parent to offspring, number of triplet repeats may increase.
• In this way the condition may worsen
• or have an earlier onset from generation to generation (anticipation)

Question 4

CAG codes for…

Answer 4

Glutamine

Question 5

Give examples of Poly-Q diseases?

Answer 5

• Huntington’s disease AD

- Inherited cerebellar degeneration (spinocerebellar ataxis)

Question 6

What is spinocerebellar ataxia?

Answer 6

• Group of genetic disorders.

- degenerative changes in part of brain related to movement

Question 7

State some examples of triple repeat disorders?

trinucleotides other than CAG

Answer 7

Most common TRDs = AD

• Fragile X syndrome
• Myotonic muscular dystropy
• Huntington’s disease

Question 8

Briefly describe Fragile X syndrome?

Answer 8

• Moderate mental retardation in males, mild mental retardation in females.
• Increased CGG repeats in FMR1 gene on X-chromosome
• inheritance is X-linked dominant
• males: long face, large ears, prominent jaw, macroorchidism (v. large testes)
• females: milder features

Question 9

Briefly describe Myotonic muscular dystropy? (2)

Answer 9

1. Muscle weakness
2. Myotonia (slow relaxation of muscles after contraction)
   - can affect eyes, heart and brain
   - exhibits variable presentation even within families

Question 10

Briefly describe Huntington’s disease? (3)

Answer 10

1. Chorea (invol movements)
2. Dysarthria (difficult, unclear articulation of speech which is otherwise normal)
3. Dysphagia (swallowing difficulties)
   - associated with increased CAG repeats in HD gene on chromosome 4.

Question 11

What is Friedreich’s Ataxia?

Answer 11

• Autosomal recessive.
• Triplet expansion in nuclear gene with metabolic mitochondrial function.
• Difficulty walking, loss of sensation in arms and legs.
• Patients will often also have form of heart disease known as cardiomyopathy (enlarges and weakens the heart muscle).

Question 12

What is haploinsufficiency?

Answer 12

• Dominant phenotype in diploid organisms

- that are heterozygous for loss of functional allele.

Question 13

What are amyloid precursor proteins?

Answer 13

• Suggested that in brain, aids to direct movement of nerve cells during early development.
• APP, when cut by enzymes forms fragments: sAPP (soluble amyloid precursor protein) and AbP (amyloid beta peptide).
• These may play role in formation of nerve cells in brain, before and after birth.

Question 14

How may anti-sense oligonucleotide treatments work?

Answer 14

• they’re short, single stranded DNA molecules
• that interact with mRNA to prevent translation of a targeted gene.
• leads to degradation of DNA sequences with failure of protein production.

Question 15

What is spinal muscular atrophy?

Answer 15

• Genetic condition that makes muscles weaker.

- Progressive muscle wasting.

Question 16

Give examples of X-Linked recessive?

Answer 16

Neurological examples

• Duchenne muscular dystrophy
• Adrenoleukodystrophy
• Peripheral nerve degeneration

Question 17

What is Adrenoleukodystrophy?

Answer 17

• X-linked.
• progressive neurologic deterioration in boys
• due to demyelination of the cerebral white matter.

Question 18

What is Duchenne muscular dystrophy?

Answer 18

• Genetic disorder characterised by progressive muscle degeneration and weakness.
• Caused by absence of protein dystrophin which keeps muscle cells in tact.

Question 19

What is Charcot-Marie-Tooth disease?

Answer 19

Group of inherited conditions that damage the peripheral nerves. 
Causing:
- muscle weakness 
- awkward gait 
- highly arched / flat feet

Question 20

What is Pes Cavus:

Answer 20

‘concave’ foot

occurs in genetic (peripheral) neuropathies.

Question 21

Give an example of Gower’s sign

Answer 21

• Sign is used to indicate weakness of proximal muscles.

- A child using their hands to push on legs to stand.

Question 22

Describe: Phenylketonuria

Answer 22

• Inborn error of metabolism

- results in decreased metabolism of amino acid: phenylalanine

Question 23

Describe: Zellweger’s disease

symptoms

Answer 23

• Commonly caused by mutations in PEX1 gene.
• Inherited in an autosomal recessive manner.
• Symptoms: poor muscle tone, poor feeding, seizures, hearing loss

Question 24

Describe: Gaucher’s disease

Answer 24

• Genetic disorder where glucocerebroside accumulates in cells and certain organs.
• Most common of the lysosomal storage diseases.

Question 25

Describe: Wilson’s disease

scrubs ‘my princess’ episode ;)

Answer 25

aka Hepatolenticular degeneration.

• Cause’s copper poisoning.
• Liver cannot remove extra copper properly
• this build up in organs such as the brain, liver and eyes.

Question 26

Describe: dopa-responsive dystonia

involves (3)
related to (1)

Answer 26

• Disorder than involves:
  1. involuntary muscle contractions
  2. tremors
  3. other uncontrolled movements.
• related to dopamine metabolism.

Question 27

What are some characteristics of Parkinson’s disease? (3)

Answer 27

1. Bradykinesia (slowness of movement)
2. Limb stiffness (Rigidity)
3. Shaking (tremor)

Question 28

What is Park 1, 2,3 known as?

Answer 28

Genetic loci for conditions identified by linkage studies.

e.g. many genetic diseases cause dystonia (rigidity and spasm). BUT several familial monogenetic cases mimic clinical and micrscopic characteristics of Parkinsons disease.

Question 29

Describe Myasthenia Gravis?

Answer 29

• Antibodies block receptors for ACh at neuromuscular junction.
• Muscle prevented from contracting.
• Antibodies to other proteins such as Muscle-specific kinase MuSK protein can also lead to impaired transmission at neuromuscular junction.

Question 30

Define: Channelopathies

Answer 30

Membrane channel function may be affeted by gene mutations of autoantibodies in immune disorders.