Neurodegenerative Diseases Pt. 3

Question 1

What type of inheritance pattern is associated with Huntington Disease?

Answer 1

Autosomal dominant

Question 2

Describe the onset of motor, cognitive, and behavioral symptoms in Huntington Disease

Answer 2

• Motor symptoms are predominant at the onset of HD in 60% of cases (chorea)
• Cognitive symptoms may occur at or before the onset of motor symptoms (patients become demented as disease progresses)
• Neuropsychiatric symptoms in 98% of patients (10% have attempted suicide)

Question 3

How long does it take for Huntington Disease to reach complete motor disability and dementia?

Answer 3

aproximately 20 years

Question 4

What mutation is associated with Huntington Disease (HD)?

What is the hypothesized mechanism of this gene in contributing to HD?

Answer 4

• Mutation on huntingtin gene on chromosome 4
  
  • Expanded trinucleotide repeat in gene (CAG) causes structural abnormalities in huntingtin protein
• Hypothesized that gene expansion causes a toxic gain of function in huntingtin protein

Question 5

What is Anticipation in terms of HD?

Answer 5

Earlier age of onset in subsequent generations, found when mutated gene passed to offspring from father

Question 6

What microscopic changes to the brain are seen in HD?

Answer 6

• Loss of medium striatal neurons in the caudate and putamen (increased motor output)
• Neuronal loss in cerebral cotex - cognitive changes

Question 7

What gross changes are seen in HD?

Answer 7

• Atrophy of caudate and putamen
• Ventricular enlargement
• Mild to moderate atrophy of gyri

Question 8

How are the following symptoms of Huntington Disease treated?

• Depression
• Delusions and paranoia
• Uncontrolled Movement

Answer 8

• Depression: Fluoxetine
• Delusions and paranoia: Low dose antipsychotics
• Uncontrolled Movement: Tetrabenzine (inhibits Vesicular monoamine transporter)

Question 9

What is the typical age of onset of ALS?

Answer 9

60 years old

Question 10

Is ALS more likely to be sporadic or familial?

Answer 10

Sporadic; only 5-10% of cases are believed to be familial

Question 11

What features of ALS are associated with…

Lower motor neuron degeneration:

Upper motor neuron degeneration :

Answer 11

• Lower motor neuron degeneration:
  
  • Muscular atrophy, weakness, fasciculations (amytrophy) –
  • Degeneration of anterior horn cells/axons
• Upper motor neuron degeneration
  
  • Spastic tone, hyperreflexia, Babinski signs
  • Degeneration of the corticospinal tracts in lateral column of spinal cord (lateral sclerosis)

Question 12

What does bulbar dysfunction cause in ALS?

Answer 12

Dysarthria and dysphagia (involvement of the brainstem motor cranial nerves)

Question 13

What is the mean survival of ALS and cause of death?

Answer 13

Mean survival is 3-5 years and death is from respiratory failure

Question 14

How many geness have been associated with familial ALS?

What type of inheritance pattern does ALS follow?

What is the most common mutation?

Answer 14

14 different genes have been described

Most often - autosomal dominant inheritance

Superoxide dismutase 1 gene (SOD1)

Question 15

What are some potential outcomes of the SOD1 mutation associated with ALS?

Answer 15

• SOD1 mutations:
  
  • Decreased ability to detoxify free radicals
  • Misfolded proteins

Question 16

What changes in the brain are associated with ALS?

Answer 16

• Anterior motor roots of spinal cord are atrophic
• Primary motor cortex (cerebrum) may show atrophy
• Reduced numbers of anterior horn cells
• Loss of corticospinal tract axons and myelin (brainstem motor cranial nerves may be affected)

Question 17

What is the role of Riluzole in treating ALS?

Answer 17

Inhibitor of NMDA channels, inhibits glutamate release; increases uptake

Modest but genuine effects on ALS

Increases lifespan 2-3 months