Huntington's

Question 1

HD ages on onset:

Answer 1

§ < 20 years: 10% (juvenile HD)
§ 35-45 years
§ > 55 years: 10%

Question 2

The HD triad of symptoms:

Answer 2

§ Movement disorder
§ Cognitive impairment (e.g. impulsivity)
§ Emotional disturbances

Question 3

HD motor impairments

Answer 3

§ Chorea = χορεία, dance
§ Incoordination: gross motor coordination skills: gait
and postural maintenance deteriorate
§ Motor impersistency: inability to maintain a
voluntary muscle contraction at a constant level
§ Slowed saccadic eye movements

Question 4

HD cognitive symptoms

Answer 4

§ Impairment of executive functions; organising,
planning and checking
§ Adapting alternatives
§ Delay acquisition of new motor skills

Question 5

HD psychiatric symptoms:

Answer 5

§ Depression
§ Suicide
§ Manie
§ Psychosis

Question 6

HD genetics:

Answer 6

1983: localization of HD gene on chromosome 4

Chromosome 4p16.3: linkage analysis of venezualian families led to the localization of the HD gene

Question 7

HD epidemiology:

Answer 7

§ Prevalence: 7-10 : 100.000
§ Incidence: 60 : 100.000
§ Netherlands:
§ 1200-1500 HD patients
§ 6000-9000 persons at risk

Question 8

HD pathology

Answer 8

§ HD gene encodes polyglutamine
(CAG)repeats in the huntingtin (Htt) protein
§ Results in a stretch of polyglutamine (polyQ) residues, translated into a polyQ tract
§ > 36-40 uninterrupted CAG triplet repeats, the gene encodes a mutated form of Htt
- atrophy in the striatum
- cell loss usually involves medium spiny neurons (neurons and enkephalin in the GPe are more affected)

Question 9

DBS in HD

Answer 9

§ Globus Pallidus internus
(GPi)
§ Improvement of motor
function (chorea)
§ No effect on cognitive
functions

Question 10

Animal models of HD

Answer 10

§ Excitotoxic rodent models
§ Quinolinic acid (QA)
§ 3-nitropropionic acid (3-NP)
§ Transgenic rodent models
§ Yeast artificial chromosome (YAC)
§ R6/1, R6-2
Similarities with human HD -
§ Genetic: cDNA fragment: 51 CAG repeats in the HD gene
§ Symptoms: motor and cognitive alterations /
late-onset / slow disease progression
§ Neuropathological changes: striatal cell loss
§ Transgenic rhesus monkey

Question 11

Potential HD treatments:

Answer 11

• DBS in the GPe
• Molecular therapy - RNA modification
  
  • antisense oligonucleotides will reduce htt mRNA levels and reduce the synthesis of the mutant htt protein & prevent cellular damage