Clinical Genetics

Question 1

What are the early symptoms of Huntington’s Chorea?

Answer 1

• Slight, uncontrollable muscular movements
• Stumbling and clumsiness
• Lack of concentration
• Short-term memory lapses
• Depression
• Changes of mood, sometimes including aggressive or antisocial behaviour

Question 2

What are the later symptoms of Huntington’s Chorea?

Answer 2

• Involuntary movements
• Difficulty in speech and swallowing
• Weight loss

as well as emotional changes resulting in:

• Stubbornness
• Frustration
• Mood swings
• Depression

Question 3

What is the pathogenic mechanism of Huntington’s Chorea?

Answer 3

Expansion of a CAG triplet repeat stretch within the Huntingtin gene results in a mutant form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood

Question 4

What is the pattern of inheritance for Huntington’s Chorea?

Answer 4

• Autosomal Dominant
• High penetrance
• Shows anticipation
• Instability is greater in spermatogenesis than oogenesis (maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length)

Question 5

What repeat numbers identify Huntington’s Chorea?

Answer 5

A repeat 36-100+ identifies an individual with Huntington’s Chorea

A repeat number of 6-35 CAG identifies a normal individual

Question 6

What are the penetrance cut offs for Huntington’s Chorea?

Answer 6

40 or more CAG repeats: full penetrance allele - 100%

36 to 39 repeats: incomplete or reduced penetrance allele

• 60% chance of becoming symptomatic by age 65
• 70% chance of becoming symptomatic by age 75

27 to 35 repeats: intermediate allele (IA), or large normal allele.
- It is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.