T5: Huntington's Disease

Question 1

Describe the symptoms of Huntington’s Disease.

Answer 1

• Movement disorder – chorea involuntary unpredictable movements), dystonia (involuntary muscle contractions), bradykinesia (slow movements), swallowing/ choking, dysarthria (difficulty in speech due to weakened muscles)
• Mood – depression, euphoria, apathy, anxiety, aggression, psychotic symptoms
• Cognition – loss of executive functioning, rigidity of thought, memory loss, dementia

Question 2

What is the genetic basis of Huntington’s Disease?

Answer 2

• AD disorder
• There is complete penetrance - anyone who has the mutation will develop the disease
• HTT gene at 4q16.3
• Normal HTT gene contains within exon 1, a run of CAG trinucleotide repeats
• The HD mutation = expansion of the CAG repeats > 40 triplite repeats
  A few people will develop HD with 36-39 CAG repeats with reduced penetrance alleles. 27-35 repeats = intermediate alleles. This may expand into the next generation and lead to an expansion that causes disease in the next generation.

Question 3

What is the role of glutamine in Huntington’s Disease?

Answer 3

The Normal HTT protein is widely expressed in different tissues, most importantly in the brain, and the function is unknown. In the abnormal protein, there is an increased number of glutamine amino acids. The polyglutamine (PolyQ) expansion - alters protein structure/properties. PolyQ aggregates in cells. Basal ganglia are affected especially caudate nucleus primarily affected.

Question 4

What increases the risk of Myotonic dystrophy?

Answer 4

Maternal inheritance

Question 5

What increases the risk of Fragile X Syndrome?

Answer 5

Maternal inheritance

Question 6

What increases the risk of Huntington’s Disease?

Answer 6

Paternal inheritance

Question 7

What is Juvenile HD?

Answer 7

• Onset under 20 years
• It is rare
• Usually paternally inherited
• Expansions are large - CAG repeat length of 60+
  Symptoms include: bradykinesia, memory decline in school work, decline in social interaction and friends. Other siblings are at risk of HD however this may be an adult onset.

Question 8

What testing is involved in HD?

Answer 8

• Diagnostic gene test (neurology)
• Predictive gene test (clinical genetics)

HD predicative testing is different to conventional medical testing as the patient is well. It is a unique situation of knowing in advance about the future. There is a minimum of 2 different people - genetic counsellors and doctors.

Question 9

What other disease can we use predictive testing?

Answer 9

• BRCA gene (Breast and Ovarian Cancer)
• HNPCC - Hereditary non-polyposis colon cancer
• Myotonic dystrophy

Question 10

What are the prenatal options involved in HD?

Answer 10

1. Have the children - commonest option#
   
   2. Predictive testing in at risk parent and then sampling test pregnancy at 11-12 weeks using CVS. IF positive result it is expected to terminate the pregnancy. We do not do predictive testing in foetuses.
   3. Exclusion Testing - For parents who do not want predictive testing but want to ensure their children are not at risk. It is expected to terminate pregnancies at 50% risk. Using the parent at risk we see whether the foetus has the same genetic make-up and therefore inherited the gene from the grandparents.
   4. Pre-implantation genetic diagnosis - only implanting the embryos without the expansion
   5. Sperm or egg donor
      Adoption