Huntington Disease

From Iusmgenetics

Contents 1 Huntington Disease 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[edit] Huntington Disease

[edit] General background information

• Ethical issues in genetic counseling include whether or not presymptomatic testing is apparopriate for those with the potential of inheriting Huntington disease.
  • Do / should people want to know their fate?
  • If it doesn't change treatment, why find out?
  • Is the burden of knowing right?

[edit] Mode of inheritance

• Autosomal dominant
• 97% of cases are inherited
• 3% of cases are de novo mutations
  • New mutations are generally paternally derived
• Because of anticipation, there are many ethical issues around presymptomatic testing.
• Genetic counseling is important in Huntington disease.

[edit] Single important gene

• The Huntingtin protein has an unknown function but is known to be the site of repeat expansion that causes Huntington Disease

[edit] Etiology

• Repeat of CAG occurs in the coding region of exon 1, generating a polyglutamine tract.
  • Normal: 10-26 CAG repeats
  • Premutation: 27-35 CAG repeats
  • Reduced penetrance: 36-41 repeats
  • Increasing penetrance: 42+ repeats
  • Adult onset: 40-55 repeats
  • Juvenile onset: >60 repeats

• The glutamine tract causes the protein to accumulate in the nucleus and cytoplasm.
• We call this a gain of negative function at the protein level.
  • Recall that myotonic dystrophy was a gain of negative function at the mRNA level.

[edit] Pathogenesis

• The number of repeats correlates with onset: more repeats -> earlier onset.
  • 40-55 repeats manifest adult onset
  • > 60 repeats manifest juvenile onset
  • Penetrance is high with larger mutant alleles (e.g., >40 repeats)

• Huntington disease demonstrates gender-specific anticipation:
  • Note that this gender-specific anticipation refers to the gender of the parent.
  • 80% of juvenile cases are paternally derived.

• Opposite to myotonic dystrophy and Fragile X sydnrome, Huntington disease demonstrates paternally derived mutations bias.
  • 80% of juvenile cases (repeats > 60) come from the father.
  • This causes a gender-specific anticipation because when the father has HD, anticipation will be accelerated when compared to a similar case in which the mother has the mutant allele.

[edit] Phenotypic information

• Pts survive for 15-18 years after diagnosis
• Huntington disease affects motor, cognitive, behavioral, and psychiatric function.
  • Behavior and psychiatric deterioration occur later in the disease course.
• Motor: involuntary movements (called chorea) that cannot be suppressed voluntarily.
  • 90% of pts
  • Converts to rigidity later in disease
• All aspects of cognition are affected
  • Language is affected later in disease.
• Behavioral disturbances develop later in the course of the disease
  • Aggression, apathy, sexual deviation
• Psychiatric: personality changes, affective psychosis, schizophrenia

[edit] Diagnosis

[edit] Treatment

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers