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

Huntington Disease

General background information

Mode of inheritance

• Autosomal dominant
• 97% of cases are inherited
• Because of anticipation, there are many ethical issues around presymptomatic testing.
• Genetic counseling is important in Huntington disease.

Single important gene

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

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
• 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.

Pathogenesis

• The number of repeats correlates with onset: more repeats -> earlier onset.
  • 40-55 repeats manifest adult onset
  • > 60 repeats manifest juvenile onset

• 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.

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 distrubances develop later in the course of the disease
  • Aggression, apathy, sexual deviation
• Psychiatric: personality changes, affective psychosis, schizophrenia

Diagnosis

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers