Huntington's Disease

 

• Background

  Pathophysiology and genetics

  • Autosomal dominant CAG triplet repeat in Huntingtin gene (HTT) on chromosome 4 → expanded polygluatmine tail on Huntingtin protein (Htt) → cleavage and generation of toxic fragments with many effects, including mitochondrial toxicity, especially in the striatum. Other areas, such as the cerebellum and frontal lobe, may also be affected.
  • Demonstrates genetic anticipation: each successive generation may have more repeats and hence earlier onset.

  Epidemiology

  • UK prevalence: 1/10,000.
  • Onset usually 35-50 years old.

  Juvenile Huntington's

  • Onset <21 years old.
  • 10% of cases
  • Genetics: paternal inheritance.
  • Presents with rigidity, and may not have chorea.

• Signs and symptoms

  Motor:

  • Chorea: irregular, spontaneous movements. Ranges from hand twitches to gait problems. May include 'motor impersistence', an inability to maintain posture e.g. involuntarily release when squeezing something ('milkmaid's grip').
  • Bradykinesia and rigidity.
  • Dysarthria and dysphagia.
  • Generalised tonic-clonic seizures.

  Psychiatric:

  • Depression (25%).
  • Psychosis, including mania (10%).
  • Behavioural disorders including apathy, irritability, impulsivity and disinhibition.
  • May appear long before other symptoms, up to 15 years.

  Later features:

  • Dementia
  • Weight loss (very late).

• DDx: Chorea

  • Huntington's
  • Benign familial chorea.
  • Neuroacanthosis
  • Wilson's
  • Parkinsonism
  • Levodopa
  • Encephalitis
  • Rheumatic fever (Sydenham chorea).

• Investigations

  Genetic testing can be before or after symptom onset, or even prenatal:

  • ≥40 CAG repeats in either HTT allele is +ve. 36-39 is intermediate. >60 CAG repeats in Juvenile Huntington's.
  • Known as predictive testing if pre-symptomatic. Good to have several consultations first so they can think over consequences including who to share it with.
  • Prenatal testing: CVS or amniocentesis is required for a definite answer. Alternatively, if the parent doesn't want to know their status, use linked markers (related polymorphisms) which can rule it out or say "they have the same risk as you". Preimplantation testing is becoming available.

  CT/MRI head may show:

  • Caudate, striatal, or frontal atrophy.
  • Dilated lateral ventricles.

• Management

  Supportive treatment:

  • Counselling and support for patient and family.
  • Manage psychiatric features e.g. SSRIs, ECT, antipsychotics, CBT.
  • Chorea: tetrabenazine, benzodiazepines, or antipsychotics.
  • Bradykinesia and rigidity: dopamine agonists, levodopa.

• Complications and prognosis

  Complications:

  • Choking and aspiration.
  • Accidents and falls.
  • ↓Self-care and child protection issues.

  Average of 20 years from diagnosis to death.