Huntington's Disease (HD)

Primer

Huntington's Disease (HD) is a hereditary, neurodegenerative illness characterized by a triad of symptoms including motor disturbance, cognitive impairment, and psychiatric symptoms. It is an autosomal dominant disorder caused by an expanded trinucleotide repeat (CAG) mutation in the coding region of the huntingtin gene on chromosome 4.

Epidemiology
  • The worldwide prevalence is estimated to be 2.7 per 100,000 individuals.
  • The prevalence in North America, Europe, and Australia is 5.7 per 100,000 individuals.
    • It is much lower in Asia, at 0.40 per 100,000 individuals.
Prognosis
  • The average age at diagnosis of Huntington's disease is approximately 40 years, although this varies widely.
  • Age at onset is inversely correlated with CAG expansion length.
Comorbidity
  • Major depressive disorder is highly comorbid and considered a prodrome of the disease.
Risk Factors
  • A family history of Huntington's disease is the highest risk factor, and associated with the length of the CAG trinucleotide repeat expansion.

Prodrome

  • Psychiatric and cognitive abnormalities can predate the motor abnormality by at least 15 years.
  • Initial symptoms requiring care often include irritability, anxiety, or depressed mood.
    • In fact, depression is considered to be the first neuropsychiatric symptom of Huntington's disease.[1]
  • Other behavioural disturbances may include pronounced apathy, disinhibition, impulsivity, and impaired insight, with apathy often becoming more progressive over time.

Diagnosis

Huntington's disease is diagnosed when there are unequivocal extrapyramidal motor abnormalities in an individual with either a family history of Huntington's disease, or if there is genetic testing showing a CAG trinucleotide repeat expansion in the huntingtin (HIT) gene, located on chromosome 4.

Major or Mild Neurocognitive Disorder Due to Huntington’s Disease

Criterion A

The criteria are met for major or mild neurocognitive disorder.

Criterion B

There is insidious onset and gradual progression.

Criterion C

There is clinically established Huntington’s disease, or risk for Huntington’s disease based on family history or genetic testing.

Criterion D

The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder.

Signs and Symptoms

Psychiatric

There are four main clusters of psychiatric symptoms:

  1. Depression and anxiety (including low mood, suicidal ideation)
  2. Drive and executive function impairment (perseveration, compulsions, apathy)
  3. Irritability and aggression
  4. Psychosis (delusions and hallucinations)

Apathy is one of the most prevalent behavioural symptoms, occurring in close to 70% of symptomatic cases.[2] Progressive cognitive impairment is a core feature of Huntington's. There are early changes in executive function (i.e. - processing speed, organization, and planning) rather than learning and memory.

Neurologic

  • Cognitive and associated behavioural changes often precede the emergence of the motor abnormalities. Chorea, dystonia, bradykinesia, and oculomotor dysfunction can all occur.

Pathophysiology

  • Autosomal dominant trinucleotide (CAG)n repeat expansion in the huntingtin (HTT) gene on chromosome 4
  • The pathophysiology and neurochemical basis of Huntington's are poorly understood. Dopamine and glutamate transmission is hypothesized to be affected, leading to striatal and cortical changes resulting in motor dysfunction such as chorea.
    • Increased dopamine, decreased GABA, and decreased acetylcholine in brain
    • Neuronal death via NMDA receptor binding and glutamate excitotoxicity
  • On pathology there is atrophy of caudate and putamen with ex vacuo ventriculomegaly

Investigations

Neuroimaging

  • The caudate nucleus in Huntington's Disease is dramatically affected prior to symptom onset.[3]
  • A classic neuroimaging finding to aid with the diagnosis of HD is caudate nucleus atrophy and enlargement of the frontal horns of the lateral ventricles.[4][5]

Treatment

Motor

  • Chorea is one of the core symptoms of Huntington's, and when there is significant motor dysfunction, this needs to be treated., since untreated chorea can cause weight loss and increase falls risk.
  • Tetrabenazine (up to 100 mg/day), amantadine (300 to 400 mg/day), or riluzole (200 mg/day) can be prescribed.
    • Adverse effects such as depression, suicidality, parkinsonism (with tetrabenazine), and elevated liver enzymes (with riluzole) should be monitored for.

Psychiatric

  • Comorbid mood, anxiety, and psychotic symptoms can be treated with antidepressants and antipsychotics (preferably second generation).
    • Risperidone in particular has been well studied and can improve both psychiatric functioning and motor stabilization.[6]
  • As needed use of benzodiazepines may also be helpful.

Resources

For Patients

For Providers

Articles
Research

References

1) American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
2) Krishnamoorthy, A., & Craufurd, D. (2011). Treatment of apathy in Huntington’s disease and other movement disorders. Current treatment options in neurology, 13(5), 508.
3) The caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal Huntington’s disease brain
4) Kassubek, J., Juengling, F. D., Kioschies, T., Henkel, K., Karitzky, J., Kramer, B., ... & Landwehrmeyer, G. B. (2004). Topography of cerebral atrophy in early Huntington’s disease: a voxel based morphometric MRI study. Journal of Neurology, Neurosurgery & Psychiatry, 75(2), 213-220.
5) Hobbs, N. Z., Barnes, J., Frost, C., Henley, S. M. D., Wild, E. J., Macdonald, K., ... & Tabrizi, S. J. (2010). Onset and progression of pathologic atrophy in Huntington disease: a longitudinal MR imaging study. American journal of neuroradiology, 31(6), 1036-1041.
6) Duff, K., Beglinger, L. J., O'Rourke, M. E., Nopoulos, P., Paulson, H. L., & Paulsen, J. S. (2008). Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington's disease. Annals of Clinical Psychiatry, 20(1), 1-3.