Huntington Disease

Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Psychiatric and cognitive features are also characteristic, and patients with HD are at an increased risk for suicide throughout the course of the disease. The diagnosis is primarily clinical, often with a positive family history followed by genetic confirmation. Management by an interdisciplinary team is supportive, with the goal of maintaining quality of life. Treatment of depression, agitation, and psychosis is the 1st priority for patients with Huntington disease over the treatment of chorea.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Huntington disease (HD) is an inherited and progressive neurodegenerative disorder that causes a choreiform movement disorder, unsteady gait, and depression.

Epidemiology

  • Age of onset is between 20 and 50 years, with an average of 40 years.
  • Worldwide prevalence is 2.7 cases per 100,000 people.
    • Higher in Europe: 5.7/100,000
    • Lower in Asia: 0.4/100,000
  • No gender predominance
  • Affects all races and ethnic groups
  • Juvenile HD can present before age 20.
  • Tendency for paternal transmission: 70%–88% of children with juvenile HD inherit the gene from their father.

Etiology

Huntington disease is caused by an autosomal dominant genetic alteration in the huntingtin gene (HTT) present on chromosome 4p.

  • Every child of a parent with HD has a 50/50 chance of inheriting the expanded gene.
  • Expansion of the cytosine-adenine-guanine (CAG) repeat number over successive generations → HD presents earlier and becomes more severe

Pathophysiology

HD is caused by CAG trinucleotide repeats in the HTT gene. 

Normal physiology 

  • In the basal ganglia: Equilibrium is maintained between direct and indirect pathways to facilitate normal motor movements.
    • Direct pathway: dopamine → excitatory connections with the thalamic neurons → activate the motor cortex → facilitates movement
    • Indirect pathway: dopamine → inhibitory effect → inhibits thalamic neurons → inhibits motor cortex → inhibits movement
  • In the striatum: degeneration → loss of GABAergic neurons → imbalance between dopamine and GABA → abnormal movements

Pathophysiology

  • The huntingtin protein is physiologically expressed throughout the body tissues and brain; its function remains unexplained. Pathophysiology in HD is limited to the CNS.
  • CAG triplet repeats on chromosome 4—normally encode the protein huntingtin
    • Normal CAG repeats are 27 or less in the HTT gene.
    • The threshold for developing HD is 36 repeats.
    • The length of the CAG repeats correlates with the severity of the disease symptoms.
  • Mechanism of anticipation is unique to HD: increases in the number of repeats → earlier age of onset in subsequent generations → increased severity of disease
  • Toxic gain-of-function mechanism:
    • The mutant form of the protein gains a deleterious function, which leads to clinical HD.
    • Abnormal HTT protein fragments undergo misfolding and aggregation.
      • Fibrillar aggregates → form neuronal inclusion bodies 
      • Neurodegeneration → begins in caudate, putamen of basal ganglia, and cortex → eventually involves the whole brain → neuronal death
  • Heightened susceptibility in the striatum to the abnormal protein causes symptoms of abnormal movements.
Huntington disease genetics

Cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin gene (HTT) resulting in Huntington disease

Image: “Huntington’s disease patient” by National Institute of Standards and Technology. License: Public Domain

Clinical Presentation and Diagnosis

Huntington disease affects generations of family members and typically spans several decades. The symptoms can be motor, cognitive, and behavioral.

Clinical presentation

  • Motor manifestations:
    • Huntington’s chorea = the cardinal feature of HD
      • Abrupt, involuntary, “dance-like” movements involving the face, trunk, and extremities
      • Later involves diaphragm, larynx, and pharynx → dysphagia and dysarthria
    • Athetosis: involuntary writhing movements involving hands, fingers
    • Signs on physical exam:
      • Nystagmus
      • Reduction in velocity of saccadic eye movements
      • Hyperreflexia
      • Rigidity
      • Dystonia
      • Tics
  • Cognitive/behavioral symptoms: present early in the course of the illness 
    • Memory deficits
    • Diminished decision-making ability
    • Affective disturbances
      • Personality changes
      • Irritability
    • Mood disturbances
      • Depression is common.
      • Suicidal ideation is a major concern.
    • Dementia/psychosis
    • Aggression/impulsivity
    • Apathy
  • Atypical neurologic symptoms:
    • Seizures
    • Ataxic gait
    • Dystonia
    • Parkinsonism
  • Other symptoms:
    • Weight loss
    • Cachexia
  • Juvenile-onset HD
    • Minimal or no chorea
    • May have myoclonus and seizures
    • Children have a more rapidly progressive disease.

Diagnosis

  • Based on clinical history and pattern of movement disorders exhibited by the patient 
  • Family history: highly significant in diagnosing HD
  • Genetic testing:
    • > 36 CAG repeats in genetic testing of the HTT gene confirm the diagnosis.
    • 99% sensitive and 100% specific for HD
    • Indicated for symptomatic patients with or without a positive family history
  • Imaging with MRI/CT scan:
    • Caudate atrophy correlates with changes in cognitive function.
    • Hydrocephalus ex vacuo = compensatory enlargement of the lateral ventricles

Progression

  • Slow and continual deterioration:
    • Early stage:
      • Patients are generally functional and independent.
      • Able to drive
    • Middle stage: 
      • Lose the ability to work, drive, or manage their own finances
      • Most patients need help with activities of daily living.
      • Impairments in balance and walking → falls
    • Late stage: 
      • Can last a decade or more
      • Severe loss of motor and cognitive function
      • Patients require 24-hour care.
  • Average length of survival is 10–20 years from the onset of HD but may be longer.

Management

Management of HD includes medical and psychological support to manage symptoms and maintain quality of life. Treatment of depression, agitation, and psychosis is the 1st priority for patients with HD over the treatment of chorea.

Treatment

  • Multidisciplinary approach:
    • Neurology
    • Psychiatry
    • Other supportive care
      • Social work
      • Physical therapy (PT)
      • Occupational therapy
    • Driving restrictions with cognitive impairment 
  • Medications for chorea/hyperkinetic movements in patients without depression:
    • Vesicular monoamine transporter 2 (VMAT2) inhibitors:
      • Tetrabenazine or deutetrabenazine
      • The precise mechanism is unknown but believed to be related to its effect as a reversible depletor of monoamines (e.g., dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.
      • Can increase the risk of depression and suicidal thoughts and behavior in patients with HD
      • Must balance the risks of depression and suicidality with the clinical need for control of chorea
    • 2nd-generation antipsychotics: risperidone, olanzapine, and aripiprazole
      • If VMAT2 inhibitors fail to control symptoms
      • Block dopamine transmission
    • 1st-generation antipsychotics if severe symptoms
      • Haloperidol
      • Chlorpromazine
    • Benzodiazepines for short-term control of chorea
  • Treat concomitant depression: Up to 25% of patients with HD attempt suicide.
    • Selective serotonin reuptake inhibitors (SSRIs)
    • Tricyclic antidepressants
    • 2nd-generation antipsychotics for psychosis or severe behavioral symptoms
  • Medications for dystonia:
    • Benzodiazepines
    • Baclofen
    • Botulinum toxin for focal dystonia
  • Disease-modifying treatment is not yet available, but pharmacologic and genetic approaches are being studied.
  • Advance care planning 
    • Palliative care 
    • Hospice

Complications

  • Pain 
    • May develop contractures or musculoskeletal injuries
    • Simple analgesics may be helpful.
    • Low-dose opioids in late-stage HD
  • Constipation
  • Urinary retention
  • Pressure sores
  • For severe dysphagia → palliative care
  • Causes of death are related to the motor impairments seen with HD:
    • Pneumonia (85% due to aspiration)
    • Dysphagia

Differential Diagnosis

  • Tourette syndrome (TS): a severe form of tic disorder in children ages 2 to 15, involving both motor and vocal tics. Although there is no definite cause of TS, the condition has genetic and environmental factors that contribute to disease development. The disease is clinically diagnosed. Treatment involves behavioral therapy, antipsychotics, and treatment of comorbid conditions.
  • Sydenham chorea: a movement disorder that can be seen with rheumatic fever several weeks to months after a Group A streptococcus (GAS) infection. The disorder manifests clinically with rapid, irregular, and involuntary movements (chorea), as well as neuropsychiatric symptoms. Diagnosis is made clinically. The management includes antibiotics, symptomatic treatment with antipsychotic and anticonvulsant medications, and possibly steroids.
  • Drug-induced movement disorders: include tardive dyskinesia, a serious side effect of 1st-generation antipsychotics or metoclopramide, which can last for up to a month after discontinuing the causative agent; and dystonia, seen following treatment with an antihistamine or anticholinergic. Frequent early monitoring is necessary for patients taking these medications. The symptoms include smacking of the lips, twisting of the tongue, speech problems, headache, and seizures. Diagnosis is clinical, and management includes avoiding future use of the causative agent. Treatment with a VMAT2 inhibitor, such as deutetrabenazine or valbenazine, may be helpful. 
  • Wilson disease (WD): can manifest with unexplained dystonia, tremor, chorea, or other neurologic symptoms, and this diagnosis should be considered in younger patients with no known family history of HD. Patients often present in adolescence or young adulthood (though WD can be diagnosed later in life as well) with a combination of elevated liver function tests and neurologic and psychiatric symptoms. Diagnosis is by clinical features and lab testing for liver abnormalities, anemia, and copper overload. Treatment is with lifelong therapy to remove excess copper with a chelating agent and maintain proper copper balance.
  • Schizophrenia: a serious psychiatric disorder characterized by relapsing episodes of psychosis. The disorder is due to alterations in the level of dopamine in different neural circuits of the brain. Symptoms include hallucinations (mainly auditory) and delusions. Schizophrenia causes social impairment due to disorganized speech and behavior. Antipsychotics and CBT are treatments of choice.

References

  1. Ghosh, R, & Tabrizi, SJ. (2018). Huntington disease. Handbook of Clinical Neurology, 147, 255– 278. https://doi.org/10.1016/B978-0-444-63233-3.00017-8
  2. Suchowersky, O. (2021).Huntington disease: Management. UpToDate. Retrieved June 23, 2021, from https://www.uptodate.com/contents/huntington-disease-management
  3. Ha, A. (2021). Huntington Disease and Other Genetic Causes of Choreas. DeckerMed Medicine. Retrieved July 31, 2021. https://doi.org/10.1016/j.ncl.2009.04.001
  4. Suchowersky, O. (2021). Huntington disease: Clinical features and diagnosis. UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/huntington-disease-management
  5. Zoghbi, HY, & Orr, HT. (2020). Huntington disease: Genetics and pathogenesis. UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/huntington-disease-genetics-and-pathogenesis

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details