Huntington disease

Synonyms

3

Overview

Huntington disease (HD) is an inherited condition that causes progressive degeneration of neurons in the brain. Signs and symptoms usually develop between ages 35 to 44 years and may include uncontrolled movements, loss of intellectual abilities, and various emotional and psychiatric problems. People with HD usually live for about 15 to 20 years after the condition begins. It is caused by mutations in the HTT gene and is inherited in an autosomal dominant manner. Treatment is based on the symptoms present in each person and may include various medications.

There is also a less common, early-onset form of HD which begins in childhood or adolescence called juvenile Huntington disease.

Symptoms

Huntington disease (HD) is a progressive disorder that causes motor, cognitive, and psychiatric disorders. On average, most people begin developing features of HD between ages 35 and 44. Signs and symptoms vary by stage and may include:

Early stage:

  • Behavioral disturbances
  • Clumsiness
  • Moodiness
  • Irritability
  • Paranoia
  • Apathy
  • Anxiety
  • Hallucinations 
  • Abnormal eye movements
  • Depression
  • Impaired ability to detect odors

Middle stage:

  • Dystonia (movement disorder that causes involuntary contractions of muscles)
  • Involuntary movements
  • Trouble with balance and walking
  • Chorea with twisting and writhing motions (abnormal involuntary movement disorder)
  • Unsteady gait (style of walking)
  • Slow reaction time
  • General weakness
  • Weight loss
  • Speech difficulties
  • Stubbornness

Late stage:

  • Rigidity (continual tension of the muscles)
  • Bradykinesia (difficulty initiating and continuing movements) 
  • Severe chorea
  • Serious weight loss
  • Inability to speak
  • Inability to walk
  • Swallowing problems
  • Inability to care for oneself

Causes

Huntington disease (HD) is caused by a mutation in the HTT gene. This gene gives instructions for making a protein called huntingtin. The exact function of this protein is unclear, but it appears to be important to nerve cells (neurons) in the brain.

The HTT gene mutation that causes HD involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of three DNA building blocks that repeat multiple times in a row. The CAG segment in a normal HTT gene repeats about 10 to 35 times. In people with HD, it may repeat from 36 to over 120 times. People with 36 to 39 CAG repeats (an intermediate size) may or may not develop HD, while people with 40 or more repeats almost always develop HD.

An increased number of CAG repeats leads to an abnormally long version of the huntingtin protein. The long protein is then cut into smaller, toxic pieces that end up sticking together and accumulating in neurons. This disrupts the function of the neurons, ultimately causing the features of HD.

Prevention

Huntington disease (HD) is inherited in an autosomal dominant manner. This means that in only one of the 2 copies of the HTT gene is enough to cause the condition. When a person with HD has children, each child has a 50% (1:2) chance to inherit the mutated gene and develop the condition. Most people with HD have an affected parent. The family history can sometimes appear negative for various reasons even though a parent carries, or carried, a mutation in the HTT gene. In rare cases, HD is caused by a new (de novo) mutation in the HTT gene, in which case the disease occurs for the first time in the affected person and is not inherited from a parent.

As HD is passed through generations, the size of the mutation in the HTT gene often increases. A longer repeat in the HTT gene may cause earlier onset of symptoms.  If you're at risk of passing the genetic defect that causes Huntington disease to your children, you may wish to consider adoption or certain forms of assisted reproduction. One possibility is in vitro fertilization with pre-implantation screening. In this procedure, embryos are screened for the Huntington's disease gene mutation, and those that don't have the mutation are then implanted in the woman's uterus.

Diagnosis

A diagnosis of Huntington's disease is based primarily on your answers to questions, a general physical exam, a review of your family medical history, and neurological and psychiatric examinations.

Neurological examination:

The neurologist will ask you questions and conduct relatively simple tests in the office to judge:

Motor symptoms:

  • Reflexes
  • Muscle strength
  • Muscle tone
  • Coordination
  • Balance

Sensory symptoms:

  • Sense of touch
  • Vision and eye movement
  • Hearing

Psychiatric symptoms:

  • Mental status
  • Mood

Neuropsychological testing. The neurologist may also perform standardized tests to assess:

  • Memory
  • Reasoning
  • Mental agility
  • Language function
  • Spatial reasoning

Psychiatric evaluation:

  • Emotional state
  • Patterns of behaviors
  • Quality of judgment
  • Coping skills
  • Signs of disordered thinking
  • Evidence of substance abuse

Brain imaging and function:

Your doctor may order brain-imaging tests for assessing the structure or function of the brain. The imaging technologies may include MRI, which can produce detailed cross-sectional and 3-D images of the brain, or CT scan, which produces cross-sectional images.

These images may reveal structural changes at particular sites in the brain affected by Huntington's disease, although these changes may not be apparent early in the course of the disease. These tests can also be used to rule out other conditions that may be causing symptoms.

Genetic counseling and testing:

If symptoms strongly suggest a diagnosis of Huntington's disease, your doctor may recommend a genetic test for the defective gene. This test can confirm the diagnosis, and it may be valuable if there's no known family history of Huntington's disease or if no other family member's diagnosis was confirmed with a genetic test.

The test won't provide information that is beneficial in determining a treatment plan.

Before undergoing such a test, the genetic counselor will explain the benefits and drawbacks of learning test results. The genetic counselor can also answer questions about the inheritance patterns of Huntington's disease.

Predictive genetic test:

A genetic test can be given to someone who has a family history of the disease but shows no signs or symptoms. This is called predictive testing. The test result has no treatment benefit, and it doesn't indicate when disease onset will begin or what symptoms are likely to appear first.

Some people may elect to do the test because they find it more stressful not knowing. Others may want to take the test before they make decisions about having children.

Risks may include problems with insurability or future employment and the stresses of facing a fatal disease. These tests are only performed after consultation with a genetic counselor.

Prognosis

Huntington disease (HD) is progressive, eventually leading to disability and death (usually from a coexisting illness or infection). However, the disease affects everyone differently; the age of onset, specific symptoms, and rate of progression varies for each person with HD.

While the symptoms of HD are well-characterized, their progression (especially in the early and middle stages) remains unpredictable. With the approach of late-stage HD, affected people have speech difficulty and weight loss. In the late stage, affected people lose bowel and bladder control.

The duration of the disease (from onset until death) varies considerably, with an average of approximately 19 years. Most people with HD survive for 10-25 years after the onset of symptoms. The average age at death ranges from 51-57 years, but the range may be broader. In a large study, pneumonia and cardiovascular (heart) disease were the most common primary causes of death.

The length of the CAG repeat (the type of mutation in the HTT gene responsible for HD) is the most important factor that determines age of onset of HD. However, there is still a lot of variability. Both genetic and environmental factors are thought to play a role on the age of onset in people with a mutation. Inheritance through the father can lead to more repeat expansion and earlier onset through succeeding generations, a phenomenon called anticipation.

Treatment

There is currently no cure for Huntington disease (HD). The current goal of treatment is to slow down the course of the disease and help affected people function for as long and as comfortably as possible.

Current treatment strategies involve the use of various medications to treat specific symptoms such as abnormal movements and behaviors. Depression and suicide are more common among affected people, so caregivers should monitor for associated symptoms and seek help if necessary. As symptoms of the disease worsen, affected people need more assistance, supervision, and care.
Approved therapies:
Tetrabenazine ( Xenazine) - FDA-approved indication: Treatment of chorea associated with Huntington's disease 

Resources

Refer to Research Publications.