Huntington Disease

Original Editor - Wendy Walker

Lead Editors  

General

Huntington disease (HD) is an incurable, adult-onset, progressive deurodegenerative disorder which presents with involuntary movements, dementia, and behavioral changes[1].

HD is named after George Huntington, the physician who described it as hereditary chorea in 1872[2].

Mechanism of Injury / Pathological Process

The most obvious neuropathology in HD occurs within the neostriatum, comprising gross atrophy of the caudate nucleus and putamen, accompanied by selective neuronal loss and astrogliosis (an abnormal increase in the number of astrocytes)[2]. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the stage of the disease.

Pathophysiology

In HD there is an excessive sequence of CAG repeats in part of the HTT ("Huntingtin") gene, which is located on the short arm of chromosome 4[3]. Healthy individuals have between 9 and 35 CAG repeats, while patients diagnosed with HD, as well as carriers, have an abnormal expansion accommodating 36 or more CAG repeats.[3] The HTT gene, or HD gene, codes for a protein called huntingtin. This protein is found in neurons throughout the brain; its normal function is unknown. In affected patients, neuronal degeneration initiates in the striatum and progresses to the cerebral cortex, following a pattern that correlates to clinical progression of HD[3].

The Human Genome Project first identified the mutation in the HTT gene as the cause of HD in 1993.

Inheritance of HD

The mutation is a dominant gene, so if a parent has HD then the children have a 50-50 risk of inheriting it.

There is a genetic test to make or confirm the diagnosis of Huntington's disease. Using a blood sample, the genetic test analyses DNA for the HD mutation by counting the number of CAG repeats in the huntingtin gene. Individuals who do not have HD usually have 28 or fewer repeats. Individuals with HD usually have 40 or more repeats, sometimes more than 100.

Clinical Presentation

The clinical manifestations of HD usually present between the ages of 35 and 45 years, but can begin at any age from childhood to old age.

The clinical features of Huntington disease (HD) include a movement disorder, a cognitive disorder, and a behavioral disorder[2]. Patients may present with one or all disorders in varying degrees. Early stages of HD are characterized by deficits in short-term memory, followed by motor dysfunction and a variety of cognitive changes in the intermediate stages of dementia[4].

Movement Disorder

Chorea (derived from the Greek word meaning to dance) is the most common movement disorder seen in HD.

Initially, mild chorea may cause the patient to appear restless, as if they are fidgeting. This progresses, and severe chorea may appear as uncontrollable writhing and flailing of the extremities, which interferes with function.

As the disease progresses, chorea coexists with ,and gradually is replaced by, dystonia and parkinsonian features, such as bradykinesia, rigidity, and postural instability.

In advanced disease, patients develop an akinetic-rigid syndrome, with minimal or no chorea. Other late features are spasticity, clonus, and extensor plantar responses.

The clinical manifestations of HD usually present between the ages of 35 and 45 years, but can begin at any age from childhood to old age.

Dysarthria and dysphagia are common. Abnormal eye movements may be seen early in the disease. Other movement disorders, such as tics and myoclonus, may be seen in patients with HD.

Cognitive Effects

Cognitive decline is characteristic of HD, but the rate of progression among individual patients can vary considerably. Dementia and the psychiatric features of HD are frequently the earliest symptoms[5]

The dementia syndrome associated with HD includes early onset behavioral changes, such as irritability, untidiness, and loss of interest. Slowing of cognition, impairment of intellectual function, and memory disturbances usually occur later[4].

Mood Effects

Depression is the most common mood effect[4], with a small percentage of patients experiencing episodic bouts of mania characteristic of bipolar disorder.

Patients with HD also can develop psychosis, hallucinations, delusions, or schizophrenia-like symptoms, obsessive-compulsive symptoms, sexual and sleep disorders, as well as changes in personality. 

Diagnostic Procedures

Measurement of the bicaudate diameter (ie, the distance between the heads of the 2 caudate nuclei) by CT scan or MRI is considered to be a reliable marker of HD[6].

Genetic testing (reported as the CAG repeat number for each allele) is now widlyavailable.
Genetic testing may not be necessary in a patient with a typical clinical picture and a genetically proven family history of HD.

Management / Interventions

Medical Management

There is no therapy or medication currently available which will delay the onset of symptoms or prevent (or even retard) the progression of HD.

Control of symptoms with medication is invariably required during the middle and late stages of the disease.

Symptoms & commonly used medications:

  • Chorea - benzodiazepines eg. clonazepam or diazepam, valproic acid; dopamine-depleting agents eg. reserpine or tetrabenazine
  • Rigidity and bradykinesia -  levodopa or dopamine agonists[7]
  • Depression - SSRIs and all other antidepressent medication
  • Hallucinations, delusions, or schizophrenia-like syndromes - anti psychotics

Physiotherapy

Standard physiotherapy for HD includes:

Gait re-education

Balance retraining

Fall prevention/management

Aerobic capacity

Muscle strengthening

Wheelchair prescription and training

Respiratory function

Task-specific reach, grasp, and manipulation

Differential Diagnosis

Chorea Gravidarum

Multiple Sclerosis

Systemic Lupus Erythematosus (SLE)

Neuroacanthocytosis

Appropriate Outcome Measures

TUG  Timed up and go test has been shown to be a good measure of mobility in HD[8].

As has the short form Berg Balance Scale, BBT.

Resources

HDBuzz "Huntington’s disease research news. In plain language. Written by scientists. For the global HD community".

HDSA The HD Society of America

American site, the National Human Genome Research Institute's page on HD.

Case Studies

add links to case studies here (case studies should be added on new pages using the case study template)

Recent Related Research (from Pubmed)

References

References will automatically be added here, see adding references tutorial.

  1. Folstein SE. Huntington's Disease: A Disorder of Families. The Johns Hopkins University Press. 1989
  2. 2.0 2.1 2.2 Huntington G. On chorea. Med Surg Report. 1872. 26:320
  3. 3.0 3.1 Quintanilla RA, Johnson GV. Role of mitochondrial dysfunction in the pathogenesis of Huntington's disease. Brain Res Bull. 2009 Oct 28. 80(4-5):242-7
  4. 4.0 4.1 4.2 Ho A, Hocaoglu M. Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective. Clin Genet. Sep 2011
  5. Loy CT, McCusker EA. Is a motor criterion essential for the diagnosis of clinical huntington disease?. PLoS Curr. Apr 11 2013. 5
  6. Stober T, Wussow W, Schimrigk K. Bicaudate diameter--the most specific and simple CT parameter in the diagnosis of Huntington's disease. Neuroradiology. 1984. 26(1):25-8
  7. Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntington's disease. J Neurol Neurosurg Psychiatry. Oct 1998. 65(4):577-9
  8. Busse M1, Quinn L1, Khalil H2, McEwan K. Optimising mobility outcome measures in Huntington's disease. J Huntingtons Dis. 2014;3(2):175-88