eMedicine Specialties > Psychiatry > Adult

Huntington Disease Dementia

Author: Idan Sharon, MD, Consulting Staff, Departments of Neurology and Psychiatry, Cornell New York Methodist Hospital; Private Practice
Coauthor(s): Tulay Ersan, MD, Chief of Geriatrics, Department of Internal Medicine, Division of Geriatrics, Monmouth Medical Center; Roni Sharon, University of Michigan
Contributor Information and Disclosures

Updated: Aug 20, 2007

Introduction

Background

Huntington disease (HD) is a genetic, autosomal dominant, neurodegenerative disorder characterized clinically by disorders of movement, progressive dementia, and psychiatric and/or behavioral disturbance. In 1872, George Huntington, MD, presented a disease featuring "hereditary nature, adult onset, chorea, mind impairment," and "with a tendency to insanity and suicide." Although Huntington was not the first to describe this "dancing mania," his account was so comprehensive that he received international recognition. In the following 128 years, HD has inspired thousands of research papers in which elucidation of this unrelenting neurodegenerative disorder has been attempted.

Pathophysiology

HD is associated with an excessive sequence of CAG repeats in the IT15 (interesting transcript number 15) gene located on arm 4p; researchers are looking into which chromosome contains that gene. The HD gene codes for a protein called huntingtin. This protein is found in neurons throughout the brain; its normal function is unknown. Possibly, the abnormal huntingtin protein undergoes proteolysis and is then transported to the nucleus, where it undergoes aggregation. Transport to the nucleus may involve specific protein-to-protein interactions that occur in certain cell types only, possibly explaining the selective neuronal vulnerability present in patients with HD. The genetic mutation is theorized to cause an imbalance between free radical production and removal, resulting in the subsequent neuronal degeneration and neurotransmitter decline.

Great insight has been shed on the IT15 gene on a molecular level; however, if and how this leads to the clinical symptoms of HD still are not clear. Evidence also indicates the presence of inappropriate neuronal apoptosis in persons with HD. Symptoms result from the selective loss of neurons, mostly in the caudate nucleus and putamen. Vonsattel et al devised a neural pathologic grading system that scaled the microscopic and gross striatum changes. The grades of this scale range from 0 (normal) to 4 (severe neuronal loss; astrocytosis; and atrophy of the globus, pallidus, and caudate putamen).

Neurochemically, levels of transmitter substances (eg, GABA and its synthetic enzyme glutamic acid decarboxylase) are markedly decreased throughout the basal ganglia. Levels of acetylcholine, substance P, and enkephalins are also reduced. Nuclear magnetic resonance spectroscopy in living subjects with HD has shown elevated levels of lactate in the basal ganglia.

HD supposedly can cause psychiatric disorders in 2 ways, (1) by the direct action of the gene on striatal neurons and (2) by the indirect effect of the disordered family environment on the children regardless of whether they inherited the HD gene.

Frequency

United States

Several epidemiological studies in the United States, conducted from 1945-1980, show consistent statistics stating that approximately 30,000 people have HD.

International

HD occurs in various geographic and cultural ethnicities worldwide. The worldwide prevalence of this disorder is 5-10 cases per 100,000 persons. In North America and Europe, HD has a prevalence of 0.5-9.95 cases per 100,000 individuals. In a particular study by Walker et al in South Wales, a prevalence of 7.61 cases per 100,000 persons was reported. This study was reanalyzed in 1988 and showed the prevalence to be higher (8.85 cases per 100,000 persons), indicating a slight rise over the years.

Mortality/Morbidity

HD is a progressive disorder, typically lasting approximately 15 years.

• Early onset affecting patients younger than 20 years (juvenile HD) is associated with rigidity, ataxia, cognitive decline, and more rapid progression. The typical duration is approximately 8 years. Seizures are more common with juvenile-onset disease than other forms.
• Individuals who inherit the disease from their fathers tend to become symptomatic much earlier in life than those who inherit it from their mothers.
• Death is usually secondary to pneumonia, cardiopulmonary failure, trauma, or suicide.

Race

• No significant differences exist among national and ethnic groups in the number of CAG repeats; however, the higher frequency of HD among white persons and its lower prevalence in other populations, including black persons and Japanese persons, has led to the hypothesis that the mutation responsible for the disease was carried to different parts of the world by immigrant European settlers.
• This theory is further supported by the suggestion that the mutation rate in the HD gene is exceedingly low, perhaps the lowest such rate for any human genetic disease. The fact that the mutation rate for HD is higher than previously estimated and that new mutations may account for as many as 3% of the cases is now apparent; therefore, new mutations, in addition to European migration, may account for the disease's presence in many different and sometimes isolated communities.

Sex

HD affects males and females in relatively equal numbers.

Age

• The onset of disease usually occurs in the fourth or fifth decade of life, with a wide range in age from childhood to later years in life. Juvenile onset has a large repeat expansion and occurs most often when the father is the affected parent (a form of genetic anticipation).

Clinical

History

The first symptoms typically are choreic movements or psychiatric disorders, whereas global cognitive decline generally becomes obvious later and eventually expresses itself as a triad of disordered movement, cognitive decline, and psychiatric disturbance. Clinically, the cognitive deterioration of HD is generally thought to correlate with the number of years affected rather than the age of onset. In an interesting study conducted by Jason et al in 1997, cognitive manifestations were examined in relation to age, clinical onset, progression, and genetic analysis. Evidence showed an inverse correlation between the onset of cognitive impairment and the number of trinucleotide repeats in the HD gene. Additionally, this study showed that although a statistically significant correlation exists between the number of repeats and the progressive dementia, the relationship is tenuous.

• Psychiatric symptoms are prominent in patients with HD, as follows:
  • Symptoms range from personality alterations to mood disorders, aggressiveness, hypersexuality or impotence, alcoholism, and psychosis, including schizophrenia.
  • Psychiatric disorders may occur in 35-73% of patients with HD, and behavioral changes may represent the initial manifestation of the disease in one third to one half of the cases.
  • Depression is the most common psychiatric condition.
  • Mania occurs in 2-12% of patients, whereas suicide occurs in nearly 6% of patients.
  • Eccentricity, inappropriateness, loss of social amenities, excess irritability, and sexual hyperactivity can mark the early stages.
  • Occasionally, a schizophreniform illness precedes the motor abnormality by several years.
  • Depression, apathy, social withdrawal, and intermittent disinhibition are common.
  • Suicide occurs frequently, partially because the progressing dementia often fails to blunt insight.
• When HD starts as subtle fidgeting, it may be unrecognized by the patient and family. Patients have a history of progressive generalized choreiform activity accompanied by behavioral or personality changes, especially in those with a family history. Sporadic cases are also possible.

Physical

• Early motor symptoms often include dystonic posturing and rigidity, but these changes give way to prominent choreiform activity in most affected adults.
• Frequent, irregular, and sudden jerks and movements of any of the limbs or trunk occur.
• Grimacing, grunting, and poor articulation of speech may be prominent.
• Mental status exam 
  • The patient appears older than stated age. 
  • Patient is well oriented in all spheres.
  • Patient appears alert.
  • Affect is appropriate.
  • Mood is euthymic. 
  • Presents self in a disheveled and sloppy fashion.
  • Eye contact can be described as limited.
  • Speech is illogical, incoherent, garbled, and not goal-directed. 
  • An increased risk for suicidal and homicidal thinking occurs due to the poor prognosis and erratic thinking, which can be accompanied by paranoia. 
  • Recent memory appears moderately to severely impaired. Remote memory is not impaired.
  • Psychomotor activity can be characterized by choreic movements and hyperactivity.
  • A negligible to severe degree of conceptual disorganization is evident. 
  • Thought content is characterized by delusions, hallucinations, and violent ideation at times.
  • Regarding perceptual functioning, the patient has hallucinations and none are evident.
  • Attitude can be described as cooperative but disinterested. 
  • The patient verbalizes no awareness of problems and does not see consequences. Judgment is poor.
  • Attention/concentration is characterized by an inability to attend and maintain focus.
  • The patient is not reflective and unable to resist urges.
• The gait is disjointed and poorly coordinated. Patients with HD, like healthy subjects, depend more on proprioceptive cues than on visual cues to maintain balance; however, patients with HD develop more sway compared with healthy subjects when proprioceptive cues and vision are altered.
• Given the presence of choreiform movement and subcortical neuropathology, performance on manual dexterity tasks is impaired.
• Cognitive symptoms include the following:
  • Memory frequently is not impaired until late in the disease, but attention, judgment, and executive functions may be seriously deficient at an early stage.
  • Early signs of dementia often include forgetfulness, disorganization, and affective disorders.
  • Free recall may be severely impaired.
  • Memory deficits involve both recent and remote function. Studies show that patients with HD can accurately recognize recently presented verbal material only when cues are used in memory retrieval. Other studies show that the patients sometimes recall words the next day that they had not recalled during testing sessions, further supporting a delayed-retrieval hypothesis.
  • Patients have significant problems with frontal executive functions, such as problems with maintenance, cognitive flexibility, abstraction, judgment, reasoning, sequencing, organizing, planning, and adapting.
  • Skilled motor-procedural learning deficits are reported. Working memory may be affected in patients with HD because of frontal lobe dysfunction associated with the bidirectional connections with the caudate.
  • Insight, orientation, factual information, and overall intelligence quotient scores are preserved relatively well into the disease process.
• Verbal skills are discussed as follows:
  • Verbal skills are the least impaired in patients with HD.
  • Reduced fluency in the face of preserved confrontation naming occurs.
  • Letter and category fluency are also impaired.
  • Sensory motor deficits occur, such as poor olfactory perception, slow sequential or graphomotor movements, and impaired prism adaptation.
• Spatial disorientation, specifically the inability to identify position relative to a fixed point, is another characteristic impairment in patients with HD. In a landmark study conducted by Podegil et al, patients with HD were asked to remember the position of a fixed target and then were asked to identify the point after being blindfolded. The patients were able to identify the markings in this setting; yet, when a variation of position was incorporated (ie, sidestepping after being blindfolded), patients showed significant impairment in target localization.
• Patients with HD have difficulty in sustaining their performance in a variety of everyday tasks that require both cognitive and motor function. Performance on the Stroop test and the Trail-Making Test are highly sensitive to these deficits, which encompass activities associated with mental arithmetic, digit or symbol matching, and reaction time.

Causes

HD is a genetic autosomal dominant disorder. Persons who have 38 or more CAG repeats in the HD gene have inherited the disease mutation and eventually develop symptoms if they live to an advanced age. Each of their children has a 50% risk of inheriting the abnormal gene. Also, rare sporadic cases without any family history occur.

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