Jang-ho Cha, MD

Initial symptoms include personality changes and the gradual appearance of small involuntary movements.

 These movements progress to frank chorea, ballism, and dystonia. Later in the disease course, a bradykinetic parkinsonian phenotype manifests. It is characterized by rigidity, severe dystonia, and contractures. Falls are common. Dysphagia is common as well and is progressive, becoming severe and often contributing to death from aspiration pneumonia.

 and is due, in part, to the extra energy required for adventitious movements

 and also increased resting basal energy expenditure.

Weight loss also may be an effect of CNS dysfunction.

A psychiatric disorder may be the first manifestation of HD in some patients. Those that occur most commonly in patients with HD are depression, obsessive-compulsive disorder, psychosis, impulse control disorder, and substance abuse. Apathy and social withdrawal are also common. Patients with HD are at an increased risk for suicide,

 and the risk of suicide appears to peak during stage 2 of the disease.

Cognitive problems are also common. The HD dementia is a classic subcortical kind. Executive functioning and sequencing are affected to a greater degree than are memory and language, which are affected in cortical dementias such as Alzheimer disease.

The juvenile form (Westphal variant) of HD is more parkinsonian in nature. Rather than chorea, the prominent features are bradykinesia, rigidity, and tremor. Seizures are another common feature.

Juvenile-onset HD usually results from paternal genetic transmission. Indeed, more than 90% of persons in whom symptoms develop before age 10 have an affected father.

The discovery of a large population of persons with HD in a Venezuelan fishing village near Maracaibo ushered in the discovery of the 

 gene, but the full recognition of the importance of this population, leading to discovery of the gene, occurred nearly 30 years after the community was first encountered by a medical professional. In 1955, a Venezuelan medical school graduate named Amerigo Negrette, who was assigned to be the area's primary care doctor, encountered the community. Negrette, shocked at the sight of persons stumbling around as if drunk in the middle of the day, was informed that the villagers were not drunk; they had 

 (ie, Saint Vitus' dance). Negrette studied the affected villagers and realized that they had HD.

In 1972, when a symposium to commemorate the 100-year anniversary of Huntington's landmark research paper was held in Columbus, Ohio,

 physicians and scientists from around the world assembled to discuss what they considered to be a rare disorder. Ramón Avila Girón, a psychiatrist and student of Negrette, however, amazed the audience by showing a movie of a Venezuelan village filled with persons who had HD.

 Negrette's work, in fact, described the largest HD population in the world.

Communities living in the area around Maracaibo were studied by the NIH, and a collaboration between the NIH and the University of Zulia in Maracaibo, dubbed the US-Venezuela Collaborative Research Project, was launched.

 gene was found by studying DNA samples collected from the Venezuelan patients.

 This ultimately led to the discovery of the gene itself.

 The US-Venezuela Collaborative Research Project continues to gather important longitudinal and prospective data.

HD is inherited in an autosomal dominant fashion. The 

 gene is located on chromosome 4p16 and encodes the huntingtin protein.

Normal huntingtin alleles contain 6 to 35 cytosine-adenine-guanosine (CAG) repeats, giving rise to 6 to 35 glutamines in the mature protein. Variation occurs in the normal human population. A repeated stretch of CAG lies within the 

 gene; HD is thus 1 of the triplet repeat diseases. CAG is the codon for glutamine, and this tri- nucleotide repeat gives rise to a polyglutamine moiety within the huntingtin protein.

Patients with HD have alleles with more than 35 repeats. Although repeats of more than 40 invariably give rise to HD, there is a "gray area" between 35 and 39 repeats whereby uncertainty about disease carriage exists. Some patients with up to 39 repeats have lived into their 70s without overt signs of HD development, although age of onset as late as 80 years has been documented.

Age at onset correlates negatively with repeat length, although the correlation is strongest for high CAG repeat numbers.

 That is, although repeat numbers of greater than 70 invariably produce juvenile-onset HD, more common repeat numbers-for example, those in the 40 to 45 range-have a varied age at onset.

 Patients with very late onset tend to have repeats of 36 to 38, which are in the low abnormal range.

Neuropathological grade also varies with CAG number, with the most damage seen in brains with the highest CAG repeats.

 However, the CAG repeat length only accounts for 50% of the variability in age at onset, suggesting that there are other genetic or environmental influences affecting age at onset.

The most common mimic of HD is tardive dyskinesia, the incidence of which is higher than that of HD. Tardive movements can be indistinguishable from the abnormal movements of HD. A history of exposure to neuroleptics is useful in discriminating the patient with tardive dyskinesia from the patient with HD. Genetic testing may be of benefit as well.

Wilson disease, which can present with dystonia and chorea, also is among the differential diagnoses. Indeed, this potentially reversible disorder should be ruled out in any case of undiagnosed extrapyramidal movement disorders.

Less common differential diagnoses include neuroacanthocytosis, Hallervorden-Spatz disease, spino- cerebellar ataxia type 3, Sydenham chorea, thyrotoxicosis, Lyme disease, and dentatorubropallido- luysian atrophy. Senile chorea primarily is a motor disorder and lacks the psychiatric involvement that is characteristic of HD.

Initial workup involves taking a detailed history, including careful family and behavioral history. If there is a known family history of HD, the clinician should inquire whether a DNA test or postmortem brain examination of the proband was performed. In obtaining a family history, the clinician should inquire whether any relatives had abnormal movements or psychiatric disturbances. Sporadic cases of HD have been described, and careful genetic analysis usually reveals the presence of an "intermediate allele" with 30 to 38 CAG repeats in 1 of the parents of the patient.

The clinical examination should focus on motor disability, with special attention given to the presence of involuntary movements, dystonia, and abnormal tone. Often, in the patient with early-stage HD, limb rigidity with activation is present. Deficits in motor persistence are present. They are evidenced as difficulty in keeping the tongue protruded or keeping the eyes closed.

Eye movement abnormalities are early and sensitive indicators of HD, with saccadic movements being an especially sensitive clinical sign.

 (Of note, kinetic nystagmus is typically normal in patients with tardive dyskinesia.)

Cognitive evaluation, including neuropsychological testing, can reveal the presence of a subcortical dementia, consistent with disruption of frontal cortical-striatal circuits.

 Cognitive symptoms can occur early and are sometimes the initial presenting symptom.

Direct DNA testing has been made feasible by isolation of the 

gene mutation. Although genetic testing for HD is now commercially available, testing should be approached judiciously. It should be performed by professionals who are familiar with the clinical signs of HD and the consequences of the test results.

Genetic testing is performed in 2 contexts. Symptomatic gene tests are performed when symptoms that could be consistent with HD manifest in a patient. Symptomatic testing is especially helpful in those instances in which a complete family history is unavailable.

Presymptomatic testing is the other context in which HD genetic testing is performed. Presymptomatic testing can be helpful in planning life events, such as whether to marry or have children, for persons who are genetically at risk. 

Proceeding with such testing should be well thought out; negative consequences above and beyond disease development itself can ensue from documentation of a positive gene test result. Difficulties in finding employment, obtaining insurance, and maintaining personal relationships may be in store for persons for whom 

 gene mutation carriage is documented. Furthermore, parents, siblings, and offspring are affected, being potential carriers of the gene mutation.

Currently, there is no known therapy to delay the onset or slow the progression of HD. With the lack of definite benefit and with clear drawbacks, it is no wonder that only 3% to 5% of persons who are genetically at risk for HD choose to undergo predictive testing. Many persons decide to be tested when they sense the onset of symptoms.

Those who do undergo presymptomatic testing should receive detailed counseling from a genetic counselor. There is also a risk of increased suicidality among persons receiving genetic testing. Some have suggested that the period just before receiving a diagnosis of a genetic disorder is particularly risky.

There are currently no effective therapies for preventing the onset or slowing the progression of HD. Indeed, a recent review highlights the lack of reliable clinical evidence regarding the value of pharmacological management of HD.

Analysis of 20 level-1 studies identified no treatment of clinical relevance, highlighting the crucial need for high-quality randomized clinical trials.

Nevertheless, current therapies address symptoms. They include the use of neuroleptics to decrease chorea and psychotropic medications to address depression, obsessive compulsive symptoms, and psychosis. In addition to pharmacological therapies, speech therapy and physical therapy are useful in addressing the swallowing and walking difficulties that many patients with HD experience.

An important principle in HD treatment is that the brain is constantly degenerating. Thus, response to medication changes over time. Therapy must be flexible, and constant reevaluation is required. In addition, because of altered neurotransmitter receptors, paradoxical reactions to medications can occur. Careful empirical trials must be performed with each patient, and only 1 alteration in a medication regimen should be made at a time.

In randomized clinical trials, chorea has been the most widely used end point, possibly because it is among the most easily measured symptoms.

 Despite this, it is not clear whether chorea is the most debilitating effect of the disease. Current efforts are targeting quality-of-life issues in the HD population to assess the burden of symptoms other than chorea.

Abnormal movements do not necessarily need to be treated. Most patients either report that they are unaware of the movements or that the movements do not bother them. However, if the movements interfere with walking, other important functions, or are socially embarrassing, then antichoreic therapy is warranted.

First-line treatment consists of low-dosage neuroleptic medications, such as haloperidol starting at 0.5 to 1 mg bid. Atypical antipsychotics also have been used, but because they have relatively less extrapyramidal effects, they are not as effective as the more conventional antipsychotic agents in treating chorea. Rigidity and dystonia are the major consequential limitations of using neuroleptics in patients with HD.

Benzodiazepines are another option for treating chorea. Tetrabenazine recently has been provisionally approved for the treatment of HD but has yet to be released in the United States. In a recent trial conducted by the Huntington Study Group, tetrabenazine (up to dosages of 100 mg/d) reduced chorea severity (decrease of 5.0 units on the Unified Huntington Disease Rating Scale) compared with placebo (decrease of 1.5 units).

Psychiatric symptoms are treated as they are in the non-HD population. Depression responds well to selective serotonin reuptake inhibitors. Irritability and impulsivity can be treated with neuroleptics, including the newer atypical neuroleptic medications. Valproic acid has been used for irritability.

 There is increasing recognition that sleep is greatly disrupted in patients with HD. Treatment of sleep disturbances has the potential to improve daytime behavioral functioning.

Because the pathological mechanisms underlying HD are not completely understood, effective therapies depend on gaining greater elucidation of pathogenic pathways.

 The Huntington Study Group is currently conducting a clinical trial of 2 compounds, remacemide and coenzyme Q10, alone and in combination. Remacemide acts as an 

-methyl-d-aspartic acid glutamate receptor antagonist.

 Coenzyme Q10 is directed toward maintaining mitochondrial membrane potential.

 Other compounds that are being tested include ethyl-eicosapentaenoic acid, minocycline, the antioxidant trehalose, the antihistamine dimebolin, and histone deacetylase inhibitors.

In addition to seeking pharmacological agents, gene therapy is another strategy under investigation whereby the aim is to decrease the amount of the mutant huntingtin protein by either targeting the protein with antibodies or the mRNA using small interfering RNAs.

 Kremer B. Clinical neurology of Huntington's disease: diversity in unity, unity in diversity. In: Bates G, Harper P, Jones L, eds. 

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 Djousse L, Knowlton B, Cupples LA, et al. Weight loss in early stage of Huntington's disease. 

 Gaba AM, Zhang K, Marder K, et al. Energy balance in early-stage Huntington disease. 

 Pratley RE, Salbe AD, Ravussin E, Caviness JN. Higher sedentary energy expenditure in patients with Huntington's disease. 

 Petersen A, Bjorkqvist M. Hypothalamic-endo- crine aspects in Huntington's disease. 

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Huntington's Disease: A Disorder of Families. 

Baltimore: Johns Hopkins University Press; 1989.


Maracaibo, Venezuela: Talleres Graficos de la Universidad de Zulia; 1962.


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Articles

Initial symptoms include personality changes and the gradual appearance of small involuntary movements. These move- ments progress to frank chorea, ballism, and dystonia. Later in the disease course, a bradykinetic parkinsonian phenotype manifests. It is characterized by rigidity, severe dystonia, and contractures. Falls are common. Dysphagia is common as well and is progressive, becoming severe and often contributing to death from aspiration pneumonia.

Author | Jang-ho Cha, MD

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