Initial symptoms include personality changes and the gradual appearance of small involuntary movements.2 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.
Weight loss also is common3 and is due, in part, to the extra energy required for adventitious movements4 and also increased resting basal energy expenditure.5 Weight loss also may be an effect of CNS dysfunction.6
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,7 and the risk of suicide appears to peak during stage 2 of the disease.8
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.1,9,10
The discovery of a large population of persons with HD in a Venezuelan fishing village near Maracaibo ushered in the discovery of the HD 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 El Mal de San Vito (ie, Saint Vitus' dance). Negrette studied the affected villagers and realized that they had HD.11
In 1972, when a symposium to commemorate the 100-year anniversary of Huntington's landmark research paper was held in Columbus, Ohio,12 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.13 Negrette's work, in fact, described the largest HD population in the world.14
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.2,15 The first marker for the HD gene was found by studying DNA samples collected from the Venezuelan patients.16 This ultimately led to the discovery of the gene itself.17 The US-Venezuela Collaborative Research Project continues to gather important longitudinal and prospective data.18
HD is inherited in an autosomal dominant fashion. The HD gene is located on chromosome 4p16 and encodes the huntingtin protein.15 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 HD 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.19,20 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.21 Patients with very late onset tend to have repeats of 36 to 38, which are in the low abnormal range.22
Neuropathological grade also varies with CAG number, with the most damage seen in brains with the highest CAG repeats.23 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.
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