Clinical Manifestations

A. Motor Dysfunction

1. Chorea

The most common motor manifestation of HD is chorea. Chorea is defined as quick, vermicular movements, which may be superimposed on a purposeful act. Chorea is more prominent in the orofacial regions and the distal musculature of hands and feet. However, as the disease progresses truncal chorea may be severe enough to cause sudden lurching of the body that leads to frequent falls. When superimposed on akathetic movements, chorea might be missed as part of motor manifestations of fidgety behavior. Chorea can be an early manifestation39 in HD and may be the only manifestation in late onset HD.40 Choreic movements of the feet and toes may be present in at-risk individuals41 and as an early manifestation of the disease. Choreiform movements of the orofacial, tongue, and oropharyngeal musculature may be severe enough to cause significant speech difficulties and dysphagia and may lead to aspiration. In patients untreated with antidopaminergic agents, chorea may be severe enough to prevent any normal voluntary and goal-directed motor activity.

2. Oculomotor Abnormalities

In terms of eye movements, HD patients have significant abnormalities of saccades, fixation, and smooth pursuit.42,43 Early in the disease, the patients have difficulties in initiating voluntary saccades, especially on command and to maintain a steady fixation. However, as the disease progresses a more severe slowing of saccades is noted. Vertical saccadic movements are more severely involved than the horizontal saccades.44,45 The eye movement abnormalities reflect dysfunctions of a significant area of the head of the caudate nucleus where projections from oculomotor centers of the frontal and parietal cortical areas, the thalamic and other brain stem regions converge.46

3. Dystonia

While chorea is the most common and widely recognized movement disorder of HD, clinicians often may not recognize the presence of dystonic movements. In one study, dys-tonic movements of different types and of varying degrees were present in 95% of patients.47 The rotatory dystonic movements of the shoulder were the most common, but dystonic movements of the foot, hands, trunk torticollis and ble-pharospasms were noted. Cervical dystonia may even be an initial manifestation of HD.48 Severe motor tics and myoclonus may also be present in patients with HD.49 It should be pointed out that tardive dystonias and tardive dyskinesias induced by antidopaminergic agents may superimpose on many of these movement disorders.

4. Parkinsonism

Even though hyperkinetic movements are the cardinal features of HD, bradykinesia may coexist39 and might even be an early manifestation of HD.50 Bradykinesia may be present during simultaneous and sequential movements;51 significant slowing of saccades is also noted in HD. Rigidity is one of the most prominent features of the Westphal variant of juvenile HD. The hypokinetic movements may also respond to L-dopa treatment. Investigators have proposed that the occurrence of both hypokinetic and hyperki-netic features may be due to differential involvement of the direct and indirect pathways of the basal ganglia.39

5. Gait Disorder

Gait dysfunction is a major and disabling feature of HD.52 A significant decrease in gait velocity and length of each stride, spontaneous flexion of the knees, swaying of the trunk, and broad-based gait are some of the features of gait dysfunctions in HD patients. A detailed study of the dynamics of gait suggests that HD patients have random fluctuation of stride, decreased stride interval, decreased correlation of one stride to the next, and in advanced stages more severely affected stride-to-stride correlation.53-55 These features of gait dysfunction may give patients with HD an appearance of being drunk, and this in fact has caused legal problems, hospitalization, or nursing home placements for many patients. While antidopaminergic therapy may reduce the severity of chorea, it does not seem to improve gait dysfunction.

6. Cerebellar Dysfunction

Despite the fact that htt is expressed most intensely in the cerebellum, severe cerebellar findings are not that common in adult-onset HD, but may be seen in juvenile HD. In contrast, many of the recently identified HD-like disorders are associated with significant cerebellar ataxia and other signs of cerebellar involvement.

B. Cognitive Manifestations

1. Dementia

Severe cognitive dysfunction reflecting both cortical and subcortical types of dementias is quite common in HD.1,56,57 The major feature is a progressive decline of attentional and executive function, which investigators speculate is due to fronto-striatal disconnection. In addition to the striatal lesions, neurons of the pyramidal and other layers of frontal, temporal, and parietal cortical areas degenerate, resulting in a wide variety of cognitive defects as the disease progresses including problems with memory acquisition and recall, decline in verbal skills, concentration, abstract thinking, and visuospatial perceptional difficulties. Severe dementia of the Alzheimer type is not a major feature of HD unless the patient is in very advanced stages of the disease.

2. Psychiatric Problems

Psychiatric and mood dysfunctions precede motor dysfunctions and can be destructive to the lives of the patients and their family members.58-60 Paranoid ideations, delusions, and other features of schizophrenia have been noted in 3-11% of HD patients. A significant bihemispheric decrease in metabolism is noted in PET scans of HD patients, a pattern very much similar to that seen in schizophrenics. Varieties of mood disorders are noted in 38% of HD patients, and the most common and fatal consequences are depression and suicidal tendencies. Suicide was the cause of death in 7.8% of HD patients in one study. Suicide risks are of higher frequency in HD patients,61-63 patients at risk for HD,64 and even in normal patients with a family history of HD.65 The suicide rate in HD is four to six times higher than in the general population and the rate is even higher in patients over the age of fifty. Investigators have observed obsessive-compulsive disorder,66,67 para-philia and other sexual disorders, aggression, irritability, agitation, delirium, and mania and hypomania in patients with HD.5960

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