Movement symptoms of PD initially respond to L-dihydroxyphenylalanine (L-DOPA), but this treatment does not slow disease progression. Over time, L-DOPA becomes less effective and begins to cause problematic fluctuations in motor function. Another treatment for the motor symptoms of PD is deep brain stimulation, in which electrodes are implanted in the globus pallidus or subthalamic nucleus to modulate basal ganglia circuitry, often allowing a significant reduction in L-DOPA dose.
While the movement disorder associated with loss of the nigrostriatal dopaminergic pathway is an important feature of PD, it is clear that the disease has more extensive clinical and pathologic manifestations. Lesions in the brain stem (in the dorsal motor nucleus of the vagus and in the reticular formation), in advance of nigral involvement, can give rise to behavioral sleep disorder often before the motor problems. Dementia, typically with a mildly fluctuating course and hallucinations, emerges in many individuals with PD and is attributable to involvement of the cerebral cortex. When dementia arises within 1 year of the onset of motor symptoms, it is referred to Lewy body dementia (LBD).
Huntington disease (HD) is an autosomal dominant movement disorder associated with degeneration of the striatum (caudate and putamen). The disorder is characterized by involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical. The disease is relentlessly progressive, resulting in death after an average course of about 15 years. Early cognitive symptoms include forgetfulness and thought and affective disorders, and there may be a progression to severe dementia. As a part of these early behavioral changes, HD carries an increased risk for suicide.
HD is caused by CAG trinucleotide repeat expansions in a gene located on 4p16.3 that encodes the protein huntingtin. Normal alleles contain 11 to 34 copies of the repeat; in disease-causing alleles, the number of repeats is increased, sometimes into the hundreds. There is a strong genotype-phenotype correlation, with larger numbers of repeats resulting in earlier-onset disease. Once the symptoms appear, however, the course of the illness is not affected by repeat length. Further expansions of the CAG (glutamine-encoding) repeats occur during spermatogenesis, so paternal transmission may be associated with earlier onset in the next generation, a phenomenon referred to as anticipation (Chapter 7).
HD appears to be caused by a toxic gain-of-function related to the expanded polyglutamine tract in huntingtin.
The mutant protein is subject to ubiquitination and proteolysis, yielding fragments that can form large intra-nuclear aggregates. As in other degenerative diseases, smaller aggregates of the abnormal protein fragments are suspected to be toxic. These aggregates have been shown to have a range of potentially injurious actions, including sequestration of transcription factors, disruption of protein degradation pathways, and perturbation of mitochondrial function. It is likely that some combination of these aberrations contributes to HD pathogenesis.
MORPHOLOGYOngrossexamination,thebrainissmallandshowsstrikingatrophyofthecaudatenucleusand,sometimeslessdramatically,theputamen(
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