DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

progresses, the involuntary movements become more
severe, dysarthria and dysphagia develop, and balance is
impaired. The cognitive disorder manifests first as slowness
of mental processing and difficulty in organizing
complex tasks. Memory is impaired, but affected persons
rarely lose their memory of family, friends, and the
immediate situation. Such persons often become irritable,
anxious, and depressed. Less frequently, paranoia
and delusional states are manifest. The outcome of HD
is invariably fatal; over a course of 15-30 years, the
affected person becomes totally disabled and unable to
communicate, requiring full-time care; death ensues
from the complications of immobility (Shoulson, 1992).
Pathology and Pathophysiology. HD is characterized by prominent
neuronal loss in the striatum (caudate/putamen) of the brain
(Vonsattel et al., 1985). Atrophy of these structures proceeds in an
orderly fashion, first affecting the tail of the caudate nucleus and then
proceeding anteriorly from mediodorsal to ventrolateral. Other areas
of the brain also are affected, although much less severely; morphometric
analyses indicate that there are fewer neurons in cerebral cortex,
hypothalamus, and thalamus. Even within the striatum, the
neuronal degeneration of HD is selective. Interneurons and afferent
terminals are largely spared, whereas the striatal projection neurons
(the medium spiny neurons) are severely affected. This leads to large
decreases in striatal GABA concentrations, whereas SST and DA
concentrations are relatively preserved (Ferrante et al., 1987).
Selective vulnerability also appears to underlie the most conspicuous
clinical feature of HD, the development of chorea. In most
adult-onset cases, the medium spiny neurons that project to the GPi
and SNpr (the indirect pathway) appear to be affected earlier than
those projecting to the GPe (the direct pathway; Figure 22–5) (Albin
et al., 1992). The disproportionate impairment of the indirect pathway
increases excitatory drive to the neocortex, producing involuntary
choreiform movements (Figure 22–7). In some individuals,
rigidity rather than chorea is the predominant clinical feature; this is
especially common in juvenile-onset cases. Here, the striatal neurons
giving rise to both the direct and indirect pathways are impaired
to a comparable degree.
Genetics. HD is an autosomal dominant disorder with nearly complete
penetrance. The average age of onset is between 35 and 45
years, but the range varies from as early as age 2 to as late as the
middle 80s. Although the disease is inherited equally from mother
and father, more than 80% of those developing symptoms before age
20 inherit the defect from the father. This is an example of anticipation,
or the tendency for the age of onset of a disease to decline with
each succeeding generation, which also is observed in other neurodegenerative
diseases with similar genetic mechanisms. Known
homozygotes for HD show clinical characteristics identical to the
typical HD heterozygote, indicating that the unaffected chromosome
does not attenuate the disease symptomatology. Until the discovery
of the genetic defect responsible for HD, de novo mutations causing
HD were thought to be unusual; but it is now clear that the disease
can arise from unaffected parents, especially when one carries an
“intermediate allele,” as described in the next paragraph.
Glu
+
Glu +
DA
SNpc
To spinal cord
and brainstem
Cerebral cortex
+
Striatum
–
D 1
Glu
D 2
Glu
ACh
– GABA
–
GPe STN
GABA
GABA
Glu +
GPi/SNpr
Glu
VA/VL
thalamus
GABA
Figure 22–7. The basal ganglia in Huntington’s disease. HD is
characterized by loss of neurons from the striatum. The neurons
that project from the striatum to the GPe and form the indirect
pathway are affected earlier in the course of the disease than
those which project to the GPi. This leads to a loss of inhibition
of the GPe. The increased activity in this structure, in turn,
inhibits the STN, SNpr, and GPi, resulting in a loss of inhibition
to the VA/VL thalamus and increased thalamocortical excitatory
drive. Structures in purple have reduced activity in HD,
whereas structures in purple have increased activity. Light blue
line indicate primary pathways of reduced activity. (See legend
to Figure 22–2 for definitions of anatomical abbreviations.)
The discovery of the genetic mutation responsible for HD
was the product of an arduous 10-year, multi-investigator collaborative
effort. In 1993, a region near the end of the short arm of chromosome
4 was found to contain a polymorphic (CAG) n
trinucleotide
repeat that was significantly expanded in all individuals with HD
(Huntington’s Disease Collaborative Research Group, 1993). The
expansion of this trinucleotide repeat is the genetic alteration responsible
for HD. The CAG repeat is unstable, and may expand during
the DNA synthesis associated with meiosis. This is particularly common
during spermatogenesis, and accounts for the phenomenon of
anticipation. The range of CAG repeat length in normal individuals
is between 9 and 34 triplets, with a median repeat length on normal
chromosomes of 19. The repeat length in HD varies from 40 to over
100. Repeat lengths of 35-39 represent intermediate alleles; some of
these individuals develop HD late in life, whereas others are not
affected. Repeat length is correlated inversely with age of onset. The
younger the age of onset, the higher the probability of a large repeat
number. This correlation is most powerful in individuals with onset
before age 30; with onset above age 30, the correlation is weaker.
Thus, repeat length cannot serve as an adequate predictor of age of
onset in most individuals. Several other neurodegenerative diseases
also arise through expansion of a CAG repeat, including hereditary
spinocerebellar ataxias and Kennedy’s disease, a rare inherited disorder
of motor neurons.
Selective Vulnerability. The mechanism by which the expanded
trinucleotide repeat leads to the clinical and pathological features of
HD is unknown. The HD mutation lies within a large gene (10 kilobases)
+
+
–
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CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS