Ganong's Review of Medical Physiology, 23rd Edition

TABLE 16–1 Examples of trinucleotide repeat
diseases.
Disease
flailing, intense, and violent movements occur. Akinesia is
difficulty in initiating movement and decreased spontaneous
movement. Bradykinesia is slowness of movement.
In addition to Parkinson disease, which is described below,
there are several other disorders known to involve a malfunction
within the basal ganglia. A few of these are described in
Clinical Box 16–4. Huntington disease is one of an increasing
number of human genetic diseases affecting the nervous system
that are characterized by trinucleotide repeat expansion.
Most of these involve cytosine-adenine-guanine (CAG) repeats
(Table 16–1), but one involves CGG repeats and another
involves CTG repeats. All of these are in exons; however, a
GAA repeat in an intron is associated with Friedreich’s ataxia.
There is also preliminary evidence that increased numbers of a
12-nucleotide repeat are associated with a rare form of epilepsy.
PARKINSON DISEASE
(PARALYSIS AGITANS)
Expanded
Trinucleotide
Repeat
Affected
Protein
Huntington disease CAG Huntingtin
Spinocerebellar ataxia, types
1, 2, 3, 7
CAG Ataxin 1, 2, 3, 7
Spinocerebellar ataxia, type 6 CAG α1A subunit of Ca 2+
channel
Dentatorubral-pallidoluysian
atrophy
CAG Atrophin
Spinobulbar muscular atrophy CAG Androgen receptor
Fragile X syndrome CGG FMR-1
Myotonic dystrophy CTG DM protein kinase
Friedreich ataxia GAA Frataxin
Parkinson disease has both hypokinetic and hyperkinetic features.
It was originally described by James Parkinson and is
named for him. Parkinson disease is the first disease identified
as being due to a deficiency in a specific neurotransmitter. In
the 1960s, Parkinson disease was shown to result from the degeneration
of dopaminergic neurons in the substantia nigra
pars compacta.
The fibers to the putamen are most severely affected. Parkinsonism
now occurs in sporadic idiopathic form in many
middle-aged and elderly individuals and is one of the most
common neurodegenerative diseases. It is estimated to occur
in 1–2% of individuals over age 65. Dopaminergic neurons
and dopamine receptors are steadily lost with age in the basal
ganglia in normal individuals, and an acceleration of these
CHAPTER 16 Control of Posture & Movement 253
losses apparently precipitates parkinsonism. Symptoms
appear when 60–80% of the nigrostriatal dopaminergic neurons
degenerate.
Parkinsonism is also seen as a complication of treatment
with the phenothiazine group of tranquilizer drugs and other
drugs that block D 2 receptors. It can be produced in rapid and
dramatic form by injection of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
(MPTP). This effect was discovered by
chance when a drug dealer in northern California supplied
some of his clients with a homemade preparation of synthetic
heroin that contained MPTP. MPTP is a prodrug that is
metabolized in astrocytes by the enzyme MOA-B to produce a
potent oxidant, 1-methyl-4-phenylpyridinium (MPP + ). In
rodents, MPP + is rapidly removed from the brain, but in primates
it is removed more slowly and is taken up by the dopamine
transporter into dopaminergic neurons in the substantia
nigra, which it destroys without affecting other dopaminergic
neurons to any appreciable degree. Consequently, MPTP can
be used to produce parkinsonism in monkeys, and its availability
has accelerated research on the function of the basal
ganglia.
The hypokinetic features of Parkinson disease are akinesia
and bradykinesia, and the hyperkinetic features are cogwheel
rigidity and tremor at rest. The absence of motor activity
and the difficulty in initiating voluntary movements are
striking. There is a decrease in the normal, unconscious
movements such as swinging of the arms during walking, the
panorama of facial expressions related to the emotional content
of thought and speech, and the multiple “fidgety” actions
and gestures that occur in all of us. The rigidity is different
from spasticity because motor neuron discharge increases to
both the agonist and antagonist muscles. Passive motion of
an extremity meets with a plastic, dead-feeling resistance that
has been likened to bending a lead pipe and is therefore
called lead pipe rigidity. Sometimes a series of “catches”
takes place during passive motion (cogwheel rigidity), but
the sudden loss of resistance seen in a spastic extremity is
absent. The tremor, which is present at rest and disappears
with activity, is due to regular, alternating 8-Hz contractions
of antagonistic muscles.
A current view of the pathogenesis of the movement disorders
in Parkinson disease is shown in Figure 16–11. In normal
individuals, basal ganglia output is inhibitory via GABAergic
nerve fibers. The dopaminergic neurons that project from the
substantia nigra to the putamen normally have two effects:
they stimulate the D 1 dopamine receptors, which inhibit GPi
via direct GABAergic receptors, and they inhibit D 2 receptors,
which also inhibit the GPi. In addition, the inhibition reduces
the excitatory discharge from the subthalamic nucleus to the
GPi. This balance between inhibition and excitation somehow
maintains normal motor function. In Parkinson disease, the
dopaminergic input to the putamen is lost. This results in
decreased inhibition and increased excitation from the STN
to the GPi. The overall increase in inhibitory output to the
thalamus and brain stem disorganizes movement.