Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 16Control of Posture & Movement 253

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 malfunc-
tion 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 sys-
tem 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)

Parkinson disease has both hypokinetic and hyperkinetic fea-
tures. 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 de-
generation of dopaminergic neurons in the substantia nigra
pars compacta.
The fibers to the putamen are most severely affected. Par-
kinsonism 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

losses apparently precipitates parkinsonism. Symptoms

appear when 60–80% of the nigrostriatal dopaminergic neu-

rons 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-tet-

rahydropyridine (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 pri-

mates it is removed more slowly and is taken up by the dopa-

mine 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 avail-

ability 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 con-

tent 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 disor-

ders 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.

TABLE 16–1 Examples of trinucleotide repeat
diseases.

Disease

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 Ca2+

channel

Dentatorubral-pallidoluy-

sian 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