What is Huntington disease (HD) ?
It is an autosomal dominant disease characterized clinically by progressive movement disorders and dementia, and histologically by degeneration of striatal
What is the clinical characteristic of Huntington's Disease?
- Jerky, hyperkinetic,
- sometimes dystonic movements involving all parts of the body
(chorea) are characteristic;
- affected individuals may later develop parkinsonism with
- bradykinesia and rigidity.
The disease is relentlessly progressive, with an average course of
about 15 years to death.
Huntington disease is the prototype of the_____________e repeat expansion
diseases (see Chapter 5 ).
The HD gene, located on chromosome __________, encodes a
348-kD protein known as huntingtin
In the first exon of the gene there is a stretch of CAG
repeats, which encodes a polyglutamine region near the N terminus of the protein
. Normal HD
genes contain 6 to 35 copies of the repeat; when the number of repeats is increased beyond this level it is associated with disease. There is an inverse relationship between repeat number and age of onset, such that longer repeats are associated with earlier onset.
factors modify the effect of the repeats, determination of repeat length is not an accurate predictor of age of onset. Repeat expansions occur during spermatogenesis, so that paternal transmission is associated with early onset in the next generation, the phenomenon of
Newly occurring mutations are uncommon; most apparently sporadic cases can be related to non-paternity, the death of a parent before expression of the disease, or a father as
yet unaffected but with a mild repeat expansion that further enlarged during spermatogenesis.
What is the macroscopic finding in HD?
Macroscopically, the brain is small and shows striking atrophy of the caudate
nucleus and, less markedly at early stages, the putamen ( Fig. 28-41 ).
The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated.
frequently also seen in the frontal lobe, less often in the parietal lobe, and occasional in the
What is the microscopic appearance of HD?
On microscopic examination, there is severe loss of striatal neurons; the most
marked changes are found in the caudate nucleus, especially in the tail and portions nearer
The putamen is involved in the later stages of disease.
What is the direction of Pathologic changes in HD?
develop in a medial-to-lateral direction in the caudate and from dorsal to ventral in the
What is the best preserved portion in HD?
The nucleus accumbens is the best preserved portion of the striatum.
large and small neurons are affected, but loss of the small neurons generally occurs first.
The medium-sized, spiny neurons that use γ-aminobutyric acid as theirneurotransmitter, along with enkephalin, dynorphin, and substance P, are especially affected.
Two populations of neurons are relatively spared, the diaphorasepositive neurons that contain nitric oxide synthase and the large cholinesterase-positive neurons; both appear to serve as local interneurons. \
is also fibrillary gliosis that is more extensive than in the usual reaction to neuronal loss.
There is a direct relationship between the degree of degeneration in the striatum and the
severity of clinical symptoms. Protein aggregates containing huntingtin can be found in
neurons in the striatum and cerebral cortex ( Fig. 28-41, inset ).
WHat is the pathophysio of HD?.
The loss of medium spiny striatal neurons leads to dysregulation of the basal ganglia circuitry
that modulates motor output.
These neurons normally function to dampen motor activity; thus, their degeneration in HD results in increased motor output, often manifested as choreoathetosis.
The cognitive changes associated with the disease are probably related to the neuronal loss from cerebral cortex
The biologic function of normal huntingtin remains unknown, but there is little evidence to
suggest that the disease is caused by haploinsufficiency related to a mutated allele.
expansion of the polyglutamine region seems to bestow a toxic gain of function on huntingtin.
While the expanded polyglutamine repeat results in protein aggregation and formation of
intranuclear inclusions as described above, it is not established that this is a direct pathway to
Transcriptional dysregulation has been implicated in HD, with mutant forms of huntingtin binding important transcriptional regulators such as Sp1 and CBP (cyclic adenosine
monophosphate response-element binding protein).
A proposed consequence of this
sequestration of critical transcription factors is the down-regulation of PGC-1α, itself a
transcription factor involved in mitochondrial biogenesis and protection against oxidative injury.
What is the age of onset of HD?
The age at onset is most commonly in the fourth and fifth decades and is related to the length
of the CAG repeat in the HD gene.
Motor symptoms often precede the cognitive impairment.
The movement disorder of HD is _______, with increased and involuntary jerky movements of
all parts of the body; writhing movements of the extremities are typical
What is the early symptom of HD?
. Early symptoms of
higher cortical dysfunction include forgetfulness and thought and affective disorders, but there
is progression to a severe dementia.
What is the most common cause of death in HD?
Although individuals with HD have an increased risk of
suicide, intercurrent infection is the most common natural cause of death
. Given the ability to
screen for disease-causing mutations and the devastating nature of the disease, HD is often
the focal point of discussion of ethical issues in genetic diagnosis.