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Huntington's disease is a devastating
disorder, some of a more dominant
neurodegenerative disease, that typically
presents with the triad of symptoms.
These include abnormal movements,
as you can see in the slide.
But perhaps more devastating to the family
and to the patients are the psychiatric
disturbances, and cognitive deterioration
that characterize this disorder.
Huntington's disease can
present at any age, however,
the median age at onset
is around 40 years.
This results in many cases of Huntington's
disease presenting with symptoms or
signs after they've already had children.
Huntington's patients typically die
about 15 years after disease onset.
The analysis of postmortem brains
has provided important insights into
the regional specificity of
the Huntington mutations effects.
The top brain in the slide represents
a normal sample, while the bottom brain
represents a sample from a Huntington's
patient at the end stages of the disease.
The CNP in the top panel
represent the caudate and putamen.
If you look at the Huntington's brain,
you can see that these regions are almost
completely absent, and
there's also significant cortical atrophy.
Indeed, loss of cells from the caudate and
from the cortex represent fairly
early events in the disease course.
The gene causing Huntington's
disease was identified in 1993,
by a large consortium headed
up by Jim Gazelle at Harvard.
The Huntington's disease gene
encodes a very large protein of
more than 3000 amino acids, and
this protein is called huntingtin.
The Huntington's mutation causes
changes close to the amino
terminus of this protein.
The coding region in the gene
at this position comprises
a series of uninterrupted
CAG trinucleotide repeats.
So the sequence reads CAG,
CAG, CAG, CAG, CAG etc.
Normal individuals have 35 or
fewer of these uninterrupted CAGs,
while diseases are associated with 36 or
more of these repeats.
Each of these CAG repeats
represents the codon for
the amino acids glutamine, so
the mutant protein has a very long and
abnormally expanded polyglutamine stretch.