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"Huntington's Disease
and HD-like Disorders."
Sarah Tabrizi, professor of
neurology at the Institute
of Neurology, University
College London.
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Genetic causes of chorea:
HD and HD-like disorders.
HD-like disorders can be
called HD phenocopies.
They're all characterized by
variable presentation of chorea,
dystonia, and parkinsonism,
cognitive impairment,
and psychiatric disturbance.
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The CAG repeat diseases
comprise Huntington's disease,
DRPLA, SBMA, and SCA1,
2, 3, 6, 7 and 17.
They're sometimes called
the PolyQ disorders.
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Huntington's disease.
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This was first described by
George Huntington in 1872.
It is the commonest
genetic cause of chorea.
It is dominantly inherited.
And the mean age of
onset is about 40.
About 8% of new cases
have no family history.
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Huntington's disease is caused
by a CAG repeat expansion
in the Huntington gene encoding
the Huntington protein.
It was cloned in 1993 by a large
collaborative research group.
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HD genetics are interesting.
And there is a CAG repeat threshold.
Normal individuals have
less than 29 CAG repeats.
And this is not pathogenic,
and it's not unstable.
Between 29 and 35, it's an
intermediate repeat range.
It's not pathogenic
to that individual,
but it may expand into disease
range in future generations
and appear like a new mutation.
This is because of paternal meiotic
instability during spermatogenesis
where CAG repeat
expansions can occur
during spermatogenesis due
to meiotic instability.
This means that in
future generations,
the expansion can be pathogenic.
There is a reduced penetrance range
of 36 to 39 CAG repeats, which
can be pathogenic and has a risk
of HD of between 25% at 36 repeats
and 90% at 39 repeats.
However, if you have
40 or more CAG repeats,
that is fully pathogenic
and fully penetrant
and always causes
Huntington's disease.
