Research articles and discussion on Hunt-Dis/view comments
Almqvist, E., D. Elterman, et al. (2001)
"High incidence rate and absent family histories in one quarter
of
patients newly diagnosed with Huntington disease in British Columbia."
Clin Genet 60(3): 198-205.
The advent of the direct mutation
test for Huntington disease
(HD) has made it possible to identify a previously unrecognized
symptomatic population of
HD, including those with an atypical
presentation or patients without a family history of HD.
The present study
investigated the uptake of this test in the province
of British Columbia (BC), Canada and assessed the incidence rate
and
rate of identification of new mutations for HD.
All symptomatic individuals residing in BC who were referred for the
genetic
test for HD between 1993 and 2000 (n=205) were analyzed
for CAG expansion, baseline demographics and clinical data, and
a
family history of HD. A total of 141 (or 68.8%) had a CAG expansion
>/=36. Of these, almost one-quarter (24.1%)
did not have a family
history of HD.
An extensive chart review revealed that 11 patients (or 7.8%) had
reliable information on both parents (who lived well into old age)
and
therefore possibly could represent new mutations for HD.
This indicates a three to four times higher new mutation
rate than
previously reported. Our findings also show that the yearly incidence
rate for HD was 6.9 per million, which
is two times higher than
previous incidence studies performed prior to the identification of
the HD mutation.
All symptomatic individuals residing in BC who were referred for the
genetic test for HD between 1993
and 2000 (n=205) were analyzed
for CAG expansion, baseline demographics and clinical data, and
a family history of HD.
A total of 141 (or 68.8%) had a CAG expansion
>/=36. Of these, almost one-quarter (24.1%) did not have a family
history
of HD.
An extensive chart review revealed that 11 patients (or 7.8%) had reliable
information on both parents
(who lived well into old age) and
therefore possibly could represent new mutations for HD.
This indicates a three to four times higher new mutation rate than
previously reported. Our findings
also show that the yearly incidence
rate for HD was 6.9 per million, which is two times higher than
previous incidence
studies performed prior to the identification of
the HD mutation.
Viewer Comments
(1) I wouldn't
put too much stock in this. Apparently, no tests were done to
assure paternity. As the eminent HD researcher,
the late Dr. Harold Klawans
of Rush-Presbyterian-St. Luke's in Chicago used to say, "The adultery rate
is much higher
than the HD mutation rate."
(2) Dr. Michael Hayden puts the new mutation rate at ten percent of cases.
When you add in misdiagnoses, especially of late onset HD, the 24 percent rate
seems right to me.
The instability of the transmission of CAG repeats when
the parent has 29 or more repeats seems like a far more likely cause of new
cases without a family history than adultery.
(3)
Actually, I would expect that the number of HD cases due to new mutation
exceeds the number due to misassigned paternity. I don't know what effort
Almqvist and colleagues took to establish paternity, but I hardly think that,
as clinical geneticists, they're unaware of the impact!
----------------------
We also
identified five persons with a clinical presentation of HD
but without CAG expansion (genocopies) (2.4%).
Viewer Comment
I remember a researcher (Nancy Wexler, I'm pretty sure) saying at one of the
conventions that down
in Venezuela they had found a young man with all the
symptoms but low repeats. Their feeling was that, having lived
with all the
HD down there, he was infinitely familiar with the symptoms, so was quite
capable of faking them, the motivation
being to share in some of the
attention that the pHDs were getting from the researchers.
=============================================================
Society
for Neuroscience
http://www.sfn.org/briefings/huntingtons.htmlNormally the CAG sequence repeats between 11 and 30 times.
People with HD
may have CAG repeated between 36 and 125 times. The onset of the disease
generally is in the 30s and
40s (with a range of age 2 to 82), but more than
60 repeats of CAG often are associated with an onset of HD before age
20.
With the majority of people who have fewer than 60 repeats, there is great
variability. A person can have 40
CAG repeats in his or her DNA sequence and
have onset at age 17 or 70.
On average, however, a feature dubbed "genetic
anticipation" occurs. Each time
the unstable DNA is passed on to offspring, the affected person experiences
an earlier
onset.
