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
Normally 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 off-spring, the affected person experiences an earlier onset. |
