A baker's dozen mutations in a gene called
plakophilin-2 have been identified by Johns Hopkins
scientists as the most likely origins of a rare heart
condition that is among the top causes of sudden cardiac
death among young athletes. The condition, arrhythmogenic
right ventricular dysplasia, runs in families and is marked
by a poorly functioning right ventricle that beats
irregularly and over time weakens the muscle from the
buildup of excess fatty and scar tissue. Untreated ARVD can
trigger a fatal heart rhythm disturbance.
In a report on what is believed to be the first
comprehensive analysis of these genetic mutations in
patients with the disease, published in the journal
Circulation online Feb. 20, the scientists say that
some combination of the PKP2 mutations was commonly found
in 43 percent of them.
Daniel P. Judge, senior study author and a cardiac
geneticist, said, "We believe we have pinpointed the
genetic mutations responsible for the syndrome in many
people, and we expect to have a blood test to identify
those at greater risk of developing ARVD clinically
available within the next couple of months."
Judge, an assistant professor at the School of
Medicine and its
Heart Institute, said that it makes sense to screen the
immediate family members of those already diagnosed with
ARVD and PKP2 mutations for the presence of these
mutations, but he cautions that the mere presence of
mutations does not indicate an urgent risk of a fatal
arrhythmia or need of preventive therapy, such as
implantation of a defibrillator.
Estimates from researchers and the Heart Rhythm
Society suggest that ARVD accounts for up to 5 percent of
the 300,000 deaths each year in the United States from
sudden cardiac death.
As part of the study, the Johns Hopkins team analyzed
blood samples from 58 men and women previously diagnosed
with ARVD, sequencing the genetic content, or DNA, from
each sample to determine any common genetic mutations in
Study participants, 30 of whom were involved in
competitive sports, were part of Johns Hopkins' registry of
U.S. patients with the condition, which appears on MRI
scans as either a protruding pouchlike bulge from the right
side of the heart or a dilated malfunctioning right
Researchers then compared patients with PKP2 mutations
to those without. They also compared what happened in those
who had received preventive therapy for the disease and
those who had not received any. The leading therapy for
ARVD is an implantable defibrillator, which delivers a mild
shock to the heart to correct irregular rhythms and
prevents the heart from suddenly ceasing to function as the
result of a runaway heartbeat.
PKP2 was selected for initial analysis as a possible
source of ARVD because the gene is known to be more common
in patients with the condition, although previous research
did not identify how many mutations or describe them.
In the Johns Hopkins study, researchers found a total
of 13 different mutations in PKP2, with 25 patients (43
percent) having one each. Five of the mutations were new
discoveries, with four of them appearing in different,
unrelated families. Three of the mutations were determined
to be critical to overall gene translation, with another
two altering the gene's components. Two others led to
production of completely different proteins than originally
intended. These proteins act like "glue," the researchers
say, binding heart cells together. But abnormalities make
the heart more vulnerable to mechanical stresses, such as
those experienced during intense exercise.
Those with PKP2 mutations were found more likely to
develop symptoms of ARVD almost a decade earlier than those
without, at age 28 for those with mutations, compared to
age 36 for those without. Arrhythmias were also more
likely to happen earlier, by age 32 if mutations were
present, but not until age 40 if they were absent.
However, the disease appeared the same in both groups,
producing similar symptoms and clinical testing results.
Initial symptoms include palpitations, dizziness and
fainting after exercise. Previous research by the Johns
Hopkins team, also published in Circulation, showed that
ARVD frequently strikes people who are relatively young
(after puberty and before age 50), and its symptoms may
appear up to 15 years before diagnosis.
Of the 48 patients in the latest study who had an
implanted defibrillator, patients with and without PKP2
mutations had statistically similar rates for device
firings, at 52 percent and 63 percent, respectively.
"Preventive treatment with an implantable
defibrillator appears to eliminate the risk of sudden
death," said study lead author Darshan Dalal, a
cardiology research fellow at Johns Hopkins. "This
highlights why it would be a life-saving advance to have a
test for identifying precisely who should get one and who
is most at risk for this serious disease, which can
suddenly and unexpectedly strike apparently healthy
Dalal said that a screening test could also help
improve diagnosis of ARVD, which is often misdiagnosed
based on single diagnostic tests, such as MRI showing fatty
tissue in the heart muscle. A screening test, he said,
could add a more decisive and powerful tool to confirmation
of the diagnosis, currently based on a four-point scale and
up to 10 cardiac tests. Electrocardiograms and
echocardiograms are performed along with MRI tests and
tissue biopsy to confirm the buildup of fat and fibrous
tissue in the right ventricle.
Researchers say their next steps are to identify the
presence of PKP2 mutations in families of patients with
ARVD and to more precisely define the genetic mutations and
any additional environmental factors likely to trigger the
disease. "We are also going to closely monitor the
remaining 57 percent of patients without PKP2 mutations for
other possible genetic links to ARVD," Judge said.
Funding for this study, conducted at Johns Hopkins in
2005, was provided by the Bogle Foundation, Campanella
family, Wilmerding Endowments, National Institutes of
Health, Donald W. Reynolds Foundation and W.W. Smith
Charitable Trust. Other researchers were Lorraine Molin,
Jonathan Piccini, Crystal Tichnell, Cynthia James, Chandra
Bomma, Kalpana Prakasa, Philip Spevak, David Bluemke,
Theodore Abraham, Stuart Russell and Hugh Calkins. The
terms of these arrangements are being managed by JHU in
accordance with its conflict-of-interest policies.