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progeria hutchinson

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progeria hutchinson

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correspondence

ified events included acute coronary syndromes,
symptomatic cardiac arrhythmia, cardiac arrest,
and therapeutic discharge of an implantable cardioverter–defibrillator. However, the authors make
no mention of stress-induced (takotsubo) cardiomyopathy as an alternative diagnosis that can
mimic acute coronary syndromes in this setting.1
Given that cardiovascular events were based on
presumptive diagnoses made by emergency room
physicians, misclassification bias is likely. Stressinduced cardiomyopathy can be diagnosed only
after significant coronary artery disease has been
ruled out by angiography.2
Ramin Farzaneh-Far, M.D.
University of California, San Francisco
San Francisco, CA 94143
[email protected]

Afshin Farzaneh-Far, M.D.
Duke University Medical Center
Durham, NC 27710
1. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral

features of myocardial stunning due to sudden emotional stress.
N Engl J Med 2005;352:539-48.
2. Abdulla I, Ward MR. Tako-tsubo cardiomyopathy: how
stress can mimic acute coronary occlusion. Med J Aust 2007;
187:357-60.

Spitters points out that besides the overall increase in cardiovascular events during the days
when the German team played, the association
between the magnitude of this increase and the
amount of stress presumably imposed by the
individual games further supports a causal relationship.
Lippi and Targher comment that — besides
stress — certain lifestyle habits may contribute
to cardiovascular events in association with
broadcast sports matches. Heavy alcohol drinking was ruled out in all our patients who present­
ed to the emergency medicine physicians from
May 1 to July 31, 2006. Otherwise, we agree with
these comments, as well as the reasonable suggestions for treatment.
R. and A. Farzaneh-Far discuss stress-associated takotsubo cardiomyopathy as an underlying
cause of acute coronary syndromes. This disease
is diagnosed in about 1 to 2% of all patients
presenting with chest pain and ST-segment elevation, and almost exclusively in postmenopausal
women without clinically significant coronary
heart disease; few cases have been reported in
men.1 This rare disease — if it occurred at all
— went undetected in our study.

The authors reply: In response to the com- Ute Wilbert-Lampen, M.D.
ments of Schwenk: no decrease in acute cardiac Gerhard Steinbeck, M.D.
events was observed for 3 weeks after the final
Ludwig-Maximillians-Universität Munich
and 4 weeks after the most dramatic match against D-81377 Munich, Germany
Italy. Thus, a phase shift did not occur after a [email protected]
period of 4 weeks; the long-term outcome for the
1. Prasad A. Apical ballooning syndrome: an important difpatients with cardiac events is not known because ferential diagnosis of acute myocardial infarction. Circulation
of the preclinical study design.
2007;115(5):e56-e59.

Hutchinson–Gilford Progeria Syndrome
To the Editor: In an otherwise elegant clinical
description of the Hutchinson–Gilford progeria
syndrome by Merideth and colleagues (Feb. 7 issue),1 we take exception to the authors’ suggestion that their findings have overarching significance with respect to an understanding of normal
aging. Although some of the changes that characterize the Hutchinson–Gilford progeria syndrome look like aging, other characteristic features
of the syndrome (e.g., elevated platelet counts, pro­
longed prothrombin times, and functional oral
deficits) do not. Moreover, certain prominent fea-

tures of human aging — for example, the activation of inflammatory pathways — are not typical
of the Hutchinson–Gilford progeria syndrome.
On the basis of studies in mice, it is likely that
every organ undergoes distinct molecular changes
with age.2-4 Authentic genetic models of accelerated aging should not only give rise to phenotypes that mimic aging but also produce changes in gene expression that are typical of normal
aging. This is not the case for the Hutchinson–
Gilford progeria syndrome or other progeria syn­
dromes. It is time to relinquish the myth that

n engl j med 358;22  www.nejm.org  may 29, 2008

The New England Journal of Medicine
Downloaded from nejm.org on August 29, 2012. For personal use only. No other uses without permission.
Copyright © 2008 Massachusetts Medical Society. All rights reserved.

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The

n e w e ng l a n d j o u r na l

the Hutchinson–Gilford progeria syndrome and
related “progeria” syndromes hold the key to an
understanding of aging. This is a convenient and
hopeful conclusion, but it is inconsistent with
what is known about aging.
William B. Ershler, M.D.
Luigi Ferrucci, M.D., Ph.D.
Dan L. Longo, M.D.
National Institute on Aging
Baltimore, MD 21225
1. Merideth MA, Gordon LB, Clauss S, et al. Phenotype and

m e dic i n e

1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the

mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51.
2. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts
canonical FGF receptor into a specific receptor for FGF23. Nature
2006;444:770-4.
3. Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B.
Premature aging-like phenotype in fibroblast growth factor 23 null
mice is a vitamin D-mediated process. FASEB J 2006;20:720-2.
4. Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y.
Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin
D endocrine system. Mol Endocrinol 2003;17:2393-403.

To the Editor: The lamin A gene (LMNA) mutation in the Hutchinson–Gilford progeria syndrome
results in the synthesis of progerin. How progerin
causes the clinical phenotype is poorly understood. Dysregulated gene expression is one possibility. The search for dysregulated genes may be
based on the phenotypic characterization. Merideth et al. report a previously unrecognized phenotypic feature of progeria — namely, elevated
serum phosphorus levels associated with an inappropriately low fractional excretion of phosphorus and normal creatinine clearance. Hyperphosphatemia and evidence of accelerated aging are
features of klotho deficiency and fibroblast growth
factor (FGF)–23 deficiency in mice.1-3 Klotho is a
hormone secreted by the kidney that has several
roles, including its role as a cofactor that is essential for activation of FGF-receptor signaling by
FGF-23.2 FGF-23 is a phosphaturic hormone that
increases the fractional excretion of phosphate.3
Correction of hyperphosphatemia in Fgf-23−/− mice
or klotho−/− mice by targeting vitamin D reduces
the accelerated aging that is characteristic of the
model.3,4 The hypothesis that disruption of the
klotho–FGF-23 axis is one potentially treatable
downstream consequence of the expression of
progerin should be explored.
Alberto Ortiz, M.D.

The authors reply: We agree with Ershler et al.
that the Hutchinson–Gilford progeria syndrome
does not perfectly model the aging process, just
as, for instance, familial hypercholesterolemia
does not produce every characteristic of coronary
artery disease and alpha1-antitrypsin deficiency
does not exactly recapitulate emphysema. In these
examples, however, important insights may be
derived from imperfect models, and certain aspects of the aging process may be informed by
the Hutchinson–Gilford progeria syndrome. In
fact, evidence continues to accrue in support of a
role of progerin, the abnormal lamin A protein
that accumulates in the Hutchinson–Gilford progeria syndrome, in promoting aging. Specifically,
increasing levels of progerin are found in normal
cells as people age,1 and individual cells with increased progerin show nuclear membrane abnormalities.2 Furthermore, levels of progerin accumulate with age in the skin of normal persons.3
Regarding the relationship between hyperphos­
phatemia and aging, our data indicate that the
set point for renal phosphorus (phosphate) re­
absorption in the Hutchinson–Gilford progeria
syndrome may be slightly altered; the fractional
excretion of phosphate, although within normal
limits, may be relatively low, allowing serum
phosphorus to remain high. Ortiz suggests that
impaired renal expression of klotho and Fgf-23
may account for this. Our own data, as well as
published information,4,5 indicate that the expression of KLOTHO and FGF-23 is not affected
by the Hutchinson–Gilford progeria syndrome,
at least not in skin fibroblasts.
Melissa A. Merideth, M.D., M.P.H.
Francis S. Collins, M.D., Ph.D.
William A. Gahl, M.D., Ph.D.

Fundacion Jimenez Diaz
28040 Madrid, Spain
[email protected]

National Human Genome Research Institute
Bethesda, MD 20892
[email protected]

course of Hutchinson–Gilford progeria syndrome. N Engl J Med
2008;358:592-604.
2. Lustig A, Weeraratna AT, Wood WW III, et al. Transcriptome
analysis of age-, gender-, and diet-associated changes in murine
thymus. Cell Immunol 2007;245:42-61.
3. Xu X, Zhan M, Duan W, et al. Gene expression atlas of the
mouse central nervous system: impact and interactions of age,
energy intake and gender. Genome Biol 2007;8:R234.
4. Zahn JM, Poosala S, Owen AB, et al. AGEMAP: a gene expression database for aging in mice. PLoS Genet 2007;3(11):e201.

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n engl j med 358;22  www.nejm.org  may 29, 2008

The New England Journal of Medicine
Downloaded from nejm.org on August 29, 2012. For personal use only. No other uses without permission.
Copyright © 2008 Massachusetts Medical Society. All rights reserved.

correspondence
1. Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in

human aging. Science 2006;312:1059-63.
2. Cao K, Capell B, Erdos MR, Djabali K, Collins FSA. A lamin
A protein isoform overexpressed in Hutchinson-Gilford progeria
syndrome interferes with mitosis in progeria and normal cells.
Proc Natl Acad Sci U S A 2007;104:4949-54.
3. McClintock D, Ratner D, Lokuge M, et al. The mutant form of
lamin A that causes Hutchinson-Gilford progeria is a biomarker
of cellular aging in human skin. PLoS ONE 2007;2(12):e1269.

4. Csoka AB, English SB, Simkevich CP, et al. Genome-scale

expression profiling of Hutchinson-Gilford progeria syndrome
reveals widespread transcriptional misregulation leading to meso­
dermal/mesenchymal defects and accelerated atherosclerosis.
Aging Cell 2004;3:235-43.
5. Ly DH, Lockhart DJ, Lerner RA, Schultz PG. Mitotic misregulation and human aging. Science 2000;287:2486-92.

Effect of Cost Sharing on Screening Mammography
To the Editor: The study of cost sharing on
mammography by Trivedi et al. (Jan. 26 issue)1
and the editorial by Bach2 may lead policymakers
to favor value-based insurance over high-deductible health plans. Following the principles of
value-based insurance to their logical end, Americans might consider health insurance that imposes no cost sharing whatsoever for cost-effective
health care while excluding unproved technologies from coverage. Such insurance does exist —
the National Health Service in the United Kingdom and Medicare in Canada are two examples.
The hypothetical paradox described by Bach,
in which a value-based insurance plan might
encourage the use of implantable cardioverter–
defibrillators (ICDs) while discouraging prostatespecific antigen (PSA) testing, accurately describes
reality in Ontario, Canada. ICDs are free, but
asymptomatic men currently pay the full cost of
PSA testing — about $25. (Notably, with evidence
accumulating that PSA testing may have contributed to reductions in mortality due to prostate
cancer, Ontario’s Minister of Health has pledged
to add PSA testing to the list of covered benefits.)
Although the Canadian system does have prob­
lems,3 it is sustainable,4 health outcomes are relatively good,5 and administrative costs are low.6
Irfan A. Dhalla, M.D.
University of Toronto
Toronto, ON M5G 2C4, Canada
[email protected]

4. Dhalla I. Canada’s health care system and the sustainability

paradox. CMAJ 2007;177:51-3.
5. Nolte E, McKee CM. Measuring the health of nations: updating an earlier analysis. Health Aff (Millwood) 2008;27:58-71.
6. Woolhandler S, Campbell T, Himmelstein DU. Costs of health
care administration in the United States and Canada. N Engl J
Med 2003;349:768-75.

To the Editor: Trivedi et al. describe cost sharing by patients as a mechanism “designed to control health care spending.” They report that fewer
women have biennial mammograms when they
must pay part of the cost of screening. What is
not reported is whether health care spending is
decreased and, if so, by how much.
It seems reasonable to assume that there will
always be trade-offs in calculating how much to
spend for health care and that some care for
some people will be judged “unaffordable.” The
details of that calculation in a publicly financed
system are a public policy matter and should be
democratically determined. To do that rationally,
both the health costs and dollar costs must be
known.
The article by Trivedi et al. provides only one
element of this important calculation. To conclude that cost sharing for mammograms is bad
policy when the patient must pay requires that
we know both elements.
Harvey E. Golden, M.D.
Rush Medical College
Chicago, IL 60612
[email protected]

Tara Kiran, M.D.
Regent Park Community Health Centre
Toronto, ON M5A 2B2, Canada
1. Trivedi AN, Rakowski W, Ayanian JZ. Effect of cost sharing

on screening mammography in Medicare health plans. N Engl J
Med 2008;358:375-83.
2. Bach PB. Cost sharing for health care — whose skin? Which
game? N Engl J Med 2008;358:411-3.
3. Detsky AS, Naylor CD. Canada’s health care system — reform delayed. N Engl J Med 2003;349:804-10.

The authors reply: As Dhalla and Kiran indicate, our study supports policies to reduce or
eliminate copayments for cost-effective health
services, such as screening mammography, that
provide relatively greater value than other screening services, such as PSA testing. Ironically, the

n engl j med 358;22  www.nejm.org  may 29, 2008

The New England Journal of Medicine
Downloaded from nejm.org on August 29, 2012. For personal use only. No other uses without permission.
Copyright © 2008 Massachusetts Medical Society. All rights reserved.

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