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The n e w e ng l a n d j o u r na l of m e dic i n e

review article
Dan L. Longo, M.D., Editor

The -Thalassemias
Frdric B. Piel, Ph.D., and David J. Weatherall, M.D.

T
From the Evolutionary Ecology of Infec- he thalassemias are the most common human monogenic dis-
tious Disease Group, Department of Zo- eases.1 These inherited disorders of hemoglobin synthesis are characterized
ology (F.B.P.), and the Weatherall Institute
of Molecular Medicine, John Radcliffe by a reduced production of globin chains of hemoglobin.2 Worldwide, the
Hospital (D.J.W.), University of Oxford, most important forms are the - and -thalassemias, which affect production of
Oxford, United Kingdom. Address reprint the -globin and -globin chains, respectively. Although -thalassemia is the more
requests to Dr. Piel at the Department of
Zoology, University of Oxford, Tinbergen clinically significant form,3 -thalassemia occurs at a high frequency across the
Bldg., South Parks Rd., Oxford OX1 3PS, tropical belt, almost reaching fixation (a term in population genetics denoting that
United Kingdom, or at fred.piel@zoo.ox a mutant allele of a particular gene has become the only allele expressed in the
.ac.uk.
population i.e., that it has reached a frequency of 100%) in parts of southern
This article was updated on November 13, Asia. It has been estimated that about 5% of the population worldwide carry an
2014, at NEJM.org. -thalassemia variant.4-7
N Engl J Med 2014;371:1908-16. There is growing evidence that the health and economic burden of the thalas-
DOI: 10.1056/NEJMra1404415 semias is increasing owing to population growth and epidemiologic transition in
Copyright 2014 Massachusetts Medical Society.
tropical regions8 and to human migrations in other parts of the world.9-12 (Epide-
miologic transition refers to a change in patterns of population age distributions,
mortality, fertility, life expectancy, and causes of death, usually reflected by a shift
from deaths caused by infectious diseases to deaths caused by chronic and degen-
erative diseases.) Population growth leads to an absolute increase in the number
of births affected. Epidemiologic transition improves the diagnosis of hemoglo-
binopathies and the survival of affected persons, increasing the incidence of the
disorders. Population migrations, although not always leading to an increase in
global prevalence, contribute to the spreading of hemoglobinopathies and thus
increase the number of countries that require the implementation of specific inter-
ventions to educate larger populations, diagnose the disorders, and counsel affected
patients and that must account for these interventions in their health budget.
Although our epidemiologic knowledge of the distribution, prevalence, genetic
diversity, and health burden of both -thalassemia and -thalassemia is limited
and largely outdated, gaps are more pronounced in the case of -thalassemia. This
relative lack of a strong evidence base is likely to contribute to the low priority of
this disorder on many public health agendas. Existing reviews focus mainly on
molecular and clinical aspects of -thalassemia.13-16 Our aim in this article is to
provide a contemporary summary of our epidemiologic knowledge of -thalassemia
and to discuss the various challenges faced by the medical and public health com-
munities in light of recent findings on the severity and genetics of this inherited
disorder.

CL INIC A L R EL E VA NCE

Normal adult hemoglobin consists of pairs of and chains (22), and fetal he-
moglobin has two chains and two chains (22). The genes for the chains and
chains are duplicated (/, /), whereas the chains are encoded by a
single gene locus (/). In the fetus, defective production of chains is reflected
by the presence of excess chains, which form 4 tetramers, called hemoglobin

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The -Thalassemias

Barts; in adults, excess chains form 4 tetra- delivery of both the fetus and the hugely en-
mers, called hemoglobin H (HbH). Because of larged placenta.18,19 Although these complica-
their very high oxygen affinity, both tetramers tions have been well documented, there are very
cannot transport oxygen, and, in the case of HbH, limited data regarding the frequency of maternal
its instability leads to the production of inclusion deaths, particularly in the developing countries
bodies in the red cells and a variable degree of in which this condition is so common.
hemolytic anemia. HbH disease is often considered to be a rela-
More than 100 genetic forms of -thalassemia tively mild disorder. Studies have nevertheless
have thus far been identified,17 with phenotypes highlighted clinically severe phenotypes, notably
ranging from asymptomatic to lethal. Despite in nondeletional variants of the disease.20-22 In
this complexity, the severity of this disorder is fact, HbH disease is characterized by a wide
usually well correlated with the number of non- range of phenotypic characteristics. The form
functional copies of the -globin genes (Fig. 1). that results from deletions (/) usually fol-
On the basis of the numbers of -globin genes lows a relatively mild course, with moderate
lost by deletion or totally or partially inactivated anemia and splenomegaly. Aside from episodes
by point mutations, the -thalassemias are clas- of intercurrent infection, this form of HbH dis-
sified into two main subgroups: +-thalassemia ease does not require blood transfusions. How-
(formerly called -thalassemia 2), in which one ever, the variety that results from the interac-
pair of the genes is deleted or inactivated by a tions of a nondeletional -globin gene mutation
point mutation (/ or ND/, with ND de- together with 0-thalassemia (ND/) follows
noting nondeletion), and 0-thalassemia (former- a much more severe course. This is particularly
ly called -thalassemia 1), in which both pairs of
-globin genes on the same chromosome are Chromosome 16
Normal -globin gene
deleted (/).
Deletion
Clinically relevant forms of -thalassemia Nondeletional mutation
usually involve 0-thalassemia, either coinherited
with +-thalassemia (/ or ND/) and re- NORMAL SEVERITY LETHAL
sulting in HbH disease or inherited from both
parents and resulting in hemoglobin Barts hy- -Thalassemia
Normal Carrier minor HbH disease Hemoglobin Barts
drops fetalis (/), which is lethal in utero or (asymptomatic) (asymptomatic) (symptomatic) hydrops fetalis
soon after birth. Affected embryos succumb to
severe hypoxia either early in gestation (e.g., in
the case of FIL/FIL [with FIL referring to a
deletion that causes 0-thalassemia and that is
prevalent among Filipinos]) or during the third
trimester (e.g., in the case of SEA/SEA [with
SEA referring to a deletion that causes 0-thalas-
semia and that is prevalent among persons from
Southeast Asia]).18
A few children with hemoglobin Barts hydrops
fetalis who received an intrauterine transfusion
or a transfusion immediately after delivery have
Figure 1. PhenotypeGenotype Relationship in -Thalassemia.
survived to 5 years of age. These children require
In rare cases, hemoglobin H (HbH) disease or hemoglobin Barts hydrops
regular transfusions and, when appropriate, iron- fetalis can result from homozygosity for nondeletional forms of -thalas-
chelation therapy; they usually have serious clini- semia. Although HbH disease is usually symptomatic, some patients, par-
cal complications, congenital anomalies, and ticularly those with deletional variants of -thalassemia, are asymptomatic.
delays in cognitive and motor functions.9 The Furthermore, threeAUTHOR:
-globin gene Pieldeletions
- ra1404415involving severe nondeletional
mutations (e.g., hemoglobin Constant Spring) can also cause the hemoglo-
hemoglobin Barts hydrops fetalis syndrome is FIGURE: 1 of 2 With regard to the lethality of hemo-
bin Barts hydrops fetalis syndrome.
often accompanied by a variety of congenital globin Barts hydropsARTIST:
fetalis, four
AB -globin gene deletions with persistence
malformations and maternal complications, in- of an intact embryonic -globin gene for example, ()20.5 in the Medi-
AUTHOR, PLEASE NOTE:
cluding severe anemia of pregnancy, preeclamp- terranean area may behas
Figure associated
been redrawn withand
neonatal
type hassurvival.
been reset.
sia, polyhydramnios, and extreme difficulty in Please check carefully.
Issue date: 11-13-14 OLF:

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The n e w e ng l a n d j o u r na l of m e dic i n e

true when the nondeletional mutation is the alternative methods of preimplantation and pre-
-globin chain termination mutant hemoglobin conception genetic diagnosis or prenatal diagno-
Constant Spring, which is very common in many sis for example, analysis of maternal blood for
Asian countries. Nondeletional forms of HbH fetal DNA and identification of fetal cells in ma-
disease are characterized by severe anemia, of- ternal blood by staining with antibodies against
ten occurring from early life, and are associated globin chains are still at relatively early stages
with increasing splenomegaly, iron loading, and of study. Meanwhile, attempts at intrauterine and
a variety of other clinical complications, includ- postnatal therapy are associated with numerous
ing infections, leg ulcers, gallstones, and folic ethical challenges.29
acid deficiency. Although splenectomy is often The homozygous state of +-thalassemia and
indicated, nondeletional HbH disease is associ- the heterozygous state of 0-thalassemia (grouped
ated with a particularly high rate of thrombotic under the term -thalassemia minor) are asso-
complications. This observation makes the deci- ciated with a substantial reduction in the mean
sion between splenectomy and lifelong transfu- corpuscular volume and mean corpuscular hemo-
sion extremely difficult. globin. In +-thalassemia heterozygotes, the mean
Milder variants of -thalassemia act as genetic corpuscular volume and mean corpuscular hemo-
modifiers of other inherited conditions, as illus- globin are usually reduced, but there is a small
trated by epistatic interactions (when one gene overlap with normal values. Milder forms of
influences another) between -thalassemia and -thalassemia are often misdiagnosed as iron
-thalassemia23 or between -thalassemia and deficiency, although the exact frequency of mis-
hemoglobin S (sickle hemoglobin).24 Triplica- diagnosis is unknown.30 Ultimately, the diagno-
tions and quadruplications of the -globin gene sis of a particular variant of -thalassemia can
have been frequently observed in many popula- be confirmed only at the DNA level.
tions, and these can interact with -thalassemia In the pregenomic era, the frequency of
variants to produce more severe phenotypes.25,26 -thalassemia was assessed according to the
Finally, there are two syndromes in which presence of hemoglobin Barts in cord blood.
-thalassemia is associated with mental retarda- The detection of hemoglobin Barts in newborns
tion (ATR syndromes).14,27 Details regarding indicates that one or more of the four -globin
these syndromes are provided in the Supplemen- genes are dysfunctional, causing -thalassemia.
tary Appendix, available with the full text of this Although the level of hemoglobin Barts at birth
article at NEJM.org. was initially thought to be a sensitive indicator
of the presence of -thalassemia and to correlate
DI AGNOSIS well with its severity, later DNA-based studies
showed that this diagnostic method fails to de-
Prenatal diagnosis is required to identify fetuses tect a substantial number of +-thalassemia
affected by hemoglobin Barts hydrops fetalis heterozygotes and therefore underestimates the
and to reduce the risks to the mothers. The deci- frequency of -thalassemia.18 It is now well es-
sion to consider such a diagnosis usually follows tablished that diagnosis of -thalassemia on the
the finding of hypochromic microcytic red cells basis of hemoglobin Barts alone is not reliable
in both parents, in association with a normal he- and does not allow identification of the geno-
moglobin A2 level; this combination would rule types. This method is nevertheless still widely
out -thalassemia, which usually involves an ele- used in low- and middle-income countries be-
vated hemoglobin A2 level. Iron deficiency also cause it is relatively straightforward and much
has to be ruled out. When facilities for rapid cheaper than DNA analysis.
DNA diagnosis are available, the hematologic ex-
amination is followed by confirmation of the GEO GR A PHIC DIS T R IBU T ION
presence of 0-thalassemia in the parents. The
fetal diagnosis is usually made early in pregnancy Evidence that -thalassemia is highly protective
by means of chorionic-villus sampling, although against severe malaria is well established.5 As a
fetal anemia may also be diagnosed later during result of this selective advantage, heterozygous
gestation by quantitation of the peak systolic -thalassemia has reached high frequencies
velocity in the middle cerebral artery.28 Various throughout all tropical and subtropical regions,

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The -Thalassemias

including most of Southeast Asia, the Mediter- lished data). This variability is likely to be the
ranean area, the Indian subcontinent, the Middle result of a series of complex environmental fac-
East, and Africa. Common 0-thalassemia vari- tors, including the rate of malaria transmission.
ants, predominantly the SEA mutation in South- A better understanding of these interactions will
east Asia and the MED mutation in the Mediterra- help considerably in refining estimates of popu-
nean, have reached frequencies of approximately lations affected in tropical regions (Fig. 2B and
5%. Although there are at least seven deletional 2C) and in developing policies for the diagnosis
forms of +-thalassemia, as shown in Figure 2A, and management of -thalassemia on the basis
the 3.7 variants are the most common. Frequen- of characteristics of the local population. A pre-
cies of 70% and up to 90% have been reported in cise quantification of the populations at risk for
Melanesia5 and in parts of Nepal,7 respectively. -thalassemia syndromes at the national, re-
The mechanisms by which such frequencies close gional, and global levels is necessary to define
to fixation have been reached require further in- current and future resources required to provide
vestigation.31,32 In addition to studies that have accurate prenatal diagnosis of -thalassemia
revealed negative epistasis between +-thalas variants, emergency management of pregnancies
semia and the sickle cell trait, resulting in a re- involving hemoglobin Barts hydrops fetalis and
duced level of malaria protection when the two associated maternal complications, and long-
are coinherited,24 mathematical models have sug- term management of HbH disease.
gested that the frequency of +-thalassemia
might be constrained by the presence of the sick- SCR EENING
le cell gene in Africa and the Mediterranean.33,34
In conjunction with large-scale global popu- The primary objectives of thalassemia screening
lation movements in recent decades, -thalas programs are to determine the frequency of the
semia has spread to many other parts of the different genetic variants observed in the com-
world, including northern Europe and North munities and to identify and inform couples who
America. This phenomenon is best illustrated by are at risk, particularly for severe forms of the
the implementation in 1998 of a universal screen- disease occurring in areas of high frequency.
ing program for -thalassemia in California. Screening for -thalassemia is especially helpful
After the immigration of large numbers of peo- in preventing severe maternal complications in
ple from the Philippines and other Southeast the case of hemoglobin Barts hydrops fetalis and
Asian countries, the incidence of -thalassemia in providing accurate diagnosis in cases in which
syndromes in California between January 1998 -thalassemia is coinherited with hemoglobin S
and June 2006 was 11.1 cases per 100,000 persons or -thalassemia or in cases in which iron defi-
screened, with 406 cases of HbH disease and ciency is detected. Most -thalassemia screening
5cases of hemoglobin Barts hydrops fetalis.15 surveys are conducted as part of a -thalassemia
Because of the high frequency of +-thalassemia prevention program and are therefore not ade-
variants worldwide (Fig. 2A), it is likely that, quate to determine population frequencies of
with admixture of local populations and immi- -thalassemia. The benefits of population screen-
grants, such spread will increase the incidence ing should be carefully considered in any popu-
of HbH disease (Fig. 2C), in addition to creating lation in which -thalassemia variants are prev-
a health burden in a growing number of coun- alent and cases of unexplained microcytic
tries or regions. hypochromic anemia in the absence of iron defi-
Various population surveys of hemoglobinopa- ciency are observed.18 Major screening efforts
thies have revealed remarkable geographic hetero- that have been implemented in various countries
geneities in the prevalence of these disorders.35 and their main outcomes are summarized in the
In the mid-1980s, Flint and colleagues observed Supplementary Appendix.
frequencies of +-thalassemia ranging from 6 to
68% across Melanesian islands.5 Similar hetero- HE A LTH A ND EC ONOMIC BUR DEN
geneities were later described in Vanuatu.36 In a
recent micro-mapping survey conducted across Early studies of the global burden of hemoglobin
Sri Lanka, the prevalence of -thalassemia ranged disorders that evaluated the frequency of the dis-
from 2 to 20% (Weatherall DJ, et al.: unpub- orders and the number of disability-adjusted life-

n engl j med 371;20nejm.orgnovember 13, 2014 1911


The New England Journal of Medicine
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The n e w e ng l a n d j o u r na l of m e dic i n e

A Genetic Variants of -Thalassemia


515%
MED 60% 515%
3.7 I (3.7) SEA
T T 3.7 I
4.2
T

580%
4.2
3.7 III
T

1580%
540% (3.7 I)
(3.7 I) (3.7 II)
T (4.2)
+-thalassemia
0-thalassemia

B Hemoglobin Barts Hydrops Fetalis

?
Annual no. of ?
births affected
0
118
1958
59258
2591017
10183742

C HbH Disease

?
?
?
?
Annual no. of
?
births affected
0 ?
134
35131 ?
1321102
11032515
25164281

years (DALYs) associated with them were limited births, and the only data that were available pro-
by a lack of data on -thalassemia,AUTHOR:
particularly vided an estimate of 1250 pregnancies involving
Piel - ra1404415
with regard to hemoglobin Barts hydrops
FIGURE:
fetalis
2 of 2
homozygous 0-thalassemia per year in Thailand,
and its burden through stillbirths or deaths a figure that amounts to 37,242 DALYs. In com-
ARTIST: AB
shortly after delivery.37 The World Health Orga- parison, homozygous -thalassemia and hemo-
nization (WHO) does not collect data on AUTHOR, PLEASE NOTE:
still- globin E -thalassemia were estimated to result
Figure has been redrawn and type has been reset.
Please check carefully.
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The -Thalassemias

testing was cost-effective, although no published


Figure 2 (facing page). Geographic Distribution of
-Thalassemia, Hemoglobin Barts Hydrops Fetalis, data on the cost of managing a pregnancy af-
and HbH Disease. fected by hemoglobin Barts hydrops fetalis were
Panel A shows a map of our current knowledge of the available.28 Whether these results apply to coun-
distribution, prevalence, and genetic diversity of -thalas tries with larger populations and lower incomes
semia globally. Only the most common variants for than those in Hong Kong needs to be carefully
+-thalassemia (3.7and 4.2) and 0 -thalassemia
investigated.40 The benefits of accurate diagno-
( MED and SEA) are shown for each region. The vari-
ants that appear in parentheses in Panel A are those sis of iron deficiency and other hemoglobinopa-
for which the data used to make this map are limited. thies hemoglobin S and -thalassemia in
The information in Panel A is based on data from particular should also be considered. Cost
Weatherall and Clegg.18 Panel B shows current estimates benefit analyses of -thalassemia prevention pro-
of the annual number of births affected by hemoglobin
grams in Quebec,41 Iran,42 Israel,43,44 and the
Barts hydrops fetalis (/), and Panel C shows births
affected by HbH disease (/). No difference is indi- United Kingdom45 have generally confirmed the
cated between countries in which the disorder has not overall benefits of such programs (i.e., the costs
been reported and those for which no data are available. of prevention were lower than the costs of treat-
The maps in Panels B and C highlight various inconsis- ment), but the studies did not include -thalas
tencies (indicated by a question mark) in current esti-
semia. In low- and middle-income countries, the
mates, particularly in the Mediterranean area and, with
regard to HbH disease, in India and western Europe. implementation of such programs could benefit
These maps also reveal the need for subnational esti- from existing infrastructures (e.g., ongoing
mates, as in the United States and China. The informa- screening programs for phenylketonuria or glu-
tion in Panels B and C is based on data from Modell cose-6-phosphate dehydrogenase deficiency) or
and Darlison.4
could result in an overall improvement in access
to health care for local communities.46

in a total of 53,600 DALYs in Thailand, on the M A NAGEMEN T


basis of a life expectancy of 10 years and 30
years, respectively. These are likely to be under- A detailed knowledge of the prevalence of -thal
estimates because the mothers disability was assemia (including carrier status) and of its ge-
accounted for only in the last trimester of preg- netic diversity is essential to define policies aimed
nancy, without consideration of postnatal com at reducing the long-term health burden of hemo-
plications that can result in death, and because globinopathies, allowing for precise diagnosis
estimates were not calculated for HbH disease, (and therefore avoiding inaccurate and expensive
since data were collected before it was realized investigations), establishing the real cause of mi-
that a particularly severe form of HbH disease crocytosis, providing adequate genetic counseling,
occurs in many Asian countries. Information on and allocating resources to address the emergen-
the incidence of -thalassemia was insufficient cy and long-term needs of patients and their rela-
to permit calculation of the regional and global tives in a cost-effective manner. To achieve these
burden of disease.37 Global estimations of the goals, the medical community faces several im-
number of DALYs resulting from hemoglobinop- portant challenges, summarized in Table 1.
athies have recently been reported in the Global Most couples at risk for conceiving fetuses
Burden of Disease Study 2010, although no ac- with hemoglobin Barts hydrops fetalis are not
curate data on the various subtypes of thalas- currently identified. It is therefore highly likely
semia have yet been added to this project.38,39 that current estimates represent large underesti-
To our knowledge, there has been only one mates of stillbirths caused by this disorder.4 In
study to date that has investigated the costbene- the absence of specific treatments and a clear
fit ratio of an -thalassemia prevention program, understanding of the underlying mechanisms re-
whether established on its own or as part of a sponsible for the wide range of congenital ab-
broad program for all the thalassemias or for normalities associated with this lethal disorder,
genetic conditions (e.g., phenylketonuria) in gen- screening and early prenatal diagnosis represent
eral. The study, conducted in Hong Kong, con- the only options to identify pregnancies at risk
cluded that universal prenatal screening for the and to prevent severe maternal complications.
- and -thalassemias with the use of DNA Although termination of affected pregnancies is

n engl j med 371;20nejm.orgnovember 13, 2014 1913


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The n e w e ng l a n d j o u r na l of m e dic i n e

relationship in HbH disease improves, correct


Table 1. Main Challenges Associated with the Increasing Health Burden
of -Thalassemia and Recommendations for Addressing Them. genotype identification will become essential to
inform parents about reproductive risks during
Challenge Recommendation genetic counseling and to provide appropriate
Prevention of hemoglobin Barts Education, screening and counseling; care to affected patients.
hydrops fetalis prevention of maternal complications
With increasing population movements, the
Accurate diagnosis of hemoglobin Affordable DNA-screening methods diversity of combinations of -thalassemia
H disease
variants or coinherited hemoglobinopathies will
Increase in international migration International collaborations continue to increase. Although it is difficult to
Geographic heterogeneities Micro-mapping studies predict the exact phenotype of such new com-
Better understanding of phenotype Theoretical epidemiologic modeling binations, a detailed knowledge of the current
genotype interactions and of alongside clinical studies distribution of genetic variants will at least help
the role of environmental and
genetic modifiers in defining diagnostic procedures and in assess-
Need for reliable population esti- Population surveys and data sharing
ing the potential risks. Collaborations between
mates of affected persons source areas (those with a high prevalence of
Sustainable allocation of resources Greater awareness and more cost -thalassemia and substantial emigration) and
for the management and control benefit analyses sink areas (those with substantial immigra-
of thalassemias tion from source areas), as have developed be-
tween the Philippines and California and between
Sri Lanka and the United Kingdom, certainly
usually recommended owing to the increased risk represent beneficial models for both sides and
of severe maternal and fetal complications and should be replicated more widely.50,51
the psychological effects on families, cultural and The health burden of +-thalassemia is cur-
religious backgrounds need to be carefully taken rently not known. Although +-thalassemia vari-
into account when counseling couples at risk, ants alone do not represent a direct clinical prob-
both in communities in which -thalassemia has lem, they are probably the most common genetic
traditionally been prevalent and in those in which disorders in the world, and they represent impor-
it has recently been introduced through migra- tant genetic modifiers for a range of other con-
tion.18,47 A correct diagnosis early in pregnancy is ditions, including malaria, sickle cell disorders,
essential to avoid severe medical complications -thalassemia, and iron deficiency. A better
and psychological trauma. Such a diagnosis can understanding of these interactions is crucial to
be made reliably with relatively low costs provided provide appropriate diagnosis and treatment for
that pregnant women receive regular follow-up affected patients but is relevant only if interven-
care from medical staff familiar with this syn- tions resulting from our improved understand-
drome. ing are implemented in all areas in which these
Recent progress in DNA testing has revealed interactions are occurring. For example, whether
a greater phenotypic diversity in HbH disease epistatic interactions between the sickle cell trait
than previously thought.20,22 As noted above, non- and +-thalassemia that have been observed in
deletional variants are usually more severe than Kenya24 are also occurring in Indian populations
deletional variants. It is therefore crucial to con- is currently not known.
duct DNA analyses to identify the underlying Because of the remarkable geographic hetero-
genetic variant responsible for this disorder. Gap geneities in the prevalence of -thalassemia, inter-
polymerase chain reaction (PCR) and multiplex- ventions have to be tailored to the specific charac-
PCR assays allow easy screening for a range of teristics of the local population (e.g., prevalence of
common variants,48 but such methods remain the disorder in the population, ethnic makeup, and
costly and are not widely used in low- and middle- consanguinity) and the local health care sys-
income countries. With DNA testing methods tem.35,52 A better understanding of the relationship
becoming more and more affordable, it is likely among the prevalence of -thalassemia variants,
that this will become a regular part of the ser- environmental factors, and infections, combined
vices available for the control and management with modern analytic and modeling methods,
of thalassemias, particularly in Asian countries.49 would support more refined estimates of affected
As our knowledge of the phenotypegenotype populations. Such knowledge would also help

1914 n engl j med 371;20nejm.orgnovember 13, 2014

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The -Thalassemias

in the development of stratified prevention pro- munities and the support of international fund-
grams that focus, for example, on regions in which ing agencies to collect and share epidemiologic
0-thalassemia variants are the most prevalent. data.55 The recent inclusion of hemoglobinopa-
thies in the Global Burden of Disease Study56 and
C ONCLUSIONS the assessment of the burden of -thalassemia in
terms of DALYs will be meaningful only if con-
The -thalassemias represent a global health temporary and reliable data are available.
problem with a growing burden.11 A refined
knowledge of the molecular basis of -thalas No potential conflict of interest relevant to this article was
53,54 reported.
semia will be fully relevant from a public Disclosure forms provided by the authors are available with
health perspective only if it is complemented by the full text of this article at NEJM.org.
detailed epidemiologic data. To ensure appropri- We thank Sunetra Gupta, Bridget S. Penman, and Carinna
Hockham for comments on earlier versions of the manuscript;
ate care of patients and the sustainability of and Michael Angastiniotis, J. Kevin Baird, Vivian Chan, Roshan
health care systems, more effort must be put into Colah, Raffaella Colombatti, Dappa Diallo, Rick M. Fairhurst,
obtaining evidence-based estimates of affected Jeremy Farrar, Freya J.I. Fowkes, Suthat Fucharoen, Elizabeth
George, Scott D. Grosse, Batrice Gulbis, Cornelis L. Harteveld,
populations, providing resources for the preven- Simon I. Hay, Douglas R. Higgs, Dipty Jain, Marina Kleanthous,
tion, control, and management of the thalas- Dominic P. Kwiatkowski, Bernadette Modell, Robyn Norton,
semias, and performing cost-effectiveness analy- Franois Nosten, Kwaku Ohene-Frempong, Carmencita D. Padilla,
Mohamed C. Rahimy, Vadlamudi R. Rao, David C. Rees, Kirk A.
ses.28 Such goals will be achieved only through a Rockett, Mary Anne Tan, Lon Tshilolo, Elliott P. Vichinsky, and
concerted effort by the research and medical com- Thomas N. Williams for their general support.

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