Professional Documents
Culture Documents
Talasemia Beta PDF
Talasemia Beta PDF
Review Article
Medical Progress
T HE b-T HALASSEMIAS
NANCY F. OLIVIERI, M.D.
Numb e r 2
99
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Chromosome 11
Locus-control
region
Globin-Chain Synthesis
(% of total)
50
cb
a
b
30
10
z
d
18
30
Birth
18
30
42
Figure 1. The b -Globin Gene Cluster on the Short Arm of Chromosome 11.
In Panel A, the b -globinlike genes are arranged in the order in which they are expressed during development. The Gg and Ag genes
are both active genes that produce g -globin chains that differ only at position 136 (glycine is the product of the Gg gene, and alanine
is the product of the Ag gene). The cb gene is a pseudogene, an evolutionary remnant of a previously active b -globinlike gene.
Areas of nucleotide homology upstream from the initiation codon of each active gene, termed promoter elements, are involved in
the initiation of transcription and hence play a vital part in gene regulation. The cluster also contains regulatory elements that interact to promote erythroid-specific gene expression and to coordinate the developmental regulation of each gene, including hemoglobin switching. These include enhancers, distant regulatory elements that increase gene expression, and a master sequence,
the clusters essential distal regulatory element, the b -globin locus-control region. This is a region that lies 20 kb upstream from
the e-globin gene.13 It encompasses five erythroid-lineagespecific nuclease hypersensitive sites (shown in red) that permit expression of the downstream genes. In addition to these elements for up-regulation, several suppressor regions, or silencers, have been
defined in the b -globin gene cluster.
Panel B shows the timing of the normal developmental switching of human hemoglobin. Early in fetal life the synthesis of the
embryonic a-globinlike (z) chains switches to that of a-globin, which is produced thereafter. At the same time, the synthesis of
embryonic beta-like (e) chains switches to that of g -globin chains. The a-globin and g -globin chains combine to form fetal hemoglobin (a2g2), the main b -globinlike globin during the remainder of fetal life and throughout early postnatal life. As a result of the
decline in the synthesis of g -globin chains in patients with b -thalassemia, fetal hemoglobin production becomes insufficient to
compensate for the excess of a-globin chains, the production of which is unaffected in b -thalassemia.
Jul y 8 , 19 9 9
Downloaded from www.nejm.org by GERARDO JUAREZ on November 23, 2008 .
Copyright 1999 Massachusetts Medical Society. All rights reserved.
Deletions
Intron
Intron
5'
Exon 1 Intron
Exon 2
Exon 3 Intron
3'
Other Mutations
Mutation affecting initiation of
transcription
Mutation affecting splicing of
RNA from introns
Polyadenylation-signal mutation
Mutation affecting initiation of
translation
Nonsense mutation
Frame-shift mutation
Figure 2. The Normal Structure of the b-Globin Gene and the Locations and Types of Mutations Resulting in b-Thalassemia.
All b-globinlike genes contain three exons and two introns between codons 30 and 31 and 104 and 105, respectively. The primary
action of all the mutations is to abolish the output of b-globin chains (b0-thalassemia; shown in red) or reduce the output (b+-thalassemia; shown in green). The 170 different mutations that act in this way may interfere with the action of the b-globin gene at the
transcriptional level, in the processing of the primary transcript, in the translation of b-globin messenger RNA, or in the post-translational stability of the b-globin gene product.
to produce functional mRNA, result in b0-thalassemia. Mutations in highly conserved nucleotides flanking these sequences, or in cryptic splice sites, which
resemble a donor or acceptor splice site, result in
severe as well as mild b+-thalassemia. Substitutions
or small deletions affecting the conserved AATAAA
sequence in the 3' untranslated region result in ineffective cleavage of the mRNA transcript and cause
mild b+-thalassemia.
Mutations that interfere with translation involve the
initiation, elongation, or termination of globin-chain
production and result in b0-thalassemia. Approximately half of all b-thalassemia mutations interfere
with translation; these include frame-shift or nonsense
mutations, which introduce premature termination
codons and result in b0-thalassemia. A more recently identified family of mutations, usually involving
exon 3, results in the production of unstable globin
chains of varying lengths that, together with a relative
excess of a-globin chains, precipitate in red-cell precursors and lead to ineffective erythropoiesis, even in
the heterozygous state. This is the molecular basis for
dominantly inherited (b+) thalassemia. In addition,
missense mutations, resulting in the synthesis of unstable b-globin chains, cause b-thalassemia.
PATHOPHYSIOLOGY
Mechanisms of Anemia
Numb e r 2
101
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Excess free
a-globin chains
Formation of heme
and hemichromes
Denaturation
Degradation
Iron-mediated toxicity
Hemolysis
Increased
erythropoietin
synthesis
Reduced tissue
oxygenation
Skeletal
deformities,
osteopenia
Ineffective
erythropoiesis
Membrane
binding of
IgG and C3
Anemia
Erythroid
marrow
expansion
Removal of
damaged red cells
Splenomegaly
Increased
iron absorption
Iron
overload
The severe ineffective erythropoiesis results in erythroid marrow expansion to as much as 30 times the
normal level. Both an increase in plasma volume as
a result of shunting through expanded marrow and
102
Jul y 8 , 19 9 9
Downloaded from www.nejm.org by GERARDO JUAREZ on November 23, 2008 .
Copyright 1999 Massachusetts Medical Society. All rights reserved.
MED IC A L PR OGR ES S
Iron overload of tissue, which is fatal with or without transfusion if not prevented or adequately treated,
is the most important complication of b-thalassemia
and is a major focus of management.40 In patients
who are not receiving transfusions, abnormally regulated iron absorption results in increases in body
iron burden ranging from 2 to 5 g per year, depending on the severity of erythroid expansion.41,42 Regular transfusions may double this rate of iron accumulation. Although most clinical manifestations of
iron loading do not appear until the second decade
of life in patients with inadequate chelation, evidence from serial liver biopsies in very young patients indicates that the deleterious effects of iron are
initiated much earlier than this. After approximately
one year of transfusions, iron begins to be deposited
in parenchymal tissues,43 where it may cause substantial toxicity as compared with that within reticVol ume 341
Numb e r 2
103
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
A decision to initiate regular transfusions in patients with b-thalassemia may be difficult and should
be based on the presence and severity of the symptoms and signs of anemia, including failure of growth
and development. Only rarely is genotyping helpful
in this decision. The goals of transfusion include correction of anemia, suppression of erythropoiesis, and
inhibition of increased gastrointestinal absorption
of iron. Hypertransfusion and supertransfusion
Jul y 8 , 19 9 9
Downloaded from www.nejm.org by GERARDO JUAREZ on November 23, 2008 .
Copyright 1999 Massachusetts Medical Society. All rights reserved.
MED IC A L PR OGR ES S
50
40
10,000
30
Homozygous
hemochromatosis
20
5,000
Heterozygous
hemochromatosis
10
15,000
0
0
10
20
30
40
50
Age (years)
Figure 4. Hepatic Iron Burden over Time and the Effect of Various Hepatic Iron Concentrations in Patients with Thalassemia Major, Homozygous Hemochromatosis, and Heterozygous Hemochromatosis.
Because efforts to maintain normal hepatic iron concentrations in patients with thalassemia major are frequently associated with adverse reactions to deferoxamine, an optimal range within which hepatic iron may be safely maintained,
derived in part from clinical experience with the iron-loading disorder hereditary hemochromatosis, has been proposed.
In a proportion of patients who are heterozygous for hemochromatosis, moderate iron loading corresponding to concentrations of approximately 3.2 to 7 mg of iron per gram of liver, dry weight (indicated in yellow), is associated with
normal survival without complications of iron overload.60 In patients who are homozygous for this disorder, concentrations exceeding this range, up to approximately 15 mg of iron per gram of liver, dry weight (indicated in blue), are associated with an increased risk of complications of iron overload,61 whereas maintenance of levels exceeding 15 mg of
iron per gram of liver, dry weight, greatly increases the risk of cardiac disease and early death in patients with thalassemia major.52 In patients with thalassemia major who receive regular transfusions, the rate of iron loading is much
more accelerated and death usually occurs before the third decade of life. The goal of treatment is the maintenance of
a body-iron burden corresponding to a hepatic iron concentration of approximately 3.2 to 7 mg of iron per gram of liver,
dry weight, achievable with regular deferoxamine therapy.40 The serum ferritin concentrations corresponding to these
ranges of hepatic iron are not clearly defined.
regimens, which achieve these goals but are associated with substantial iron loading,40,75 have been
supplanted by regimens in which the hemoglobin
concentration before transfusion does not exceed
9.5 g per deciliter.76 These newer regimens are associated with both adequate marrow suppression and
relatively lower rates of iron accumulation.
The beneficial effects of iron-chelating therapy with
parenteral deferoxamine, the only chelating agent
widely available for clinical use, on the complications
of iron loading have recently been reviewed.40 As a
result of programs of deferoxamine therapy, the prognosis for patients in countries able to afford this
therapy has greatly improved, in contrast to the prognosis for patients in developing countries, where widespread implementation of this regimen is still awaited.
Adequate deferoxamine therapy prevents early death
from cardiac disease: maintenance of body iron burdens corresponding to hepatic iron concentrations of
less than 15 mg per gram, dry weight, greatly de-
crease the risk of clinical disease.52 Nearly normal concentrations of hepatic iron can be maintained with
modern regimens of deferoxamine. Moreover, deferoxamine arrests the progression of hepatic fibrosis to
cirrhosis, even when administered in regimens that
stabilize, rather than reduce, the body iron burden.77
The importance of this finding in the seminal study
that ushered in the modern era of deferoxamine therapy is highlighted by evidence that in another form
of iron overload, hereditary hemochromatosis, progression of hepatic fibrosis is a critical event associated with an increased risk of death.61
A favorable effect of a sustained reduction in body
iron is also suggested by the relatively low prevalence
of thyroid, parathyroid, and adrenal abnormalities in
the modern era.78 In parallel, early and intensive deferoxamine therapy may increase the incidence of
normal sexual maturation,78 but it apparently does not
reverse established abnormalities.40 Similarly, although
deferoxamine prevents diabetes mellitus,52 there is
Vol ume 341
Numb e r 2
105
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Experimental Therapies
Chelators Other Than Deferoxamine
Several trials have attempted to augment the synthesis of fetal hemoglobin in an effort to ameliorate
the severity of b-thalassemia.101 Administration of intravenous 5-azacytidine was associated with increases
in the hemoglobin concentration in a few patients102;
the potential toxicity of the drug later shifted interest
to less toxic alternatives. Therapy with hydroxyurea,103,104 butyric acid compounds,105 and these agents
in combination106 has reduced or eliminated transfusion requirements in some patients. Other studies
have reported only small increases in fetal and total
hemoglobin concentrations during the administration of hydroxyurea107,108 and both intravenous109,110
and oral111,112 butyrate compounds.
How can the augmentation of fetal hemoglobin
be optimized? Studies in humans and animal models
of b-thalassemia, including transgenic mice,113 have
Jul y 8 , 19 9 9
Downloaded from www.nejm.org by GERARDO JUAREZ on November 23, 2008 .
Copyright 1999 Massachusetts Medical Society. All rights reserved.
MED IC A L PR OGR ES S
suggested that increases in the production of g-globin chains may be influenced by the degree of erythroid marrow expansion, sequential administration of
specific combinations of agents, the degree to which
the g-globin gene is already partially activated, or all
of these.113-116 Furthermore, the striking clinical responses observed in patients with mutations104-106 that
delete specific sequences within the b-globin gene
cluster that may have a key role in the silencing of
adjacent genes117 indicate that delineation of some cis
sequences may influence the inducibility of the g-globin gene.
Although they address a highly desirable, costeffective goal in b-thalassemia, therapies to increase
the synthesis of fetal hemoglobin in the disorder have,
with few exceptions, proved disappointing to date.
Nonetheless, important avenues to be pursued in further studies include the identification of specific mutations that may respond to therapy, particularly with
specific combinations of agents.
Gene Therapy
Among the first diseases to be studied at the molecular level, the b-thalassemias remain a model for
understanding the relation between the molecular
pathology of a disease and its clinical diversity. At
the same time, these disorders have become an increasingly important part of clinical practice in all
countries with large populations from the tropics.
The marked increase in survival, to the fifth decade
of life, of patients with well-managed b-thalassemia
in developed countries represents one of the most
dramatic alterations in morbidity and mortality associated with a genetic disease in this century. Still,
nearly 75 years after the fascinating initial description of peculiar bone changes and other signs and
symptoms of the disorder, the b-thalassemias have
emerged as a huge public health problem worldwide.
They remain a therapeutic challenge for the next
millennium.
I am indebted to David Nathan, David Weatherall, Gary Brittenham, John Porter, Alan Schechter, Elliott Vichinsky, Brenda Gallie, Helen Chan, Peter Durie, John Dick, Marc Giacomelli, Paul
Ranalli, Arthur Schafer, Michele Brill-Edwards, Lori West, Miriam
Kaufman, Michael Langlois, David Kern, Bob Phillips, Maria Muraca, Bill Graham, Rhonda Love, Doug Templeton, John Polanyi,
and Michael Baker, without whose support this review would not have
been written.
REFERENCES
1. Cooley TB, Lee P. A series of cases of splenomegaly in children with
anemia and peculiar bone changes. Trans Am Pediatr Soc 1925;37:29-30.
2. Rietti F. Ittero emolitico primitivo. Alti Accad Sci Med Nat Ferrara
1925;2:14-9.
3. Greppi E. Ittero emolitico familiare con aumento della resistenza dei
globuli. Minerva Med 1928;8:1-11.
4. Micheli P, Penati P, Momigliano LG. Ulteriori richereche sulla anemia
ipocromica splenomegalica con poichilocitosi. Atti Soc Ital Ematol Haematol (Pavia) 1935;16:Suppl 1:10-3.
5. Whipple GH, Bradford WL. Mediterranean disease thalassemia
(erythroblastic anemia of Cooley): associated pigment abnormalities simulating hemochromatosis. J Pediatr 1936;9:279-311.
6. Weatherall DJ, Clegg JB. Thalassaemia a global public health problem. Nat Med 1996;2:847-9.
7. Higgs DR. a-Thalassaemia. Baillieres Clin Haematol 1993;6:117-50.
8. Chui DH, Waye JS. Hydrops fetalis caused by alpha-thalassemia: an
emerging health care problem. Blood 1998;91:2213-22.
9. Weatherall DJ. The thalassemias. In: Stamatoyannopoulos G, Nienhuis
AW, Majerus PH, Varmus H, eds. The molecular basis of blood diseases.
2nd ed. Philadelphia: W.B. Saunders, 1994:157-205.
10. Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of
the haemoglobinopathies. Baillieres Clin Haematol 1993;6:215-62.
11. Weatherall DJ. Common genetic disorders of the red cell and the malaria hypothesis. Ann Trop Med Parasitol 1987;81:539-48.
12. Allen SJ, ODonnell A, Alexander NDE, et al. a+-Thalassaemia protects children against disease caused by other infections as well as malaria.
Proc Natl Acad Sci U S A 1997;94:14736-41.
13. Orkin SH. Regulation of globin gene expression in erythroid cells. Eur
J Biochem 1995;231:271-81.
14. Wood WG, Weatherall DJ. Developmental genetics of the human haemoglobins. Biochem J 1983;215:1-10.
15. Wood WG. Increased HbF in adult life. Baillieres Clin Haematol 1993;
6:177-213.
16. Grosveld F, Dillon N, Higgs D. The regulation of human globin gene
expression. Clin Haematol 1993;6:31-55.
17. Nathan DG, Gunn RB. Thalassemia: the consequences of unbalanced
hemoglobin synthesis. Am J Med 1966;41:815-30.
18. Wickramasinghe SN. The morphology and kinetics of erythropoiesis
in homozygous b-thalassaemia. In: Congenital disorders of erythropoiesis.
Amsterdam: Elsevier, 1976:221-37.
19. Yuan J, Angelucci E, Lucarelli G, et al. Accelerated programmed cell
death (apoptosis) in erythroid precursors of patients with severe beta-thalassemia. Blood 1993;82:374-7.
20. Schrier SL. Pathobiology of thalassemic erythrocytes. Curr Opin Hematol 1997;4:75-8.
21. Shinar E, Rachmilewitz EA. Haemoglobinopathies and red cell membrane function. Baillieres Clin Haematol 1993;6:357-69.
22. Grinberg LN, Rachmilewitz EA. Oxidative stress in b-thalassemic red
blood cells and potential use of antioxidants. In: Beuzard Y, Lubin B, Rosa
J, eds. Sickle cell disease and thalassaemia: new trends in therapy. London:
Colloque INSERM/John Libby Eurotext, 1995:519-24.
23. Sorensen S, Rubin E, Polster H, Mohandas N, Schrier S. The role of
membrane skeletal-associated alpha-globin in the pathophysiology of betathalassemia. Blood 1990;75:1333-6.
24. Shalev O, Repka T, Goldfarb A, et al. Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle RBC
both in vitro and in vivo. Blood 1995;86:2008-13.
25. Rioja L, Girot R , Garabedian M, Cournot-Witmer G. Bone disease
in children with homozygous beta-thalassemia. Bone Miner 1990;8:6986.
26. Orvieto R, Leichter I, Rachmilewitz EA, Margulies JY. Bone density,
mineral content, and cortical index in patients with thalassemia major and
Numb e r 2
107
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
108
57. Witzleben CL, Wyatt JP. The effect of long survival on the pathology
of thalassaemia major. J Pathol Bacteriol 1961;82:1-12.
58. Jean G, Terzoli S, Mauri R, et al. Cirrhosis associated with multiple
transfusions in thalassaemia. Arch Dis Child 1984;59:67-70.
59. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its
influence on the diagnostic yield of the percutaneous needle biopsy of the
liver. Lancet 1986;1:523-5.
60. Cartwright GE, Edwards CQ, Kravitz K, et al. Hereditary hemochromatosis: phenotypic expression of the disease. N Engl J Med 1979;301:
175-9.
61. Niederau C, Fischer R , Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.
Gastroenterology 1996;110:1107-79.
62. Parkes JG, Randell EW, Olivieri NF, Templeton DM. Modulation by
iron loading and chelation of the uptake of non-transferrin-bound iron by
human liver cells. Biochim Biophys Acta 1995;1243:373-80.
63. Italian Working Group on Endocrine Complications in Non-endocrine Diseases. Multicentre study on prevalence of endocrine complications
in thalassaemia major. Clin Endocrinol (Oxf ) 1995;42:581-6.
64. Cavallo-Perin P, Pacini G, Cerutti F, et al. Insulin resistance and hyperinsulinemia in homozygous b-thalassemia. Metabolism 1995;44:281-6.
65. Gullo L, Corcioni E, Brancati C, Bria M, Pezzilli R , Sprovieri G. Morphologic and functional evaluation of the exocrine pancreas in b-thalassemia major. Pancreas 1993;8:176-80.
66. Magro S, Puzzonia P, Consarino C, et al. Hypothyroidism in patients
with thalassemia syndromes. Acta Haematol 1990;84:72-6.
67. Sklar CA, Lew LQ, Yoon DJ, David R. Adrenal function in thalassemia major following long-term treatment with multiple transfusions and
chelation therapy: evidence for dissociation of cortisol and adrenal androgen secretion. Am J Dis Child 1987;141:327-30.
68. Bacalo A, Kivity S, Heno N, Greif Z, Greif J, Topilsky M. Blood transfusion and lung function in children with thalassemia major. Chest 1992;
101:362-70.
69. Factor JM, Pottipati SR , Rappaport I, Rosner IK, Lesser ML, Giardina PJ. Pulmonary function abnormalities in thalassemia major and the role
of iron overload. Am J Respir Crit Care Med 1994;149:1570-4.
70. Tai DYH, Wang YT, Lou J, Wang WY, Mak KH, Cheng HK. Lungs
in thalassaemia major patients receiving regular transfusion. Eur Respir J
1996;9:1389-94.
71. Anapliotou MLG, Kastanias IT, Psara P, Evangelou EA, Liparaki M,
Dimitriou P. The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches. Clin Endocrinol (Oxf ) 1995;42:279-87.
72. Filosa A, Di Maio S, Vocca S, Saviano A, Esposito G, Pagano L. Longitudinal monitoring of bone mineral density in thalassemic patients: genetic structure and osteoporosis. Acta Paediatr 1997;86:342-6.
73. Olivieri NF. Thalassaemia: clinical management. Baillieres Clin Haematol 1998;11:147-62.
74. Cao A, Galanello R , Rosatelli MC. Prenatal diagnosis and screening
of the haemoglobinopathies. Baillieres Clin Haematol 1998;11:215-38.
75. Fosburg MT, Nathan DG. Treatment of Cooleys anemia. Blood 1990;
76:435-44.
76. Cazzola M, Bornga-Pignatti C, Locatelli F, Ponchio L, Beguin Y, De
Stefano P. A moderate transfusion regimen may reduce iron loading in
b-thalassemia major without producing excessive expansion of erythropoiesis. Transfusion 1997;37:135-40.
77. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation
therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clinical progress. BMJ 1974;2:16-20.
78. Bronspiegel-Weintrob N, Olivieri NF, Tyler B, Andrews DF, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy
on gonadal function in b-thalassemia major. N Engl J Med 1990;323:7139.
79. Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta
Haematol 1996;95:26-36.
80. Porter JB. A risk-benefit assessment of iron-chelation therapy. Drug
Saf 1997;17:407-21.
81. Brittenham GM, Cohen AR, McLaren CE, et al. Hepatic iron stores
and plasma ferritin concentration in patients with sickle cell anemia and
thalassemia major. Am J Hematol 1993;42:81-5.
82. Angelucci E, Giardini C, Brittenham GM, Lucarelli G. Hepatic iron
concentration and body iron stores determined by quantitative phlebotomy
in patients cured of thalassemia major by bone marrow transplantation.
Blood 1997;90:Suppl 1:265a. abstract.
83. Olynyk JK, ONeill R , Britton RS, Bacon BR. Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: diagnostic
implications. Gastroenterology 1994;106:674-7.
84. Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility
measurement of human iron stores. N Engl J Med 1982;307:1671-5.
85. Angelucci E, Giovagnoni A, Valeri G, et al. Limitations of magnetic
Jul y 8 , 19 9 9
Downloaded from www.nejm.org by GERARDO JUAREZ on November 23, 2008 .
Copyright 1999 Massachusetts Medical Society. All rights reserved.
MED IC A L PR OGR ES S
103. Arruda VR , Lima CSP, Saad STO, Costa FF. Successful use of hydroxyurea in b-thalassemia major. N Engl J Med 1997;336:964.
104. Rigano P, Manfr L, La Galla R, et al. Clinical and hematologic
response to hydroxyurea in a patient with Hb Lepore/b-thalassemia. Hemoglobin 1997;21:219-26.
105. Perrine SP, Ginder CD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globingene expression in the b-globin disorders.
N Engl J Med 1993;328:81-6.
106. Olivieri NF, Rees DC, Ginder GD, et al. Treatment of thalassemia
major with phenylbutyrate and hydroxyurea. Lancet 1997;350:491-2.
107. Rodgers GP, Rachmilewitz EA. Novel treatment options in the severe
b-globin disorders. Br J Haematol 1995;91:263-8.
108. Saxon BR , Rees D, Olivieri NF. Regression of extramedullary haemopoiesis and augmentation of fetal haemoglobin concentration during
hydroxyurea therapy in b thalassaemia. Br J Haematol 1998;101:416-9.
109. Sher GD, Ginder GD, Little JA, Wang SY, Dover G, Olivieri NF.
Extended therapy with intravenous arginine butyrate in patients with
b-hemoglobinopathies. N Engl J Med 1995;332:1606-10.
110. Atweh GF, Sutton M, Nassif I, et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood 1999;93:
1790-7.
111. Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW,
Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood 1995;85:43-9.
112. Cappellini MD, Graziadei G, Ciceri L, et al. Phase II open study of
oral isobutyramide in patients with thalassemia intermedia. Blood 1996;
88:Suppl 1:311a. abstract.
113. Constantoulakis P, Josephson B, Mangahas L, et al. Locus control region-Ag transgenic mice: a new model for studying the induction of fetal
hemoglobin in the adult. Blood 1991;77:1326-33.
114. Stamatoyannopoulos JA, Nienhuis AW. Therapeutic approaches to
hemoglobin switching in treatment of hemoglobinopathies. Ann Rev Med
1992;43:497-521.
115. McDonagh KT, Dover GJ, Donahue RE, et al. Hydroxyurea-induced
HbF production in anemic primates: augmentation by erythropoietin,
hematopoietic growth factors, and sodium butyrate. Exp Hematol 1992;
20:1156-64.
116. Pace B, Li Q, Peterson K, Stamatoyannopoulos G. a-Amino butyric
acid cannot reactivate the silenced gamma gene of the beta locus YAC
transgenic mouse. Blood 1994;84:4344-53.
117. Kitsberg D, Selig S, Keshet I, Cedar H. Replication structure of the
human b-globin gene domain. Nature 1993;366:588-90.
118. Verma IM, Somia N. Gene therapy promises, problems and prospects. Nature 1997;389:239-42.
119. Higgs DR , Sharpe JA, Wood WG. Understanding a-globin gene expression: a step towards effective gene therapy. Semin Hematol 1998;35:
93-104.
120. Shesely EG, Kim H-S, Shehee WR, Papayannopoulou T, Smithies O,
Popovich BW. Correction of a human b S-globin gene by gene targeting.
Proc Natl Acad Sci U S A 1991;88:4294-8.
Numb e r 2
109
CORRECTION
The -Thalassemias
The -Thalassemias . On page 101, in Figure 2, the 5 and 3 untranslated sequences (leader and trailer sequences) were incorrectly
labeled as introns.