Page 666 - Hematology_ Basic Principles and Practice ( PDFDrive )

568 Part V Red Blood Cells

birth. 477–481 It is also possible to salvage affected fetuses by in utero this large (280 kDa) DNA-binding protein is complex and contains
blood transfusions. 482,483 Limb and urogenital defects are present in two major functional domains: an N-terminal cysteine-rich zinc
a substantial portion of infants with homozygous α°-thalassemia who finger–containing domain, called the ADD domain, that has struc-
are rescued by these measures, and some infants have developmental tural features similar to those of DNA methyl transferases, and a
delay or other neurologic abnormalities. Management after the C-terminal helicase/ATPase domain. The majority of the mutations
perinatal period is similar to the management of patients with thalas- associated with the ATR-X syndrome are located in the ADD domain
semia major and includes transfusion and chelation therapy as well or the helicase domain. The ATRX protein is widely expressed in
as the possibility of BMT. 484 many different tissues and its intracellular localization is within three
Many patients with Hb H disease do not require RBC transfu- different nuclear subcompartments: heterochromatin, ribosomal
sions. For patients with more severe disease, characterized by lower DNA arrays, and PML bodies. It has been shown to interact with
Hb levels or frequent exacerbations of the anemia, splenectomy can other proteins such as the heterochromatin-associated protein HP1
be helpful. Oxidant drugs can accelerate precipitation of Hb H and and Daxx, one of the proteins localized in PML bodies. The prevail-
exacerbate hemolysis; they should therefore be avoided. Exchange ing opinion is that the ATRX protein is part of a large chromatin-
transfusion can be used to decrease deleterious levels of Hb H. Infants remodeling complex of the SWI2/SNF2 family. It also has ATPase
with heterozygous α°-thalassemia trait lose their Hb Bart during the activity and has translocase activity, that is, it can move along DNA
first few months of life and are left with the hematologic findings of as a “molecular motor.” The precise mechanism(s) by which ATRX
α-thalassemia trait, a mild hypochromic microcytosis that persists influences the expression of α-globin (and other) genes remains
1
throughout life. The degree of morphologic abnormality varies unknown.
greatly among different individuals. That α-thalassemia can be easily
diagnosed by Hb electrophoresis at birth gives some impetus to cord
blood screening studies. Confusion between heterozygous α°- Acquired Hb H Disease Associated With
thalassemia trait and iron deficiency may lead to unnecessary evalu- Myelodysplastic Syndrome
ations for possible blood loss or unnecessary supplementation with
iron unless the overlap in hematologic findings is recognized and Hb H disease has occasionally been observed to develop during the
more specific diagnostic studies are performed. course of different types of MDS and more rarely in patients with
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other hematologic malignancies. The disorder usually affects
elderly men older than the age of 60 years. The degree of imbalance
De Novo and Acquired Forms of α-Thalassemia of globin chain synthesis and of α-globin mRNA deficiency in ery-
throid cells of affected patients is greater than that observed in the
Two distinct α-thalassemia syndromes have been described that are hereditary type of Hb H disease. It is conceivable that erythroid cells
attributable to acquired or de novo mutations: (1) α-thalassemia of the abnormal clone synthesize no α-globin chains at all and that
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associated with mental retardation and (2) Hb H disease associated the expression of all four α-globin genes is suppressed or silenced,
with MDS. but this phenomenon is difficult to document in total blood as long
as some normal erythroid cells are being produced.
Until recently, the molecular basis of this fascinating disorder
α-Thalassemia Associated With Mental Retardation remained unknown. Cytogenetic, gene mapping, gene sequencing,
and gene or chromosome transfer studies failed to detect any deletion
α-Thalassemia or Hb H disease can occur as a de novo abnormality or mutation in the α-globin gene cluster or functional abnormality
in a rare disorder called the α-thalassemia with mental retardation of α-globin gene of affected patients. The results of all of these prior
syndrome (ATR). 469,470 In this disorder, affected patients have mental studies suggested that the defect responsible for this disorder probably
retardation and a number of other developmental abnormalities in involved the abnormal expression or function of a trans-acting factor
association with α-thalassemia trait or Hb H disease that is inherited capable of influencing α-globin gene expression and, indeed, such a
in a nontraditional manner. Two distinct types of the ATR syndrome factor was recently identified. The discovery of the factor responsible
have been identified. In some cases, there is the de novo appearance for Hb H disease in MDS results from cDNA microarray analysis of
of large (2000 kb or so) deletions involving the entire α-globin gene RNA isolated from granulocytes of an affected patient. One of the
cluster and adjacent DNA at the tip of chromosome 16, the so-called genes that was found to be markedly underexpressed, compared with
ATR-16 syndrome. In some of these patients, the deletion produces results obtained with RNA of normal granulocytes, was the ATRX
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detectable cytogenetic abnormalities of chromosome 16, indicating gene, the same gene that is mutated in the α-thalassemia with
that a very large segment of the chromosome is deleted, sometimes mental retardation syndrome of the ATR-X type. Sequence analysis
because of unbalanced chromosomal translocations involving the of the ATRX gene in the DNA of blood cells of affected individuals
telomeres of the affected chromosomes. In some cases, one parent is has identified a number of different mutations. It is noteworthy that
+
heterozygous for α -thalassemia by various criteria and the other the mutations of the ATRX gene associated with acquired Hb H
parent is completely normal; in such cases, the child has Hb H disease disease associated with MDS (ATMDS) occur in the same regions of
(- -/- α). In other cases, both parents are normal and the affected the gene as the mutations associated with the ATR-X syndrome, that
o
child has the hematologic phenotype of heterozygous α -thalassemia is, in the ADD or helicase domains. In fact, some of the ATRX gene
(- -/- α) without Hb H disease. In this form of ATR, the clinical mutations identified in ATMDS are identical or similar in expected
findings, such as the degree of mental retardation and associated functional consequences to various mutations found in the ATR-X
congenital abnormalities, are variable. syndrome.
The second type of ATR syndrome is not associated with detect- The hematologic features in the syndrome are characterized by
able deletions of the α-globin gene complex. The molecular basis of the presence on blood smear of a dimorphic RBC population, one
the disorder consists of mutations of a gene on the X chromosome, of which is hypochromic, microcytic, and poikilocytic. Incubation of
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and the condition has been called the ATR-X syndrome. In contrast the blood with the supravital stain brilliant cresyl blue results in the
to patients with the ATR-16 syndrome who have a varied phenotype detection of typical Hb H inclusions. Hb electrophoresis or high
of developmental abnormalities, patients with the ATR-X syndrome pressure liquid chromatography detects the presence of Hb H, usually
have a more uniform or consistent phenotype, particularly severe in greater quantities than that typically observed in inherited Hb H
mental retardation (with IQs of 50–70) and a characteristic dysmor- disease. In typical MDS, the MCV of the erythrocytes is normal or
phic facial appearance. 470 elevated, frequently higher than 100 fL. However, in ATMDS, the
The affected gene in this syndrome encodes a trans-acting factor, MCV and MCH are low: MCV usually less than 80 fL and MCH
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called ATRX, that is thought to influence the expression of the usually less than 26 pg. The amount of Hb H usually remains
α-globin genes as well as that of other genes. 486,487 The structure of stable but may actually decrease during the course of the disease and