Page 750 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 45 Red Blood Cell Membrane Disorders 637

Inheritance 2,3-DPG levels has a marked destabilizing effect on the spectrin–
protein 4.1R–actin interaction, thereby further destabilizing the
In most patients, HE is inherited as an autosomal dominant disorder. membrane skeleton.
The clinical severity is highly variable among different kindred
(reflecting heterogeneous molecular lesions) and, to a lesser extent,
within a given kindred, presumably because of other genetic or Hereditary Elliptocytosis With Chronic Hemolysis
acquired defects that modify disease expression. Occasionally HE is
inherited as an autosomal recessive condition from an asymptomatic Patients with HE with chronic hemolysis present with moderate to
parent who carries the same molecular defect of spectrin as the HE severe hemolytic anemia with elliptocytes and poikilocytes on periph-
offspring. In one kindred with a submicroscopic chromosome X eral blood film; some require splenectomy. In some of the kindred,
deletion, inheritance was X-linked. the hemolytic HE has been transmitted through several generations.
The inheritance of the related disorder HPP is autosomal reces- In some kindred, not all of the HE patients have chronic hemolysis;
sive: one of the parents carries the α-spectrin mutation and either is some have a mild hemolysis only, presumably because of another
asymptomatic or has mild HE, whereas the other parent is fully genetic factor modifying the disease expression.
asymptomatic and has no abnormalities detectable by current bio-
chemical approaches. However, several HPP patients have recently
been studied who were doubly heterozygous for two α-spectrin muta- Homozygous and Compound Heterozygous
tions; in the heterozygous parents, these mutations were either silent Hereditary Elliptocytosis
or expressed as mild HE.
Several HE individuals have been described who were apparent
homozygotes for the HE gene. These individuals were found to be
Clinical Manifestations either homozygotes or compound (double) heterozygotes for one or
two α- or β-spectrin mutations. The clinical severity is variable, from
In view of the striking molecular heterogeneity of common HE, it is a relatively mild hemolytic anemia to a severe, life-threatening disease,
not surprising that the clinical spectrum of this disorder is variable, depending on the severity of the underlying molecular defect, and in
ranging from an asymptomatic trait without hemolysis to a life- some cases is indistinguishable from HPP.
threatening hemolytic anemia.
Hereditary Pyropoikilocytosis
Mild Hereditary Elliptocytosis and Asymptomatic
Carrier State It is now established that HPP represents a subtype of common HE,
as evidenced by the coexistence of both HE and HPP in the same
In most of these patients, HE is found accidentally during evaluation family and by the presence of the same molecular defect of spectrin.
of the peripheral blood film. Although some HE patients have a mild Unlike HE patients carrying the spectrin mutation, the RBCs of HPP
compensated hemolytic anemia, others do not have any evidence of patients are also partially deficient in spectrin. Typically, one parent
hemolysis, their RBC survival is normal, and the peripheral blood of the HPP offspring carries an α-spectrin mutation, whereas the
film may reveal only modest (≥15%) elliptocytosis. The molecular other parent is fully asymptomatic and has no detectable biochemical
basis of mild HE is heterogeneous, and the reported molecular defects abnormality. In many such patients the asymptomatic parent carries
include both α- and β-spectrin mutations, partial deficiency of the a silent “thalassemia-like” defect of spectrin synthesis, enhancing the
4.1R protein, and the absence of GPC. Some individuals carrying relative expression of the spectrin mutant and leading to a superim-
the spectrin mutation are completely asymptomatic, including posed spectrin deficiency in the HPP offspring. Subsequent studies
normal RBC morphologic features; this is often the case in one of of the original HPP kindred revealed that defective spectrin synthesis
the parents of a patient with HPP. from the null allele was caused by a splicing mutation of the α-spectrin
gene. Some HPP patients inherited two α-spectrin mutations; either
their parents were hematologically normal or one had mild HE. In
Hereditary Elliptocytosis With Sporadic Hemolysis these HPP patients, spectrin deficiency may be related to instability
of the mutant spectrin. The thermal instability of spectrin originally
Worsening of hemolysis together with the appearance of poikilocytes reported as diagnostic of HPP is not unique for this disorder; it is
on the peripheral blood film has been reported in patients with also found in HE patients carrying this α-spectrin mutation, in the
hypersplenism, infections, or vitamin B 12 deficiency, as well as in homozygous and in the heterozygous states. HPP is seen predomi-
those with microangiopathic hemolysis such as disseminated intra- nantly in black patients, but it has also been diagnosed in Arabs and
vascular coagulation or thrombotic thrombocytopenic purpura. In whites.
the latter two conditions, worsening hemolysis can be caused by
microcirculatory damage superimposed on the underlying mechani-
cal instability of the RBCs. Molecular Determinants of Clinical Severity

Hereditary Elliptocytosis With The severity of hemolysis in common HE often varies not only
among different kindred but within a given family as well. The
Neonatal Poikilocytosis two principal determinants of severity of hemolysis are the spectrin
content of the cells and the percentage of dimeric spectrin in the
Neonatal offspring of parents with mild HE present with symptom- crude spectrin extract. The fraction of dimeric spectrin in such
atic hemolytic anemia and a marked poikilocytosis. During the first extracts in turn depends on several factors. The first of them is the
year of life, the hemolysis and poikilocytosis abate, and the clinical degree of dysfunction of the mutant spectrin. Typically, mutations
picture transforms into that of mild HE. Such patients typically carry that are either within or near the combined αβ triple-helical repetitive
one mutant α-spectrin allele. The severity of the molecular defect, in segment representing the spectrin heterodimer self-association site
terms of the percentage of spectrin dimers and the amount of mutant produce a more severe clinical phenotype and a more severe defect
spectrin in the cells, is the same in the neonatal period as it is later of spectrin function than those seen with point mutations in the
in life. The worsening of hemolysis in the neonatal period has been more distant triple-helical repeats. Second, the percentage of the
attributed to the presence of fetal hemoglobin, which binds poorly dimeric spectrin depends on the fraction of the mutant spectrin
to 2,3-diphosphoglycerate (2,3-DPG). The ensuing elevation of free in the cells, which in turn is determined by the gene dose (e.g.,