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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4422-4427
High Adenosine Deaminase Level Among Healthy Probands of Diamond
Blackfan Anemia (DBA) Cosegregates With the DBA Gene Region on
Chromosome 19q13
By
T.N. Willig,
J.L. Pérignon,
P. Gustavsson,
P. Gane,
N. Draptchinskaya,
H. Testard,
R. Girot,
M. Debré,
J.L. Stéphan,
C. Chenel,
J.P. Cartron,
N. Dahl, and
G. Tchernia on
behalf of the DBA Working Group of Société
d'Hématologie et d'Immunologie Pédiatrique (SHIP)
From the Département de Pédiatrie et Laboratoire
d'Hématologie, Hôpital Bicêtre, Assistance
Publique-Hôpitaux de Paris, Bicêtre, and Faculté de
Médicine Paris Sud, France; Laboratoire de Biochimie et
Unité d'Hématologie et d'Immunologie Pédiatrique,
Hôpital Necker; Unité Inserm U76, INTS; Laboratoire
d'Hématologie, Hôpital Tenon, Paris, France; Unit of
Clinical Genetics, Department of Genetics and Pathology, Uppsala
University Children's Hospital, Uppsala, Sweden; Hôpital
d'Enfants ASFA, La Réunion, France; Service de Pédiatrie,
Hôpital d'Enfants, CHU Hôpitaux de Saint Etienne, Saint
Etienne, France; Service de Pédiatrie, Centre Hospitalier
Territorial de Polynésie Française, Papeete, France.
 |
ABSTRACT |
Phenotypic characterization of Diamond Blackfan Anemia (DBA)
patients and their relatives was performed in 54 families. Complete blood count, fetal hemoglobin level, erythrocyte i antigen expression, and erythrocyte adenosine deaminase (eADA) activities were quantitated in patients and relatives. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of
erythrocyte i antigen was noticed in only 10 of 20 DBA patients. High
eADA activities were also found in 14 of 149 healthy family members,
allowing us to identify an isolated high eADA phenotype in these
families. In contrast, increase in erythrocyte i antigen expression,
elevated fetal hemoglobin levels, and macrocytosis were much less
frequently noted in nonaffected members of the DBA families
studied. Importantly, isolated high eADA phenotype was found to be
significantly associated with genetic markers on chromosome 19 that
segregate with the DBA phenotype. Isolated high eADA phenotype thus
seems to reflect a silent phenotype of DBA in affected families. These
findings suggest that elevated eADA activity in unaffected individuals needs to be taken into account during genetic assessment of DBA families and could be used for accurate assessment of mode of inheritance.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
LINKAGE ANALYSIS of Diamond Blackfan
anemia (DBA) multiplex families has recently assigned this disorder to
a locus on 19q13.2.1 Interestingly, most families shared
the same chromosomal linkage, although there were marked differences in
the phenotypic expression of the disease, including associated
malformations, therapeutic outcomes, and mode of inheritance. Previous
studies have identified several biological features in DBA patients, as well as in some of their relatives. These include increases in fetal
hemoglobin levels, macrocytosis, persistence of erythrocyte i antigen
expression, and elevated erythrocyte adenosine deaminase activity
(eADA).2,3
In the present study, we have systematically investigated each of these
abnormalities in all members of 54 DBA families. In addition, we
performed DNA analysis with markers linked to the DBA locus on
chromosome 19q13.2 in most family members. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of erythrocyte i antigen was noticed in only 10 of 20 DBA
patients. High eADA activities were also found in 14 of 149 healthy
family members, allowing us to identify an isolated high eADA phenotype
in these families. Importantly, isolated high eADA phenotype was found
to be significantly associated with genetic markers on chromosome 19 that segregate with the DBA phenotype. These data strongly support the
previous suggestion that isolated high eADA level could represent a
silent phenotype of this disease. This parameter is thus highly
relevant for familial studies.
| |
MATERIALS AND METHODS |
Study design.
The French National Register of DBA, initiated in 1985, includes 158 patients whose diagnoses fit all the criteria defined by the DBA study
group of the European Society for Pediatric Haematology and Immunology.
The criteria for the diagnosis of DBA include occurrence of anemia
before 2 years of age, exclusion of recent parvovirus B19 infection by
both serology and polymerase chain reaction (PCR) analysis of bone
marrow cells, and exclusion of Fanconi anemia by a negative chromosome
fragility test. The French DBA register was approved by the Commission
Nationale Informatique et Libertés, and the study protocol was
approved by the human experimentation committee of Hôpital
Bicêtre (France). Informed consent was obtained from each
individual and from the parents of children included in the genetic
study.
Clinical and biological evaluation were performed on all affected
individuals and on all of the available family members from 54 different families (63 patients, 93 parents or relatives, 56 siblings).
Detailed physical examination was performed on all individuals.
Biochemical and hematologic evaluation included complete blood cell
count with red blood cell (RBC) indices, hemoglobin electrophoresis,
fetal hemoglobin level determination by resistance to alkaline
denaturation,4 erythrocyte i antigen expression, and
quantification of eADA and erythrocyte purine nucleoside phosphorylase (PNP) activities. Biochemical and hematologic evaluations were not
performed on blood samples from individuals receiving regular blood
transfusions. Macrocytosis or elevation of fetal hemoglobin were not
considered to be relevant indicators of DBA phenotype in one individual
receiving chemotherapy and in another individual with chronic
alcoholism.
Flow cytometry analysis of blood group i antigen expression.
RBCs from patients, siblings, and relatives were collected in EDTA and
were rapidly cryopreserved in liquid nitrogen until used. Blood samples
from common donors and from a rare individual of the OI-negative
phenotype (Guillard) were collected and treated similarly.
Analysis of blood group i antigen expression was performed on a FACScan
cytometer (Becton Dickinson, San Jose, CA) using the murine monoclonal
antibody anti-i (NaM61-1A2, IgM) donated by Dr D. Blanchard (Nantes,
France). In 0.15 mol/L phosphate-buffered saline (PBS), 3 × 105 RBCs were incubated for 30 minutes at 22°C with
three preparations of the hybridoma culture supernatants diluted 1:20,
1:40, and 1:80. After several washings in PBS supplemented with 0.5%
bovine serum albumin, the cells were incubated for 30 minutes at
22°C with a fluorescein-conjugated anti-mouse IgM (Immunotech,
Marseille, France). After several additional washes, the
microagglutinates were gently dissociated by micropipetting and
recovered as single-cell suspensions (assessed by light scatter) and
subjected to fluorescence analysis. OI-negative cells (Guillard) which
exhibited high levels of blood group i antigen were used as positive
controls. Blood group i expression on RBCs from a population of 31 healthy adults and from the OI-negative adult controls was estimated
using serial dilutions (1:20, 1:40, 1:80) of the murine monoclonal
anti-i antibody (supernatant) by direct immunofluorescence analysis on
a flow cytometer. Under saturing conditions (1:20 dilution), the mean fluorescence intensity was 64.7 ± 31.7 for normal adult
RBCs and 893 ± 244 for OI-negative cells, indicating a low level of
expression of i antigen on adult RBCs and a significant overexpression
of i antigen on OI-negative cells.
Assessment of eADA and PNP.
eADA and PNP activities were assessed in hemolysates by radioisotopic
methods with paper chromatography separation of substrates and products
on Whatman P81 paper (Whatman, Maidstone, UK).5 Results
were expressed both as an absolute value and as the ratio of ADA to PNP
activities. Mean values from control population are 1.35 ± 0.36 nmol/mn/mg hemoglobin for eADA, and 144 ± 19 nmol/mn/mg hemoglobin
for erythrocyte PNP.
Haplotype assessment.
Genetic haplotype was studied as a part of the linkage study using
microsatellites flanking the region identified in familial cases.1 Genomic DNA was extracted from peripheral blood
leukocytes according to standard procedures. The polymorphic
dinucleotide repeats D19S200, D19S197, and D19S408, assigned to the
19q13 region,6 were chosen for the determination of
haplotypes. The markers D19S200 and D19S408 flank the DBA gene locus
and their relative order, with the approximate genetic distances, is
centromere-D19S200-1.5 cm-D19S197-1.9
cm-D19S408-telomere.1 PCR of polymorphic
markers was performed at optimized conditions as described
previously.1 The PCR reactions were performed in a reaction
volume of 10 µL with 20 ng of genomic DNA and a
 -32P-ATP end-labeled primer in 96-well microtitre
plates. The PCR products were separated by polyacrylamide gel
electrophoresis and visualized by autoradiography. The genetic
haplotypes were assigned manually.
Statistical analysis.
Analysis was focused on a subset of eight families presenting with both
classical DBA patient(s) and seemingly healthy individuals with
isolated high eADA activity. Because DNA samples were not available for
two of these eight families, correlation studies between phenotype and
genetic haplotypes could be performed in only six of the families.
Diagnosis was evoked from the occurrence of erythroblastopenia, between
birth and 14 months of age. Three patients were supposed to be sporadic
cases, whereas the three other families included between two and three
DBA cases. Genetic haplotype of each family member was compared with
those of the index DBA case, and assessed to be either the same or
different. Statistical analysis of relationship between genetic
haplotype and clinical phenotype was then performed using Yates
corrected Chi-square test, and computing of exact 95% limits of
confidence interval of odds ratio using Epi-Info 6.04b7 or
Statistica 4.0 B (Statsoft, Inc, Tulsa, OK) software.
| |
RESULTS |
Phenotypic characterization of patients.
Of the 63 DBA patients studied, 16 came from 7 multiplex families
whereas the other 47 were considered sporadic cases. Among these 63 individuals, 34 patients were transfusion independent; eADA, PNP, mean
corpuscular volume (MCV), and fetal hemoglobin level were
quantitated in these 34 individuals. As shown in
Fig 1, eADA activity was found to be
significantly above normal levels in 28 of the 34 patients. In
contrast, PNP activity was always within the normal range (data not
shown). Persistent increased erythrocyte i antigen expression (3 to 10 times higher than normal) was noted in 10 of 20 patients studied. In
our study we did not find any correlation between eADA activity and
persistence of erythrocyte i antigen expression. Fetal hemoglobin
levels were elevated in 21 DBA patients whereas macrocytosis was noted
in 16 DBA patients. Neither fetal hemoglobin levels nor MCV correlated with any of the other biochemical and hematologic parameters studied.
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| Fig 1.
Distribution of eADA in DBA patients, their siblings,
their parents, and normal controls. eADA and PNP activities were
assessed in hemolysates by radioisotopic methods with paper
chromatography separation of substrates and products, as described in
Materials and Methods and by Pérignon et al.5
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Phenotypic characterization of families.
We also studied 149 apparently healthy members from 54 DBA families.
Fourteen of the 149 healthy individuals showed elevated eADA (observed
values ranging from 2.29 to 8.6 nmol/mn/mg hemoglobin; normal values,
1.35 ± 0.36 nmol/mn/mg hemoglobin). This group of individuals with
high eADA activity consisted of 8 siblings, 1 father, 3 mothers, and 2 relatives (grandmother and great aunt) of the affected members. These
data are not sufficient to support a hypothesis of parental imprinting.
Interestingly, the erythrocyte i antigen expression was found to be
significantly elevated (1.5 to 3 times as compared with healthy adults)
in 5 of the 79 nonaffected family members studied, whereas fetal
hemoglobin and MCV were found significantly elevated in only 2 of 149.
Correlation studies between eADA activity and gene haplotype.
Haplotype analysis performed on 6 families in which DBA was associated
with isolated high eADA activity showed a cosegregation of the 19q
markers of the DBA patients with isolated high eADA phenotype in 14 of
15 individuals
(Fig 2A
through F and Table 1). On the other hand,
among 17 nonaffected individuals who showed an eADA activity in the
normal range, 3 shared the 19q markers haplotype of the affected
individual of the family. Statistical analysis of data showed a
significant association between the genetic haplotype and increased
eADA activity (P < .0001). In contrast, no significant
association was noted in this study between genetic haplotypes of DBA
patients and other hematologic markers (persistent erythrocyte i
antigen expression, fetal hemoglobin, MCV).
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| Fig 2.
Pedigrees of families simultaneously showing DBA and
isolated high eADA phenotype. (A) Recombination events occurred on
meiosis from individuals III-3 and II-5. Allele sizes for
microsatellite D19S200 could not be determined for individuals II-13
and III-13, and they were therefore not included in the haplotype
analysis. (B) Unlike the three DBA cases of this family,
individual II-1 was previously diagnosed as transient
erythroblastopenia, and her mother (I-3) was healthy. (C) DBA index
case of this family (patient IV-6) responded to interleukin-3 and is
still independent of transfusions and steroids on the long-term
follow-up. (D) All three siblings showed high eADA levels (II-1, -2, -3) and have normal blood count and hemoglobin electrophoresis, without
known history of anemia. (E) Individuals I-2 and II-3 show classical
DBA phenotype. eADA of individual II-2 was found increased at birth and
remains over normal limits without any episode of anemia, and no other
biological abnormality. eADA measurements of individuals I-1 and I-3
were performed in another laboratory, and results are within normal
values for the technique considered. (F) Individual II-3 does not share
the same haplotype as the DBA index case of the family. NA, not
available.
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Table 1.
Correlation Between Genetic Haplotype and ADA Level
in Families With Occurrence of DBA and Isolated High ADA Level
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Because these data suggest that elevated high eADA could be of use in
assessing the mode of inheritance, we reexamined families on the basis
of the measured eADA activity. Dominant mode of inheritance was
confirmed through an elevation of eADA in 2 families. In 3 other
families in which the mode of inheritance could not be established, dominant mode of inheritance could be deduced from the finding of
apparently healthy individuals with high eADA activity. In 1 multiplex
family, reassessment of previously healthy individuals suggested
reappraisal of mode of inheritance from recessive to dominant. Sporadic
occurrence of DBA was confirmed in 46 families, with normal or low
levels of eADA in parents or siblings.
| |
DISCUSSION |
In the present study, we have been able to show a significant
association between DBA phenotype and isolated high eADA activity phenotype on the basis of haplotype analysis of six DBA families. This
finding of high eADA activity in apparently normal family members could
be an important tool for a more precise characterization of nuclear
families. Isolated high eADA phenotype can represent a silent
phenotype, linked to the 19q13.2 DBA locus in affected families. We
have also confirmed the previous report of high prevalence of increase
in eADA activity in transfusion-independent DBA patients.
Previous studies have already described such a biochemical abnormality
in DBA families but could not prove any association between these
phenotypes. Glader and Backer8 had reported an elevation of
eADA activity in 26 of 29 transfusion-independent patients, as did
Filanovskaya et al9 in 10 of 13 DBA patients. The reduced
frequency of this feature in DBA patients in a third study (elevation
of eADA in 9 of 19 DBA patients only) could be explained by the
inclusion of transfusion-dependent patients.10,11 Elevation
of eADA was confirmed to be a persistent feature in DBA patients over
years, as shown through serial measurements.8 High eADA
activity in healthy relatives from DBA-affected individuals has also
been previously reported by different groups. Among 8 families where
both parents were assessed, 2 of 16 parents were found to exhibit
isolated high eADA activity.3,10 Our data confirm overall prevalence of asymptomatic high eADA phenotype in one
of the parents of sporadic DBA cases, with 14 of 149 individuals originating from 8 of 54 French families in our series (9.4% of individuals, 14.8% of families). Previous studies reported this finding in 10 of 44 cases (22%).8-11 Other nonspecific
parameters have also been described in DBA (persistence of increased
erythrocyte i antigen expression, increase in fetal hemoglobin level,
macrocytosis). According to the present study, they seem to be less
frequently abnormal than eADA, and no significant association could be
found between any of these parameters and genetic markers on the 19q DBA locus.
The pathophysiological link between DBA and elevation of eADA remains
unclear. Besides primary ADA deficiencies associated with immune
deficiency12 and hemolytic anemia with major increase in
eADA activity,13 several hematologic disorders are
characterized by a nonspecific increase in ADA activity. Indeed,
increased eADA level has been reported in myeloproliferative syndromes,
dyskeratosis, and megaloblastic anemia.8 In contrast, eADA
was reported to be normal in patients with transient erythroblastopenia
in childhood.14 As others, we have shown that
the increase in erythrocyte enzyme activity does not correlate with
biological signs of stress hematopoiesis, steroid treatment response,
or lymphocyte ADA activity (data not shown).8 ADA is one of
the enzymes of the nucleoside catabolism pathway, converting adenosine
to inosine. Two major isoforms have been characterized in the
erythrocytes.15 Analysis of these isoforms did not show any
alteration in DBA,10,11 indicating that this observed ADA
abnormality is not caused by an imbalance between isoforms of the
enzyme, but rather by an overall increase in the concentration of the
isoforms. Recent progress in molecular biology favors this hypothesis,
because most familial cases of DBA are linked on chromosome 19 (19q13.2),1 whereas the gene coding for ADA is located on
chromosome 20.16
Is the increase in eADA activity a secondary phenomenon linked to
erythroblastopenia (or one of its consequences), or do both eADA
increase and DBA phenotype result from a common genetic defect, like an
alteration of a promoter or of an enhancer regulating the expression of
two genes involved in different metabolic pathways? Mice models with
mutations in the coding sequence of c-kit or of its ligand, resulting
in strains of mice with both macrocytic anemia and elevated nucleoside
deaminase activity, favor the first hypothesis.17
Application of the present findings show that some isolated DBA cases
correspond to a dominant mode of inheritance with a variable phenotypic
expression within the family. The present study also provides some new
insights into the heterogeneity encountered in DBA. Previous studies
have emphasized the wide range of clinical presentation of DBA, which
includes long-term transfusion dependence, steroid responsiveness, and
spontaneous remissions. Our data highlight three biochemical
phenotypes, sometimes simultaneously present within a same family: DBA
cases with increased eADA activity, DBA cases with normal eADA
activity, and nonanemic individuals with high eADA activity. The
existence of a completely silent phenotype is furthermore suggested by
the occurrence of 3 of 17 healthy individuals sharing the same genetic
haplotype as the corresponding DBA case. Thus, a normal
eADA activity in a healthy individual from a DBA family is not
sufficient to provide accurate genetic counseling.
Our clinical and biochemical findings, along with analysis of molecular
basis of DBA, highlight the usefulness of complete phenotypic and
genetic characterization of all family members in DBA cases to provide
better genetic counseling to the affected families. Furthermore,
findings of linkage between markers from 19q13 region and isolated high
eADA phenotype can be used to identify a subclinical expression of DBA
in the affected families. It is anticipated that the identification of
the gene(s) responsible for the DBA phenotype will enable us to finally
understand the relationship between the classical DBA phenotype and the
intrafamilial asymptomatic isolated high eADA phenotype.
| |
ACKNOWLEDGMENT |
We acknowledge the DBA working groups of the European Society for
Pediatric Hematology and Immunology (ESPHI), and of the Société d'Hématologie et d'Immunologie
Pédiatrique (SHIP). We are grateful to V. Drouin and M. Cadoudal
for their technical assistance in the determination of eADA. We are
grateful to Drs Narla Mohandas, Philippe Gascard, and Joel Chasis for
their careful help to improve this manuscript.
| |
FOOTNOTES |
Submitted April 16, 1998;
accepted July 31, 1998.
Supported in part by Association Française contre les Myopathies
(A.F.M.), Généthon, Direction de la Recherche Clinique (DRC) (grant CRC 950183), and Assistance Publique-Hôpitaux de Paris. Haplotyping was performed thanks to grants from the Children's Cancer Foundation of Sweden, the Swedish Medical Research Council, and
the DBA Foundation Inc.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to T.N. Willig, MD, Bldg 74-157, Lawrence
Berkeley Laboratory, One Cyclotron Rd, Berkeley, CA 94720; e-mail:
tnwillig{at}lbl.gov.
| |
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Abstract
Introduction