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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4053-4058
Congenital Erythropoietic Porphyria Successfully Treated by
Allogeneic Bone Marrow Transplantation
By
I. Tezcan,
W. Xu,
A. Gurgey,
M. Tuncer,
M. Cetin,
C. Öner,
S. Yetgin,
F. Ersoy,
G. Aizencang,
K.H. Astrin, and
R.J. Desnick
From the Department of Pediatric Immunology and Hematology, Hacettepe
University, Ankara, Turkey; and the Department of Human Genetics, Mount
Sinai School of Medicine, New York, NY.
 |
ABSTRACT |
The long-term biochemical and clinical effectiveness of
allogenic bone marrow transplantation (BMT) was shown in a severely affected, transfusion-dependent 18-month-old female with congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of
heme biosynthesis resulting from mutations in the uroporphyrinogen III
synthase (URO-synthase) gene. Three years post-BMT, the recipient had
normal hemoglobin, markedly reduced urinary porphyrin excretion, and no
cutaneous lesions with unlimited exposure to sunlight. The patient was
homoallelic for a novel URO-synthase missense mutation, G188R, that
expressed less than 5% of mean normal activity in Escherichia
coli, consistent with her transfusion dependency. Because the
clinical severity of CEP is highly variable, ranging from nonimmune
hydrops fetalis to milder, later onset forms with only cutaneous
lesions, the importance of genotyping newly diagnosed infants to select
severely affected patients for BMT is emphasized. In addition, the
long-term effectiveness of BMT in this patient provides the rationale
for future hematopoietic stem cell gene therapy in severely affected
patients with CEP.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
CONGENITAL ERYTHROPOIETIC porphyria (CEP,
Gunther disease) is a rare autosomal recessive disorder of heme
biosynthesis that results from the markedly deficient, but not absent,
activity of uroporphyrinogen III synthase (URO-synthase; EC
4.2.1.75).1-4 The resultant accumulation of the
nonphysiological and pathogenic porphyrins, uroporphyrin I and
coproporphyrin I, in erythrocytes leads to hemolysis and the released
type I isomers are deposited in tissues and bones throughout the body
as well as excreted in the urine and feces. Uroporphyrin I is a
photosensitizing compound, and exposure of the skin to sunlight results
in blistering and vesicle formation. Secondary infection can lead to
scarring, tissue loss, and deformities, including loss of digits and
facial features such as eyelids, ears, and nares.5 In
addition, corneal scarring can cause blindness.
The clinical severity of the anemia and cutaneous involvement in CEP is
highly variable, ranging from nonimmune hydrops fetalis because of
severe hemolytic anemia in utero to milder, later onset forms, which
have only cutaneous lesions in adult life. Hemolysis is a feature in
moderately to severely affected patients and is accompanied by
anisocytosis, poikilocytosis, polychromasia, basophilic stippling,
reticulocytosis, increased nucleated red cells, absence of haptoglobin,
increased unconjugated bilirubin, increased fecal urobilinogen, and
increased plasma iron turnover. Severely affected patients are
transfusion dependent. Secondary splenomegaly enhances the anemia and
also may result in leukopenia and thrombocytopenia.
The availability of the full-length cDNA and genomic clones encoding
human URO-synthase6,7 permit genotype/phenotype correlations to predict the clinical severity of CEP. The single URO-synthase gene, located at chromosome
10q25.3 q26.3,8 contains 10 exons.7
Mutation analysis in unrelated patients with CEP has shown a variety of
lesions including gene rearrangements, splicing mutations, and single
base substitutions.4,9,10 The prokaryotic expression of
various missense mutations has permitted estimation of their relative
residual activities for genotype-phenotype correlations.10
At present, treatment of CEP has been nonspecfic, involving avoidance
of sunlight to prevent the skin lesions and splenectomy or chronic
transfusions for the hemolytic anemia. Protection of the skin from
sunlight and minor trauma is of the utmost importance, and aggressive
antibiotic treatment of all infections is essential to minimize scaring
and mutilation.3,11,12 For transfusion-dependent patients,
chronic erythrocyte transfusions are lifesaving and have been used
therapeutically in moderately affected patients with mild hemolytic
anemia to suppress erythropoiesis and thereby decrease porphyrin
production.13 This strategy has been effective until
puberty when porphyrin production may increase and more aggressive
treatment with hydroxyurea to reduce bone marrow porphyrin synthesis
may be considered.14
To date, allogenic bone marrow transplantation (BMT) has been performed
in three patients with CEP.15-17 The first patient was a
moderately affected 8-year-old girl who died of cytomegalovirus (CMV)
encephalitis 11 months after a successful BMT,15 whereas two other patients were engrafted, including a 2-year-old moderately affected patient transplanted in Paris who rejected the first graft,
but whose second graft was successful,17 and a 4-year-old moderately affected patient transplanted in Strasbourg with cord blood.16 These patients were not transfusion dependent, and their uroporphyrinogen III synthase mutations were not reported, so
their phenotypic severity could not be fully evaluated. After BMT, the
two living patients had remarkably reduced levels of urinary
uroporphyrin I and coproporphyrin I, normal hemoglobin values, and did
not develop skin lesions on limited exposure to sunlight at 1 year
post-BMT. Although encouraging, further experience must be gained with
BMT to evaluate its biochemical, hematologic, and clinical
effectiveness as well as its long-term ability to prevent later
manifestations caused by the progressive accumulation of type I
isomers. In addition, effective long-term treatment would justify the
risks of BMT in newly diagnosed, severely affected CEP patients, and
would provide the rationale for future hematopoietic stem cell gene
therapy endeavors.18-21
In this communication, we describe a 4-year, 5-month-old
transfusion-dependent girl, the product of a consanguineous union, who
was homoallelic for a novel mutation (G188R) and who received a
successful BMT at 18 months of age which has completely corrected her
biochemical, cutaneous, and hematologic manifestations for 35 months,
the longest posttransplant follow-up documented.
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MATERIALS AND METHODS |
Case report.
The patient was the fourth product of a first-cousin marriage of a
G4P4 female who had two healthy siblings as
well as a male sibling who died at 6 months of age from unknown causes.
Pink-reddish urine was first noted in infancy by the parents, and
splenomegaly was first detected in the first month of life. She was
referred at 9 months of age to the Ihsan Dogramaci Children's
Hospital, Hacettepe University (Ankara, Turkey) for evaluation of
severe anemia and hepatosplenomegaly. On physical examination, she had extreme pallor and hepatosplenomegaly. The liver and spleen were palpable 4 and 8 cm below costal margin, respectively. Pertinent laboratory results included hemoglobin, 5.6 g/dL; hematocrit, 22%;
reticulocyte count, 1.8%; total leukocytes, 7,000/µL. A
peripheral blood smear showed poikilocytosis, polychromasia, tear-drop
cells, and normoblasts. Hemoglobin electrophoresis, osmotic fragility, pyruvate kinase, and the Ham test were normal, as was the test for
unstable hemoglobin. Coomb's tests and cold agglutinins were negative.
Because of her severe hemolytic anemia, blood transfusions were
required every 4 weeks. Based on the elevated level of urinary porphyrins (Table 1), the diagnosis of CEP
was made. At 12 months of age, the reddish-brown discoloration of her
decidous teeth was noted, and at 13 months of age, she developed
crusted lesions on her face and dorsum of her hands
(Fig 1A and B).
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| Fig 1.
(A and B) Patient before BMT, at 18 months old; (C) patient
27 months post-BMT, at 35 months old.
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Patient specimens.
Peripheral blood was collected from the proband and her family members
with informed consent. Lymphoid cell lines were established using
cyclosporin A and Epstein-Barr virus as previously
described.22 Cells were maintained by standard procedures
in RPMI 1640 media supplemented with 10% heat-inactivated fetal bovine
serum, 1% pencillin, and 1 mg/mL of streptomycin (GIBCO Laboratories,
Grand Island, NY).
URO-synthase mutation analysis.
Genomic DNA was extracted from lymphoblasts using the Puregene DNA
Isolation Kit (Gentra Systems, Minneapolis, MN) and each exon,
including its intron/exon boundaries, was amplified by the polymerase
chain reaction (PCR)23 using primer sets in which one
primer was biotinylated as previously described.24 Each 50-uL amplification reaction contained 2 µg of genomic DNA; 20 pmol
of each primer; 10 nmol/L of each dNTP; 50 mmol/L Tris-HCl, pH 9.0; 50 mmol/L NaCl; 10 mmol/L MgCl2; and 2 U of Taq polymerase (Promega, Madison, WI). After an initial 5-minute incubation at 94°C, amplification (30 cycles) was performed with denaturation at
94°C for 1 minute, extension at 72°C for 0.5 minutes, and
annealing at the indicated conditions for each primer
set.24 An aliquot (40 µL) of each amplification product
was incubated with 40 µL of streptavidin-coated paramagnetic beads
(Dynabeads M-280 Streptavidin; Dynal, Inc, Lake Success, NY) for 30 minutes with occasional gentle mixing. Beads with bound biotinylated
PCR products were separated with a magnet as described,24
the strands were denatured in 10 µL of 0.1 mol/L NaOH for 30 minutes,
and the nonbiotinylated strands were eluted with two 50-µL washes of
0.1 mol/L NaOH. The biotinylated strands were washed with 50 µL of
the binding and washing TE buffer (10 mmol/L tris-HC1, pH 7.5, containing 1.0 mmol/L EDTA) and 2.0 mol/L NaCl, and then with 50 µL
of TE. The biotinylated strands were resuspended in 7 µL
of H2O and used as templates for dideoxy chain sequencing.
Prokaryotic expression and characterization of the URO-synthase
G188R mutation.
The normal and mutant G188R URO-synthase alleles were expressed in
E coli strain JM 109 using the pKK223-3 vector (Pharmacia LKB
Biotechnology, Inc, Piscataway, NJ) as previously
described.6,24,25 Single colonies were isolated and the
inserts were completely sequenced to confirm the engineered sequence
and the absence of PCR errors. Bacterial growth,
isopropylthiogalactoside induction, and URO-synthase assays were
performed as previously described.24-26
Analysis of possible splicing abnormalities caused by G188R.
To determine if mutation G188R caused abnormal splicing of the
patient's URO-synthase RNA, reverse transcriptase (RT)-PCR was
performed. mRNA was isolated from 5 × 107 lymphoid
cells established from the patient's white blood cells and from 5 × 107 cells of a control lymphoid line using the
FastTrack mRNA Isolation Kit version 2.0 (Invitrogen, Carlsbad, CA).
The mRNA was RT-PCR amplified using the Titan One Tube RT-PCR System
(Boehringer Mannheim, Indianapolis, IN). Two different sets of PCR
primers were used to detect the possible deletion of exon 9: one set
amplified the URO-synthase cDNA from exon 6 to exon 10, producing a
normal product of 416 bp, whereas the other set amplified a sequence
from exon 8 to exon 10, producing a normal product of 223 bp. The sense primer in exon 6 was 5 -GCCTGGATACAGAAGGAGAA-3 (cDNA nt
528-548) and the antisense primer in exon 10 was
5-CTTGTGGCGTGGGGCTCTCT-3 (cDNA nt 924-944). The sense
primer in exon 8 was 5-ATCCAAGGGAACCTGAACAG-3 (cDNA nt
722-742) and the antisense primer was the above primer in exon 10. Amplification was performed according to the RT-PCR kit's
instructions. The RT-PCR products were electrophoresed in 2% agarose
gels with 50-bp and 100-bp DNA ladders (Life Technologies, Gaithersburg, MD) as markers.
| |
RESULTS |
Mutation analysis and expression.
For genotype/phenotype analysis, the nature of the mutation(s) in the
patient's URO-synthase gene was determined as previously described.24,25 Sequencing of all exons and their adjacent intron/exon boundaries showed a single previously undescribed missense
mutation in both alleles (Fig 2), a guanine
to adenine transition at position 562 in the cDNA27 which
predicted a glycine to arginine substitution at amino acid residue 188 (designated G188R). Both parents were found to be carriers of the G188R
mutation. To confirm that this missense mutation altered URO-synthase
function, the mutation was introduced into a prokarotyic vector and
expressed in E coli. As shown in
Table 2, the G188R construct expressed less
than 5% of that expressed by the normal allele. To determine if this
mutation in the first base of exon 9 also caused abnormal splicing,
RT-PCR was performed using mRNA isolated from a lymphoid cell line
established from the patient's blood before BMT. Only PCR products
that were the expected size were detected on agarose gels with both
sets of primers used for RT-PCR (Fig 3),
showing that the mutation did not cause abnormal splicing and skipping of exon 9.
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| Fig 2.
Partial sequencing gel showing the G188R missense
mutation, a G to A transition at cDNA nt 562, the first base of exon 9, which predicts the substitution of an arginine for a glycine.
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| Fig 3.
Agarose gel electrophoresis of the URO-synthase RT-PCR
products amplifed from total lymphoblast RNA from a normal individual
(N) and the CEP patient (P). RT-PCR 1 used primers that amplified a
normal 416-bp product from exon 6 to exon 10 and RT-PCR 2 used primers
that amplified a 223-bp product from exon 8 to exon 10. Note that the
RT-PCR products of the normal individual and the CEP patient were the
same size.
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BMT.
Allogeneic BMT was performed with marrow from the patient's
histocompatible healthy sister. For pretransplant conditioning, the
patient received busulphan 16 mg/kg (total dose) for 4 days and
cyclophosphamide 200 mg/kg (total dose). Cyclosporin A was administered
for graft-versus-host disease (GVHD) prophylaxis. On June 21, 1995, bone marrow-nucleated cells (9 × 108/kg) were
administered intravenously. The patient received granulocyte colony-stimulating factor (10 µg/kg) from day +1 to day +15 and anti-CMV hyperimmunoglobulins and acyclovir for 6 months. She developed
a fever on day 3 and then purpura fulminans was noted on her hands and
fingers. Staphylococcus aureus was cultured from her blood. She
was treated with antibiotics, heparin, fresh frozen plasma, and
high-dose methylprednisolone (30 mg/kg for 4 days). Her neutrophil
count reached 500/µL on day 11. Subsequently, the purpura fulminans
completely resolved without any necrosis. She continued to improve and
was discharged on day 29 posttransplantation.
Beginning 1.5 months after BMT, there was a marked decrease in liver
and spleen volumes and at the end of the first year posttransplant, liver and spleen were nonpalpable. There was also a dramatic
improvement in her hematologic status, starting at 2 months
posttransplant. Complete engraftment was documented at 8 months
posttransplantation because 100% of the donor type apolipoprotein B
DNA polymorphism28 was detected in peripheral leukocytes.
No further blood transfusions were needed after the transplantation and
her differential count has remained normal. A striking and sustained
decrease in the urinary uroporphyrin and coproporphyrin levels also was
observed (Table 1). At 35 months posttransplant, the patient was doing well with normal physical development, a normal hemogram, no evidence of cutaneous lesions on unlimited exposure to sunlight, or other CEP
manifestations (Fig 1C).
| |
DISCUSSION |
This report documents the biochemical and clinical effectiveness
of BMT in a severely affected patient with CEP and shows that
successful BMT can cure the severe transfusion-dependent form of this
inborn error of heme biosynthesis. Our patient, now 35 months
posttransplantation, has maintained a normal hemoglobin level, markedly
reduced urinary porphyrin levels, and most notably, the patient was
able to resume a normal childhood, including exposure to sunlight
without the development of cutaneous lesions. In addition, hepatospenomegly was no longer present. Previously, successful BMT was
described in two older, less severe patients with CEP, the longest
experience being only 12 months.16,17
Successful BMT in our patient resulted in remarkable biochemical and
clinical improvement without GVHD. The level of plasma protoporphyrin
decreased and the levels of serum and urinary uroporphyrins and
coproporphyrins were markedly reduced and seemed to be decreasing with
time. The post-BMT levels presumably reflected the abnormal porphyrin
metabolism in extramedullary tissues such as the liver and kidneys.
Because our patient and her donor were anti-CMV IgG positive, acyclovir
and anti-CMV hyperimmunoglobulins were used for anti-CMV prophylaxis.
No evidence of clinical CMV infection was observed during the period
after transplantation. The only transplant complications were S
aureus sepsis and purpura fulminans, which were successfully
treated without necrosis. Purpura fulminans may have resulted
from the S septicemia and hypercoagulable state after BMT
(protein C, protein S, antithrombin III deficiencies, and factor V
Leiden mutation were not found).29 However, the possible
role of accumulated porphyrin metabolites in purpura fulminans is
unknown.
Because the manifestations of CEP are highly variable, only severely
affected patients should be considered for transplantation due to the
morbidity and mortality associated with BMT. Most often, the diagnosis
of CEP is made in the first days of life when the reddish porphyric
urine is noted in the diaper. After biochemical confirmation, the major
management issue is treatment, which ranges from BMT if an
HLA-identical donor or cord blood is available, to observation, because
nontransfusion-dependent patients may have only mild anemia and
photosensitive cutaneous manifestations that can be avoided. Moderately
affected patients may benefit from chronic transfusion therapy designed
to maintain their hemocrit above 35 to suppress
erythropoiesis.13,30 However, the benefits of this approach
may decrease at puberty, perhaps because of hormonal changes that alter
bone marrow and hepatic heme biosyntheses, thereby requiring more
aggressive approaches like hydroxyurea treatment.14
Determination of the patient's genotype and prokaryotic expression of
URO-synthase missense mutations has proven useful to estimate the
function of the mutant enzyme, thereby permitting genotype/phenotype
correlations.10,24 Such studies have shown that
transfusion-dependent patients have more severe mutations, whereas
patients with milder disease or only cutaneous lesions have at least
one mutation that results in significant residual URO-synthase
activity.10 In the milder cases, avoidance of sunlight and
use of protective clothing will minimize the cutaneous manifestations. Thus, genotype determinations in newly diagnosed infants should be
performed to predict the severity of the future clinical course, and in
particular, the likelihood of transfusion dependence.
Mutation analysis showed that the patient described here was
homoallelic for a previously undescribed URO-synthase missense mutation, G188R. Expression of the G188R allele in E coli
showed that this mutation had markedly reduced enzymatic activity
(Table 2), consistent with the patient's transfusion-dependent
phenotype. Also, because the missense mutation, a G to A transition,
occurred in the first base of exon 9, it could potentially result in
aberrant splicing and cause deletion of exon 9. However,
RT-PCR studies did not detect aberrant splicing. This finding was
consistent with the fact that either guanine or adenine can function as
the first exonic base of intron-exon junctions in vertebrate
genes.31 Thus, the homoallelism for the missense
substitution of a positively charged hydrophilic arginine for a neutral
glycine in the URO-synthase polypeptide impaired the enzyme's
function, resulting in a severe, transfusion-dependent phenotype.
The long-term effectiveness of BMT in CEP remains unknown. Whether BMT
will provide sufficient Kupffer cells to offset the accumulation of
type I porphyrin isomers in the liver will require further follow-up.
However, the findings reported here suggest that BMT is presently the
treatment of choice for CEP patients who are transfusion dependent from
infancy or for newly diagnosed patients with genotypes predicting
severe hemolytic disease, at least until gene therapy is developed. BMT
is, of course, limited by availability of suitable bone marrow donors;
however, this obstacle may be overcome with stored cord blood and bone
marrow registries.32-35
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ACKNOWLEDGMENT |
We thank Y. Wu for mutation analysis, Prof Ayhan Gogmen for
determination of porphyrin metabolites, and Raman Reddy for technical assistance.
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FOOTNOTES |
Submitted June 24, 1998;
accepted July 27, 1998.
Supported in part by grants from the National Institutes of Health,
including a research grant (5 RO1 DK26824); a grant (2 MO1 RR00071) to
the Mount Sinai General Clinical Research Center from the National
Center for Research Resources; and a grant (5 P30 HD28822) to the Mount
Sinai Child Health Research Center.
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 R.J. Desnick, PhD, MD, Professor and
Chairman, Department of Human Genetics, Mount Sinai School of Medicine,
Fifth Ave at 100th St, New York, NY 10029; e-mail:
rjdesnick{at}vaxa.crc.mssm.edu.
| |
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Abstract
Introduction