|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-02-0651.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Oncology Department, Department of
Paediatrics, Western Sydney Genetics Program, Department of
Haematology, Royal Alexandra Hospital for Children, Sydney, Australia;
and Department of Paediatrics and Child Health, University of Sydney,
Sydney, Australia.
We describe data on a 7-year-old girl with congenital
dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months
to treat her CDA led to iron overload and a persistently high ferritin
level. Her relapsing FMF made effective iron chelation therapy very
difficult. Consequently, at the age of 4 years, she underwent
allogeneic, sibling bone marrow transplantation (BMT). During
conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was
gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off
all immunosuppressants. This case demonstrates that symptoms of FMF can
be alleviated by the therapy used during allogeneic BMT. In this
patient it is likely that the missing factor in FMF is now being
provided by granulocytes derived from the stem cells within
transplanted bone marrow.
(Blood. 2002;100:774-777) Familial Mediterranean fever (FMF; Online McKusick
Inheritance in Man 249100) is an autosomal recessive disorder
characterized by short, episodic bouts of fever, inflammatory serositis
causing arthritis, abdominal pain, pleurisy and pericarditis, and an
erysipelaslike erythematous rash.1 The erythrocyte
sedimentation rate (ESR) is classically increased, with the white blood
cell count usually being normal. Amyloidosis can be a long-term
complication. Normal serosal fluid contains an inhibitor of neutrophil
chemotaxis that acts by antagonizing the complement-derived chemotactic
anaphylatoxin C5a. This inhibitory activity is less than 10% of normal
in patients with FMF, suggesting that C5a inhibitor deficiency may
contribute to the pathogenesis of the inflammatory
episodes.2 Colchicine has proved efficacious in minimizing
these acute episodes and in preventing the long-term complications of
amyloidosis.3
The gene responsible for FMF, MEFV, maps to chromosome
16p,4 and encodes a 791-amino acid protein, variously
known as pyrin5 or marenostrin.6 The function
of this protein, which is predominantly expressed in granulocytes and
synovium, remains to be established, but the most recent evidence
suggests it may be an interferon The congenital dyserythropoietic anemias (CDAs) are rare inherited
disorders affecting the normal differentiation-proliferation pathway of
the erythroid lineage. The CDAs comprise a group of heterogenous
disorders characterized by ineffective erythropoiesis as the
predominant mechanism of anemia and distinct morphologic abnormalities
of the majority of erythroblasts in the bone marrow.11 The
CDAs have been classified into 3 types based on morphologic and
serologic findings,12 but there is clearly heterogeneity within the types and many individual cases of CDA have been reported that do not fit into this classification.11
We report data on a patient who had both CDA and FMF, who required
allogeneic bone marrow transplantation (BMT) as treatment for the CDA.
As a consequence of the BMT she no longer has any symptoms that can be
attributed to FMF. We believe this is the first report of treatment of
FMF by BMT, which in this patient appears to have been curative.
Case report
She required further hospital admissions at ages 7 weeks, 10 weeks, 6 months, and 11 months with recurrent episodes of joint swellings
associated with fever and marked elevation of C-reactive protein and
the ESR. At age 6 months she was admitted with pericarditis, followed
by further admissions with episodic vomiting, lethargy, poor feeding,
diarrhea, and hepatomegaly. A presumptive diagnosis of FMF was made at
age 14 months by one of us (A.M.), and she was started on colchicine,
which led to an improvement in her symptoms.
Despite the regular colchicine therapy, she continued to suffer
frequent relapses, with abdominal pain, arthritis, fever, and
splenomegaly. Her mother would increase her dose of colchicine during
these attacks. On 4 occasions these relapses were sufficiently severe
to warrant admission, once leading to a laparotomy for suspected
small-bowel obstruction.
Her chronic ill health was associated with moderate global
developmental delay and failure to thrive. She also had complex feeding
difficulties necessitating nasogastric tube feeding from the age of 10 months.
To treat the anemia, she required several blood transfusions from age 6 months, progressing to regular transfusions after 12 months. She
developed a rising ferritin level and was started on iron chelation
therapy at age 3 years 7 months, with a deferoxamine pump 6 days of 7. Compliance with this regimen became increasingly difficult due to her
recurrent episodes of vomiting, diarrhea, and arthritis. Ten months
after chelation therapy started her ferritin level was 10 673 µg/L
(normal range, 10-150 µg/L). Her mother felt that her
symptoms of FMF were frequently exacerbated by the deferoxamine, and so
compliance with this remained poor. Her general health was not improved
by transfusion. A liver biopsy performed 6 months prior to BMT showed
no cholestasis, steatosis, or significant fibrosis, but with a liver
iron level of 180.5 µmol/g (normal range < 30 µmol/g).
Tissue typing showed that she had a matched sibling donor. Molecular
typing showed identical A, B, and DRB1 markers. The helper T-lymphocyte
precursor frequency was 1:1 081 147, suggesting a very low
risk of graft- versus-host disease (GVHD).13
Mutation analysis
Screening for the "common" mutations. The fragment encompassing the common mutations in exon 10b (Met680Ile, Asp692Ile, Met694Val, Met694Ile, Val726Ala, and Arg761His) was amplified using "hot start" polymerase chain reaction15 (PCR) and the oligonucleotide primers described by the International FMF Consortium.5 The cycling conditions used were: initial denaturation step 95°C for 10 minutes, followed by 40 cycles of 95°C for 30 seconds, 63°C for 30 seconds, 72°C for 30 seconds, and a terminal elongation step at 72°C for 4 minutes. The amplification was performed in a total of 25 µL composed of 2.5 µL 10 × PCR buffer II (Perkin Elmer, Scoresby, Victoria, Australia), 15 pmol of each primer, 0.16 mM dNTP solution, 1 U ampliTaq Gold (Perkin Elmer), 2.0 mM MgSO4 solution, and DNA 100 ng. The presence of the Val726Ala mutation (AluI site created), the Met694Val mutation (HphI site created), and the Met680Ile (NlaIII site destroyed) were analyzed by digesting 5 µL of the PCR product at 37°C overnight with 2 to 2.5 U of appropriate restriction enzyme (New England BioLabs, Beverly, MA) and digestion buffer as per the supplier's specifications to a final volume of 20 µL. The other mutations were screened by automated sequencing of the exon 10b PCR product (SUPAMAC, University of Sydney).Denaturing high-performance liquid chromatography screening. The rest of the coding sequence was screened by denaturing high performance liquid chromatography (DHPLC), using the Prostar Helix System (Varian, Walnut Creek, CA). Exons 1, 3, 4, 5, 6, 7, and 10a were amplified using the oligonucleotide sets from the International FMF Consortium.5 Exon 2 was amplified using the oligonucleotide primers described by Aksentijevich et al.9 Exons 8 and 9 were amplified with the following oligonucleotides: exon 8: 8 forward CTCAGGATAGATGGGCTTGG, 8 reverse CAGCACAAGGGAACACTGC; exon 9: 9 forward GACTCATTAGACCACAGTCC, reverse primer for exon 8/9 from the International FMF Consortium.5 Heteroduplexes were formed by denaturing the PCR products at 95°C for 10 minutes then slowly cooling to 55°C over 30 minutes. The theoretical temperature for each PCR product was determined from http://insertion.stanford.edu/melt.html and then optimized for temperatures ± 2°C the predicted temperature. The optimal temperature was determined by comparing the retention time of the same sample over the 5 different temperatures and on peak morphology. The temperature chosen was either one where a heteroduplex was seen or the temperature at or before the peak started to broaden, in cases where this was difficult to determine 2 temperatures were used. The temperatures used were as follows: exon 1 (63°C), 2a (69°C), 2b (69°C), 3 (63°C), 4 (61°C), 5 (61°C and 62°C), 6 (59°C and 60°C), 7 (61°C), 8 (60°C), 9 (60°C and 61°C), and 10a (59°C and 60°C). Where a heteroduplex was identified, the presence of a sequence variation was confirmed by automated sequencing (Australian Genomic Resource Facility, University of Queensland). Where no heteroduplex was identified in an amplicon, that amplicon was subjected to automated sequencing. Thus, the whole of the coding region was screened by DHPLC and automated sequencing.
BMT The young patient was admitted 1 month prior to the planned BMT for 2 weeks of intravenous chelation therapy, bringing her ferritin level down from 5700 µg/L to 3425 µg/L. Her main symptoms of FMF at this stage were swelling of her left elbow, splenomegaly, and diarrhea.Conditioning therapy, which was commenced at 4 years of age, consisted
of 4 doses of busulphan, 150 mg/m2 per day (6.3 mg/kg per
day) as a single daily dose on days The posttransplantation course was uncomplicated. She tolerated nasogastric feedings well throughout the BMT. She received one course of antibiotics for a Klebsiella pneumoniae septicemia. She developed clinical skin GVHD on day +38, which was treated with oral prednisolone from days +38 to +93. She showed full hematologic recovery with neutrophil count of 0.5 and 1.0 × 109/L on day +21 and platelet counts of 25, 50, and 100 × 109/L on days +45, +50, and +87, respectively. Her last transfusion of packed cells was on day +9, and she has been undergoing regular venisection since day +66. Her last serum ferritin level was 207 µg/L at 28 months after BMT and no further venisections are planned. Donor chimerism was confirmed by analysis of phytohemagglutinin-stimulated lymphocytes from peripheral blood. The first successful analysis was on day +73, when 2 of 30 cells were female. All subsequent analyses, from day +108 to 2 years after BMT revealed male cells only. Cyclosporin therapy was stopped at 8 months after BMT. Course of symptoms of FMF after BMT The patient's symptoms of FMF rapidly abated during the conditioning therapy and colchicine treatment was halted the day after BMT. Her persistent left elbow effusion resolved and her splenomegaly rapidly disappeared. She remains free of any symptoms of FMF at 28 months after BMT, 20 months after cessation of cyclosporin therapy. At 14 months following BMT, she had an episode of Enterobacter septicemia. This was associated with fever and transient splenomegaly, but no other FMF symptoms. She is feeding well orally and has started kindergarten. She has shown significant catch-up growth, with an increase in height from a standard deviation score (SDS) score of 3.55 at BMT to 1.83 at 26 months after BMT. Her weight has
increased from 19th to 50th percentile (SDS of 0.89 to
0.0).
Mutation analysis DNA extracted from peripheral blood samples was analyzed before BMT for the patient and at 10 months after BMT for the patient and donor. In the patient's DNA collected before BMT, one allele was found to have the Met680Ile mutation by NlaIII restriction digest and direct sequencing (Figure 1). However, despite DHPLC screening and sequencing of the whole coding region, no other disease-causing mutation was identified.
In addition, the patient was found to be heterozygous for the following silent polymorphisms: 414 A>G (Gly138; exon 2), 495 C>A (Ala165; exon 2), 942 C>T (Arg314; exon 3), 1422 A>G (Glu474; exon 5), 1428 G>A (Gln476; exon 5), and 1530 T>C (Asp510; exon 5) [results not shown]. Her clinically healthy donor brother did not have the Met680Ile mutation. He was also found to have the 6 silent polymorphisms, and parental studies revealed that the 6 polymorphisms were inherited from their mother, whereas the Met680Ile mutation was inherited from their father [results not shown].
Although the precise function of pyrin/marenostrin remains to be established, available evidence suggests that it plays a role in the regulation of inflammatory processes.16 Recently, it was shown that a pyrin isoform, which has an in-frame deletion of exon 2, shows a markedly different subcellular localization pattern to the full-length protein in transient expression studies, with spliced variant targeted mainly to the nucleus, whereas the full-length form localized to the cytoplasm.7 Based on these results, it has been speculated that the different mutations in the MEFV gene might have different biologic consequences.7 It would be premature at this stage, however, to speculate whether the combination of MEFV mutations in the present patient had a pathogenetic role her development of CDA. Congenital dyserythropoietic anemia type II (as in this case) is the
most frequent form of congenital dyserythropoiesis. It is characterized
clinically by an anemia of variable severity, jaundice, and
hepatosplenomegaly. Gallbladder disease and secondary hemochromatosis
are frequent complications.17 Erythroid hyperplasia with
binuclearity or multinuclearity involving late erythroblasts in the
bone marrow is a key feature of the diagnosis. In addition, the CDA
type II erythrocytes display antibody-mediated sensitivity to lysis in
acidified sera of many ABO-compatible donors, which has led to the
alternative name of HEMPAS (hereditary erythroblastic multinuclearity
with positive acidified serum).18 The erythrocyte membrane
proteins show abnormalities of glycosylation, in particular band 3, the
anion exchanger.19 Underglycosylated band 3 aggregates in
solution and clusters in membranes, resulting in membrane
disorganization.20 Evidence has been provided for the
localization of the CDA II locus to chromosome 20q11.2 by linkage
analysis, although at least 5% to 10% of cases failed to map to
20q stressing genetic heterogeneity.21 In a few
patients the underglycosylation of band 3 has been identified as
resulting from a deficiency in the activity of either
There has previously been one report of a family with 3 affected members (2 brothers and a cousin) who experienced CDA in association with chronic recurrent multifocal osteomyelitis (CRMO) and Sweet syndrome.23 Interestingly this family was of a consanguineous Palestinian Arab background. The authors proposed that the inherited tendency to the 2 disorders segregated together. Because of this report a diagnosis of CRMO was entertained in our patient early in the course of her disease when she had predominantly bone and joint inflammation. It is interesting to speculate that perhaps the patients in this report in fact had FMF and not CRMO, and perhaps the FMF and CDA segregate together. Alternatively the CDA or the defects of glycosylation may have an impact on the FMF phenotype. A disease-causing mutation was identified in only one allele of the proband, whereas the other allele harbored 6 apparently silent polymorphisms, which do not coincide with any of the previously reported founder haplotypes.24 It is possible that the pathogenic mutation in the other allele is located in the promoter region of the gene, or in an intronic region not sequenced, which might affect splicing of the messenger RNA (mRNA). Another possibility is that one of the apparent silent exonic polymorphisms affects an exonic splicing enhancer, resulting in perturbations of the normal splicing processes.25,26 It is also possible that in this family the FMF trait has been transmitted with true autosomal dominant inheritance, as has been recently reported,27,28 although this has not been observed to date for the Met680Ile mutation. Finally, it may be that together the combination of silent polymorphisms in cis alters the structure or function of the pyrin polypeptide in a deleterious manner. Confirmation or exclusion of these possibilities may be possible after the development of a functional assay for the pyrin gene product and mRNA studies. Bone marrow transplantation, once confined to the treatment of hematologic malignancy abnormalities,29,30 has now expanded to treat other stem cell and other monogenic disorders.31-33 Clearly the potential risks of BMT would not routinely be justified in the treatment of FMF, particularly when there is an effective, simple, and relatively safe treatment in the form of colchicine for both acute attacks and long-term complications. It is unclear whether the patient's hematologic condition exacerbated her FMF, but her parents had the distinct impression that deferoxamine therapy worsened her symptoms, making compliance difficult. Because of severe iron overload, BMT became mandatory to treat the CDA, with the fortuitous result that the BMT appears to have also "cured" her FMF, at least after 28 months of observation off colchicine after BMT, and 20 months off all immunosuppressants. We believe that this is the first reported case of a patient with FMF
receiving a BMT. We suggest that BMT should be considered, albeit as a
last resort, in patients who are extremely unresponsive to all
therapies including colchicine and interferon
Submitted February 28, 2002; accepted March 19, 2002.
Prepublished online as Blood First Edition Paper, June 14, 2002; DOI 10.1182/blood-2002-02-0651.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Peter J. Shaw, Oncology Department, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; e-mail: peters{at}chw.edu.au.
1. Online McKusick Inheritance in Man http://www3.ncbi.nlm.nih.gov/htbin-post/OMIM. 2. Matzner Y, Brzezinski A. C5a-inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med. 1984;311:287-290[Abstract]. 3. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;314:1001-1005[Abstract]. 4. Pras E, Aksentijevich I, Gruberg L, et al. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med. 1992;326:1509-1513[Abstract]. 5. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90:797-807[CrossRef][Medline] [Order article via Infotrieve]. 6. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25-31[CrossRef][Medline] [Order article via Infotrieve].
7.
Papin S, Duquesnoy P, Cazeneuve C, et al.
Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus.
Hum Mol Genet.
2000;9:3001-3009
8.
Samuels J, Aksentijevich I, Torosyan Y, et al.
Familial Mediterranean fever at the millennium 9. Aksentijevich I, Torosyan Y, Samuels J, et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999;64:949-962[CrossRef][Medline] [Order article via Infotrieve]. 10. Dodé C, Pêcheux C, Cazeneuve C, et al. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000;92:241-246[CrossRef][Medline] [Order article via Infotrieve].
11.
Iolascon A.
Congenital dyserythropoietic anemias: a still unsolved puzzle.
Haematologica.
2000;85:673-674 12. Heimpel H, Wendt F. Congenital dyserythropoietic anemia with karyorrhexis and multinuclearity of erythroblasts. Helv Med Acta. 1968;34:103-115[Medline] [Order article via Infotrieve]. 13. Weston LE, Geczy AF, Farrell C. Donor Helper T-cell frequencies as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings. Transplantation. 1997;64:836-841[CrossRef][Medline] [Order article via Infotrieve].
14.
Miller SA, Dykes DD, Polesky HF.
A simple salting out procedure for extracting DNA from human nucleated cells.
Nucleic Acids Res.
1988;16:1215
15.
Chou Q, Russell M, Birch DE, Raymond J, Bloch W.
Prevention of pre-PCR mis-priming and primer dimerization improves low-copy-number amplifications.
Nucleic Acids Res.
1992;20:1717-1723
16.
Centola M, Wood G, Frucht DM, et al.
The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.
Blood.
2000;95:3223-3231
17.
Iolascon A, Delaunay J, Wickramasinghe SN, Perrotta S, Gigante M, Camaschella C.
Natural history of congenital dyserythropoietic anemia type II.
Blood.
2001;98:1258-1260 18. Crookston JH, Crookston MC, Burnie KL, et al. Hereditary erythroblastic multinuclearity associated with a positive acidified-serum test: a type of congenital dyserythropoietic anaemia. Br J Haematol. 1969;17:11-26[Medline] [Order article via Infotrieve]. 19. Baines AJ, Banga JP, Gratzer WB, Linch DC, Huehns ER. Red cell membrane protein anomalies in congenital dyserythropoietic anaemia, type II (HEMP AS). Br J Haematol. 1982;50:563-574[Medline] [Order article via Infotrieve].
20.
Fukuda MN.
HEMPAS disease: genetic defect of glycosylation.
Glycobiology.
1990;1:9-15 21. Gasparini P, Miraglia del Giudice E, Delaunay J, et al. Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search. Am J Hum Genet. 1997;61:1112-1116[CrossRef][Medline] [Order article via Infotrieve]. 22. Amado M, Almeida R, Schwientek T, Clausen H. Identification and characterization of large galactosyltransferase gene families: galactosyltransferases for all functions. Biochim Biophys Acta. 1999;1473:35-53[Medline] [Order article via Infotrieve].
23.
Majeed HA, Rawashdeh M, El-Shanti H, Qubain H, Khuribulos N, Shahin HM.
Familial Mediterranean fever in children: the expanded clinical profile.
Q J Med.
1999;92:309-318
24.
Bernot A, Da Silva C, Petit JL, et al.
Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).
Hum Mol Genet.
1998;7:1317-1325 25. Cardozo AK, De Meirleir L, Liebaers I, Lissens W. Analysis of exonic mutations leading to exon skipping in patients with pyruvate dehydrogenase E1 alpha deficiency. Pediatr Res. 2000;48:748-753[Medline] [Order article via Infotrieve]. 26. Liu HX, Cartegn L, Zhang MQ, Krainer AR. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet. 2001;27:55-58[Medline] [Order article via Infotrieve].
27.
Booth DR, Gillmore JD, Lachmann HJ, et al.
The genetic basis of autosomal dominant familial Mediterranean fever.
Q J Med.
2000;93:217-221 28. Livneh A, Aksentijevich I, Langevitz P, et al. A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behcet's disease (FMF-BD). Eur J Hum Genet. 2001;9:191-196[CrossRef][Medline] [Order article via Infotrieve]. 29. Kessinger A, Armitage J, Bierman P, et al. Clinical outcome of peripheral blood stem cell support. Med Oncol. 1994;11:43-46[Medline] [Order article via Infotrieve].
30.
Pession A, Rondelli R, Paolucci P, et al.
Hematopoietic stem cell transplantation in childhood: report from the bone marrow transplantation group of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).
Haematologica.
2000;85:638-646 31. O'Marcaigh AS, Cowan MJ. Bone marrow transplantation for inherited diseases. Curr Opin Oncol. 1997;9:126-130[Medline] [Order article via Infotrieve]. 32. Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria Vol 12. Hurler: Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol.; 1999:167-176. 33. Yeager AM. Hematopoietic cell transplantation for storage diseases. In: Donnall-Thomas E,Blume KG,Forman SJ, eds. Hematopoietic Cell Transplantation. Malden, MA: Blackwell Science; 1999:1182-1194.
34.
Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N, Gonen O-V.
The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study.
Br J Rheumatol.
1997;36:1005-1008
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  I. Touitou, E. Ben-Chetrit, R. Gershoni-Baruch, G. Grateau, D. L. Kastner, I. Kone-Paut, A. Livneh, R. Manna, I. Mansour, H. Ozdogan, et al. Allogenic bone marrow transplantation: not a treatment yet for familial Mediterranean fever Blood, July 1, 2003; 102(1): 409 - 409. [Full Text] [PDF]
|
|
|
|
|
|
I. Touitou, P. J. Shaw, J. Christodoulou, and A. Mansour Should patients with FMF undergo BMT? Blood, February 1, 2003; 101(3): 1205 - 1205. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
-mediated regulator of the
inflammatory response.
-4-galactosyltransferase (GalT),
N-acetylglucosaminyltransferase (GnT II), or 
-mannosidase II (Man II). However, none of the genes for these enzymes localize to
chromosome 20,
clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health.
Medicine (Baltimore).
1998;77:268-297