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Biomedical subjects

E Beutler

Publications and source records attributed to E Beutler.

At least 145 records · Page 8Linked to original sources
PubMed1994

Complete hematologic remissions in chronic-phase, Philadelphia-chromosome-positive, chronic myelogenous leukemia after 2-chlorodeoxyadenosine.

BACKGROUND: 2-Chlorodeoxyadenosine (Cladribine, Leustatin, Ortho Biotech, Raritan, NJ) (2-CdA) is a purine analog with activity in the treatment of lymphoid neoplasms. Interferon induces cytogenetic remissions in chronic myeloid leukemia (CML) and partial remissions in hairy cell leukemia, a disorder in which single courses of 2-CdA induce complete remissions. In vitro clonal growth of immature myeloid progenitors from normal marrow is markedly inhibited by 2-CdA. METHODS: 2-CdA was administered to 12 patients with Philadelphia-chromosome-positive CML, 11 chronic phase, and 1 accelerated phase, at 0.1 mg/kg/day by continuous intravenous infusion for 7 days every 28-35 days, until maximum peripheral hematologic response. RESULTS: Of 12 patients, 10 (83%) achieved complete hematologic responses and 2 (17%) partial hematologic responses after a median of two courses of 2-CdA. The median first hematologic response duration was 3 months. Of the seven patients who relapsed and were retreated with a median of two further courses of 2-CdA, five obtained responses (four complete and one partial) and two did not respond. The median second hematologic response duration was 4 months. No patient had significant Philadelphia-chromosome suppression. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in four patients were the principal toxicities. CONCLUSIONS: 2-CdA is active in CML, inducing complete hematologic responses, but the absence of cytogenetic responses and severe immunosuppression may limit its clinical use.

Adult↗
PubMed1994

Homology between a human protein and a protein of the green garden pea.

In screening a rat mucosa cDNA subtraction library, a clone that exhibited a remarkable degree of homology with a previously described cDNA from the green garden pea, designated the 26g pea turgor protein, was found. A partial cDNA sequence from rat and a complete cDNA sequence from human were obtained. The deduced human protein had a molecular weight of 55,285 and was designated antiquitin because of its remarkable level of conservation through evolution. Human antiquitin was 60% homologous to the green pea 26g with only a single amino acid gap in each sequence. The 66 amino acids at the carboxyl ends of the human antiquitin and pea 26g proteins were 86% identical, and one segment of 52 amino acids was 92% identical. A similar partial sequence encoding 164 amino acids has been detected in Caenorhabditis elegans. Yeast DNA was found to have sequences that hybridize with a human antiquitin probe on Southern blotting. Analysis of the amount of mRNA in various rat and human tissues indicated that the largest amounts were found in rat kidney and liver and in cultured human hepatoma cells. Only minimal amounts were detected in human peripheral blood leukocytes, rat lung, or cultured human fibroblasts. Attempts to induce the mRNA by heat-shock, dehydration, ionizing irradiation, or treatment with iron, t-butylhydroperoxide, or glucocorticoids were unsuccessful. The function of the protein remains unknown.

Aldehyde Dehydrogenase↗
PubMed1994

Erroneous assignment of Gaucher disease genotype as a consequence of a complete gene deletion.

Two sisters with moderately severe Gaucher disease were diagnosed as having the usually relatively benign 1226G/1226G genotype by examination of DNA amplified from exon 9, where this mutation is located. Because of the discrepancy between the apparent genotype and the phenotype, we suspected that one of the alleles had not amplified. Therefore, the DNA of both parents was examined. The father was heterozygous for the 1226G mutation but the mother did not have this abnormality. It was shown that the mother and both daughters had a deletion of the glucocerebrosidase gene: only about one-half of the polymerase chain reaction (PCR) amplification product of the glucocerebrosidase gene in this region was found, compared to internal controls consisting of the glucocerebrosidase pseudogene and of the adjacent liver pyruvate kinase (PKLR) gene. The appearance of Southern blots developed with full length glucocerebrosidase cDNA probes showed that the band unique to the functional glucocerebrosidase gene had reduced intensity, and no abnormal bands were present after digestion with any restriction endonuclease, indicating that the entire coding region was deleted.

Diseases in Twins↗
PubMed1994

Tight linkage of pyruvate kinase (PKLR) and glucocerebrosidase (GBA) genes.

Two polymorphisms, one in the liver-type pyruvate kinase gene (PKLR) and one in the glucocerebrosidase gene (GBA), both of which are on band q21 of chromosome 1, were found to be tightly linked. Each of three Gaucher disease mutations in 112 chromosomes studied was associated with a unique haplotype. With a conservative assumption about the length of time that the Gaucher disease mutation has been present in the Jewish population, we deduce that the genetic distance between these two loci is probably under 0.2 centimorgans. Four haplotypes are produced by these polymorphic loci, but two of these are relatively uncommon because the polymorphic sites are in linkage disequilibrium. Nonetheless these markers are potentially useful in the prenatal diagnosis of pyruvate kinase deficiency in families who have at least one affected child and may also be helpful in heterozygote detection in families with Gaucher disease where a specific mutation producing the disease in unknown.

Base Sequence↗
PubMed1994

Two new Gaucher disease mutations.

Recently, a mutation at nucleotide 1193 of the glucocerebrosidase gene was described in a patient with type 1 Gaucher disease. This mutation destroys a TaqI site in a polymerase chain reaction (PCR)-amplified fragment. We used digestion with this enzyme to screen DNA samples from Gaucher disease patients representing 23 previously unidentified alleles and discovered that this site had been destroyed in three samples. However, the mutation that caused this change proved to be a CT substitution at cDNA nucleotide 1192 (Genomic 5408; 359Arg-->End). Fortuitously, another TaqI site was destroyed by a different mutation, a GA mutation at nt 1312 (Genomic 5927; 399AspAsn). Both of these mutations were functionally severe in that they were associated with type 2 (acute neuronopathic) Gaucher disease.

Alleles↗
PubMed1994

Comparison of magnetic resonance imaging and ultrasound in evaluating liver size in Gaucher patients.

Comparison is made between the reliability of two imaging methods (ultrasound and magnetic resonance imaging) to measure changes in the size of the liver in patients undergoing treatment for Gaucher disease. The reliability of either modality in estimating liver size is comparable, as is the reliability of demonstrating changes in the size of the liver with time. The precision of the two measurements is roughly the same.

Adolescent↗
PubMed1994

Marrow suppression produced by repeated doses of cladribine.

2-Chlorodeoxyadenosine (cladribine, Leustatin) is being used extensively in the treatment of hematologic malignancies, but relatively little is known regarding its toxicity to the normal marrow. Long-term serial hematologic observations have been made on 29 patients with multiple sclerosis undergoing experimental therapy with monthly courses of cladribine, each of which consisted of 0.087-0.1 mg/kg per day for 7 days. The characteristic hematologic responses of the patients consisted of acute transient monocytopenia, prolonged, profound lymphopenia especially of CD4-positive cells, and modest lowering of the granulocyte count and hemoglobin with development of long-lasting macrocytosis. Two patients developed severe aplastic anemia, requiring transfusion both of red cells and platelets. One of these had previously received extensive therapy with chlorambucil, while the other had received carbamazepine (Tegretol) and was ingesting phenytoin (Dilantin) at the time of cladribine therapy. Both patients recovered after several months of marrow suppression.

Adult↗
PubMed1994

The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

DNA was isolated from four unrelated glucose phosphate isomerase-deficient patients. Seven new mutations in the coding region were found: 247 C-->T, 671 C-->T, 818 G-->A, 833 C-->T, 1039 C-->T, 1459 C-->T, and 1483 G-->A. Three patients were compound heterozygotes, and one patient was a homozygote of 247 C-->T/247 C-->T. Six mutations were found to involve highly conserved amino acids of glucose phosphate isomerase, suggesting that these residues are crucial for the maintenance of biological activity. Two polymorphic sites were also identified, 489 A-->G and 1356 G-->C, which do not produce a change in the amino acid sequence.

Anemia, Hemolytic↗
PubMed1994

Hemolytic anemias.

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Anemia, Hemolytic↗
PubMed1994

Bone marrow transplantation beyond treatment of aplasia and neoplasia.

Marrow transplantation has proved to be an important modality in the treatment of aplastic anemia, acute leukemia, and some other malignant diseases of hemopoietic cells. Much less attention has been paid to the role of marrow transplantation in the treatment of stem cell disorders such as sickle cell disease, chronic granulomatous disease, or Gaucher's disease. Allogeneic transplantation is successful in these disorders, but carries a considerable risk to the recipient. Autologous transplantation becomes a reality when efficient gene transfer with sustained expression is developed. As methods are developed to harvest hemopoietic stem cells from the peripheral blood and to amplify these cells without causing them to differentiate, transplantation will become increasingly valuable in the treatment of stem cell disorders.

Bone Marrow Transplantation↗
PubMed1994

Glucocerebrosidase mutations in Gaucher disease.

BACKGROUND: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling. MATERIALS AND METHODS: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected. RESULTS: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-->A transversion at cDNA nt 644 (Ala176-->Asp), a C-->A transversion at cDNA nt 661 that resulted in a (Pro182-->Thr), and a G-->A transition at cDNA nt 721 (Gly202-->Arg). Two missense mutations were found in exon 7: a G-->A transition at cDNA nt 887 (Arg257-->Gln) and a C-->T at cDNA nt 970 (Arg285-->Cys). Two missense mutations were found in exon 9: a T-->G at cDNA nt 1249 (Trp378-->Gly) and a G-->A at cDNA nt 1255 (Asp380-->Asn). In addition to these disease-producing mutations, a silent C-->G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family. CONCLUSIONS: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature.

Adult↗
PubMed1993

Home treatment with intravenous enzyme replacement therapy for Gaucher disease: an international collaborative study of 33 patients.

Intravenous enzyme replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) is an effective and safe treatment for patients with type 1 Gaucher disease. In an attempt to reduce its high cost, a "low-dose high-frequency" protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we have implemented a program of home treatment for our patients. We now report the safety and feasibility of low-dose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease. The chronic nature of the treatment, its safety, lack of adverse effects, the stable condition of most patients, and the need to reduce the high cost make enzyme replacement for Gaucher disease a good candidate for intravenous home therapy.

Adolescent↗
PubMed1993

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Gaucher disease is a glycolytic storage disease caused by a deficiency in activity of the catabolic enzyme glucocerebrosidase. Over 35 different mutations have been documented, including missense and nonsense point mutations, splicing mutations, deletions and insertions, a fusion gene, and examples of gene conversion. Gaucher disease is most common in the Ashkenazi Jewish population, in which just five of the mutations in this population account for 98% of the disease-producing alleles. Each of these mutations is found in the context of a single haplotype, a finding consistent with a single origin of each mutation. Although it is clear that these mutations provide a selective advantage in the Jewish population and thus constitute a balanced polymorphism, the nature of the advantage is unknown. Gaucher disease can be treated symptomatically, by administration of the missing enzyme, by allogeneic bone marrow transplantation, and potentially by gene transfer into hematopoietic stem cells. Increasing understanding of this disease has, as in other genetic disorders, created a host of social and ethical dilemmas regarding matters such as the cost of treatment for rare diseases and the advantages and disadvantages of population-targeted genetic screening.

Amino Acid Sequence↗
PubMed1993

Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia.

The intron sequences of the human L-type pyruvate kinase gene (PKLR) were determined by using primers selected from the known cDNA sequence. Oligonucleotide primers for these determined intron sequences were used to sequence the exons. When this technique was applied to the DNA of 10 unrelated patients with pyruvate kinase deficiency, the following eight different mutations in the coding region were detected: del391-393, A401, C464, G721, A1076, T1456, T1484, A1529. The A1529 mutation was found repeatedly in unrelated individuals, even in the homozygous state. The context with respect to a polymorphism at nt 1705 was compatible with a single origin for this mutation, and it may represent a balanced polymorphism. In normal subjects, five differences from the published cDNA sequence were documented.

Amino Acid Sequence↗