Prediction of Severity of Gaucher's Disease by Identification of Mutations at Dna Level

Zimran, Ari; Gross, Eleanore A.; West, Carol; Sorge, Joseph A.; Kubitz, Mike; Beutler, Ernest

doi:10.1016/s0140-6736(89)90536-9

Cited by 253 publications

(170 citation statements)

References 19 publications

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“…For each patient, the clinical severity was calculated on the basis of the Zimran severity score index (SSI), which takes into account the age of onset, the degree of organomegaly, liver function tests, clinical signs of liver disease, cytopenia, bone involvement and other organ involvement (20).…”

Section: Clinical Evaluationmentioning

confidence: 99%

T Cell Numbers Relate to Bone Involvement in Gaucher Disease

Lacerda

Arosa

Lacerda

et al. 1999

Blood Cells, Molecules, and Diseases

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ABSTRACT:The major elements of bone pathology in Gaucher disease are a failure of osteoclast and osteoblast function, resulting in osteopenia and also osteonecrosis. T lymphocytes have recently been found to be involved in the regulation of osteoblast/osteoclast activity in vitro. In the present report the peripheral blood T major lymphocyte subsets were investigated in a group of genotyped type 1 Gaucher disease patients. A total of 31 patients were studied: 21 non-splenectomized (5 N370S homozygotes) and 10 splenectomized (of whom 1 was a N370S homozygote). The results show that non-splenectomized patients present a decrease in absolute numbers of peripheral blood T lymphocytes, specially the CD4 ϩ T subset. However, when patients were analyzed with respect to the presence of bone disease, the number of CD8 ϩ T lymphocytes was found to be statistically significantly lower in patients presenting bone involvement. Furthermore, lower numbers of CD8 ϩ T lymphocytes were significantly correlated with higher levels of plasma tartrate resistant acid phosphatase (TRAP) activity, a putative marker of osteoclast cell activity. These in vivo findings are in agreement with the results reached in vitro by others.

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Section: Clinical Evaluationmentioning

confidence: 99%

T Cell Numbers Relate to Bone Involvement in Gaucher Disease

Lacerda

Arosa

Lacerda

et al. 1999

Blood Cells, Molecules, and Diseases

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“…It was widely anticipated that the elucidation of the GBA sequence would yield an explanation of the vast phenotypic differences encountered among patients with GD. During the past two decades, there have been significant advances in understanding the organization of the gene and locus [Winfield et al, 1997], the identification of mutant alleles [Beutler and Gelbart, 1993;Grabowski and Horowitz, 1997;Tsuji et al, 1987], the enzyme structure [Dvir et al, 2003], and genotype-phenotype correlations [Beutler, 1992;Grabowski, 1997;Koprivica et al, 2000;Sidransky et al, 1994;Zimran et al, 1989]. Nevertheless, the pathological mechanisms through which the mutant enzyme acts to cause the diverse range of patient phenotypes are still elusive.…”

Section: Introductionmentioning

confidence: 99%

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

et al. 2008

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Communicated by William S. SlyGaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase.

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“…8 This index represents a point value from 0 to 30 points of organ involvement and age of onset which is calculated at presentation, and never updated; < 10 points implies mild disease and > 20 reflects severe disease. Use of ERT; reason for surgery; anesthetic management; and complications of all 31 procedures performed during 1993-2003 in 15 pediatric patients, are also presented in the Table. Anemia (≤ 10 g·L -1 ) and thrombocytopenia (< 100,000·mm 3 ) were present prior to eight surgeries (25.8%).…”

Section: Resultsmentioning

confidence: 99%