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Am J Hum Genet. 1993 June; 52(6): 1094–1101. | PMCID: PMC1682271 |
Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications. A Sibille, C M Eng, S J Kim, G Pastores, and G A Grabowski Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York. Abstract Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, and severity of bony disease. Highly statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370S/? genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. Full text Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References. These references are in PubMed. This may not be the complete list of references from this article. - Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, Mankin HJ, Murray GJ, Parker RI, Argoff CE, et al. Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 1991 May 23;324(21):1464–1470. [PubMed]
- Beighton P, Goldblatt J, Sacks S. Bone involvement in Gaucher disease. Prog Clin Biol Res. 1982;95:107–129. [PubMed]
- Beutler E. Gaucher's disease. N Engl J Med. 1991 Nov 7;325(19):1354–1360. [PubMed]
- Beutler E, Gelbart T, Kuhl W, Sorge J, West C. Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10544–10547. [PubMed]
- Beutler E, Gelbart T, Kuhl W, Zimran A, West C. Mutations in Jewish patients with Gaucher disease. Blood. 1992 Apr 1;79(7):1662–1666. [PubMed]
- Beutler E, Gelbart T, West C. The facile detection of the nt 1226 mutation of glucocerebrosidase by 'mismatched' PCR. Clin Chim Acta. 1990 Dec 24;194(2-3):161–166. [PubMed]
- Beutler E, Kay A, Saven A, Garver P, Thurston D, Dawson A, Rosenbloom B. Enzyme replacement therapy for Gaucher disease. Blood. 1991 Sep 1;78(5):1183–1189. [PubMed]
- Choy FY, Woo M, Der Kaloustian VM. Molecular analysis of Gaucher disease: screening of patients in the Montreal/Quebec region. Am J Med Genet. 1991 Dec 15;41(4):469–474. [PubMed]
- Erikson A, Groth CG, Månsson JE, Percy A, Ringdén O, Svennerholm L. Clinical and biochemical outcome of marrow transplantation for Gaucher disease of the Norrbottnian type. Acta Paediatr Scand. 1990 Jun–Jul;79(6-7):680–685. [PubMed]
- Fallet S, Grace ME, Sibille A, Mendelson DS, Shapiro RS, Hermann G, Grabowski GA. Enzyme augmentation in moderate to life-threatening Gaucher disease. Pediatr Res. 1992 May;31(5):496–502. [PubMed]
- Firon N, Eyal N, Kolodny EH, Horowitz M. Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene. Am J Hum Genet. 1990 Mar;46(3):527–532. [PubMed]
- Glew RH, Basu A, LaMarco KL, Prence EM. Mammalian glucocerebrosidase: implications for Gaucher's disease. Lab Invest. 1988 Jan;58(1):5–25. [PubMed]
- Grabowski GA, Gatt S, Horowitz M. Acid beta-glucosidase: enzymology and molecular biology of Gaucher disease. Crit Rev Biochem Mol Biol. 1990;25(6):385–414. [PubMed]
- Grabowski GA, Goldblatt J, Dinur T, Kruse J, Svennerholm L, Gatt S, Desnick RJ. Genetic heterogeneity in Gaucher disease: physicokinetic and immunologic studies of the residual enzyme in cultured fibroblasts from non-neuronopathic and neuronopathic patients. Am J Med Genet. 1985 Jul;21(3):529–549. [PubMed]
- Grace ME, Berg A, He GS, Goldberg L, Horowitz M, Grabowski GA. Gaucher disease: heterologous expression of two alleles associated with neuronopathic phenotypes. Am J Hum Genet. 1991 Sep;49(3):646–655. [PubMed]
- Grace ME, Graves PN, Smith FI, Grabowski GA. Analyses of catalytic activity and inhibitor binding of human acid beta-glucosidase by site-directed mutagenesis. Identification of residues critical to catalysis and evidence for causality of two Ashkenazi Jewish Gaucher disease type 1 mutations. J Biol Chem. 1990 Apr 25;265(12):6827–6835. [PubMed]
- He GS, Grabowski GA. Gaucher disease: A G+1----A+1 IVS2 splice donor site mutation causing exon 2 skipping in the acid beta-glucosidase mRNA. Am J Hum Genet. 1992 Oct;51(4):810–820. [PubMed]
- Hermann G, Goldblatt J, Levy RN, Goldsmith SJ, Desnick RJ, Grabowski GA. Gaucher's disease type 1: assessment of bone involvement by CT and scintigraphy. AJR Am J Roentgenol. 1986 Nov;147(5):943–948. [PubMed]
- Hong CM, Ohashi T, Yu XJ, Weiler S, Barranger JA. Sequence of two alleles responsible for Gaucher disease. DNA Cell Biol. 1990 May;9(4):233–241. [PubMed]
- Latham T, Grabowski GA, Theophilus BD, Smith FI. Complex alleles of the acid beta-glucosidase gene in Gaucher disease. Am J Hum Genet. 1990 Jul;47(1):79–86. [PubMed]
- Latham TE, Theophilus BD, Grabowski GA, Smith FI. Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. DNA Cell Biol. 1991 Jan–Feb;10(1):15–21. [PubMed]
- Lee RE. The pathology of Gaucher disease. Prog Clin Biol Res. 1982;95:177–217. [PubMed]
- Masuno M, Tomatsu S, Sukegawa K, Orii T. Non-existence of a tight association between a 444leucine to proline mutation and phenotypes of Gaucher disease: high frequency of a NciI polymorphism in the non-neuronopathic form. Hum Genet. 1990 Jan;84(2):203–206. [PubMed]
- Ohashi T, Hong CM, Weiler S, Tomich JM, Aerts JM, Tager JM, Barranger JA. Characterization of human glucocerebrosidase from different mutant alleles. J Biol Chem. 1991 Feb 25;266(6):3661–3667. [PubMed]
- Sidransky E, Tsuji S, Martin BM, Stubblefield B, Ginns EI. DNA mutation analysis of Gaucher patients. Am J Med Genet. 1992 Feb 1;42(3):331–336. [PubMed]
- Starer F, Sargent JD, Hobbs JR. Regression of the radiological changes of Gaucher's disease following bone marrow transplantation. Br J Radiol. 1987 Dec;60(720):1189–1195. [PubMed]
- Tarao K, Hoshino H, Motohashi I, Iimori K, Tamai S, Ito Y, Takagi S, Oikawa Y, Unayama S, Fujiwara T, et al. Changes in liver and spleen volume in alcoholic liver fibrosis of man. Hepatology. 1989 Apr;9(4):589–593. [PubMed]
- Theophilus BD, Latham T, Grabowski GA, Smith FI. Comparison of RNase A, a chemical cleavage and GC-clamped denaturing gradient gel electrophoresis for the detection of mutations in exon 9 of the human acid beta-glucosidase gene. Nucleic Acids Res. 1989 Oct 11;17(19):7707–7722. [PubMed]
- Theophilus B, Latham T, Grabowski GA, Smith FI. Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. Am J Hum Genet. 1989 Aug;45(2):212–225. [PubMed]
- Tsai P, Lipton JM, Sahdev I, Najfeld V, Rankin LR, Slyper AH, Ludman M, Grabowski GA. Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res. 1992 May;31(5):503–507. [PubMed]
- Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med. 1987 Mar 5;316(10):570–575. [PubMed]
- Tsuji S, Martin BM, Barranger JA, Stubblefield BK, LaMarca ME, Ginns EI. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2349–2352. [PubMed]
- Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991 Oct;49(4):855–859. [PubMed]
- Zimran A, Sorge J, Gross E, Kubitz M, West C, Beutler E. Prediction of severity of Gaucher's disease by identification of mutations at DNA level. Lancet. 1989 Aug 12;2(8659):349–352. [PubMed]
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