The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients
The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients
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DOI：
10.1002/ajh.21362
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发表时间：
2009-04-01
影响因子：
12.8
通讯作者：
Mistry, Pramod K.
中科院分区：
文献类型：
--
作者：
Taddei, Tamar H.;Kacena, Katherine A.;Mistry, Pramod K.
编码溶酶体葡萄糖脑苷脂酶的GBA 1基因突变导致1型戈谢病，这是最常见的溶酶体贮积症;最普遍的疾病突变是N370 S。我们调查了403例N370 S GD患者的异质性和自然病程。在一项横断面研究中对GD的人口统计学、临床和遗传学特征进行了研究。此外，还测定了患者患癌症的相对危险度（RR）与年龄、性别和种族群体调整的全国癌症发病率的比较。在403例患者中，54%的患者为纯合子（N370 S/N370 S），46%的患者为N370 S突变复合杂合子（N370 S/其他）。大多数N370 S/N370 S患者表现出以迟发性为主的骨骼疾病为特征的表型，而大多数N370 S/其他患者表现出早发性为主的内脏/血液疾病，P < 0.0001。在整个队列中，多发性骨髓瘤的终生风险显著增加（RR 25，95% CI 9.17-54.40），主要局限于N370 S纯合子患者。其他血液系统恶性肿瘤（RR 3.45，95% CI 1.49-6.79）和总体癌症风险（RR 1.80，95% CI 1.32-2.40）增加。纯合子N370 S GD导致成人发病的进行性骨骼疾病，内脏相对保留，多发性骨髓瘤的风险极高，其他癌症的风险增加。丙种球蛋白病的高发病率表明适应性免疫系统在GD的发展中起重要作用。应监测成人GD患者的骨骼疾病和癌症，包括多发性骨髓瘤。Am. J. Hematol. 84：208-214，2009. (C)2009 Wiley-Liss，Inc.
Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease l the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% Cl 9.17-54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% Cl 1.49-6.79), and overall cancer risk (RR 1.80, 95% Cl 1.32-2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol. 84:208-214, 2009. (C) 2009 Wiley-Liss, Inc.