Gaucher disease: Variability in phenotype among siblings
Gaucher disease: Variability in phenotype among siblings
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DOI：
10.1023/b:boli.0000042983.60840.f3
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发表时间：
2004-01-01
影响因子：
4.2
通讯作者：
Rivard, GE
中科院分区：
文献类型：
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作者：
Amato, D;Stachiw, T;Rivard, GE
虽然GBA基因的许多突变已被描述为引起戈谢病，但基因型和表型之间的相关性通常很差，只有少数例外。然而，以前大多数关于基因型-表型相关性的报道都涉及无关的个体，即使他们有相同的突变，也不像兄弟姐妹那样在遗传上接近。我们研究了24组（大多数对）加拿大同胞与I型（非神经元病）戈谢病。由于大多数加拿大省份都采用了类似的标准来制定酶替代疗法（ERT），开始ERT的年龄可以作为疾病严重程度的粗略替代，并且可以检查兄弟姐妹之间的一致性（或缺乏一致性）。在24个兄弟姐妹家庭中，有14个兄弟姐妹一致：要么兄弟姐妹都没有接受ERT，要么都接受ERT，并且开始的年龄大致相同。在这些家庭中，兄弟姐妹之间的疾病的临床特征也有很多相似之处。在其他10个家庭中，缺乏兄弟姐妹一致性，只有一个兄弟姐妹接受ERT（或者，在一个有三个受影响兄弟姐妹的家庭中，三个兄弟姐妹中有两个接受ERT）。在这些家庭中，兄弟姐妹之间的临床特征也存在很大差异（在开始ERT的指南相对统一的环境中可能会出现这种情况）。兄弟姐妹之间不一致的可能原因包括宏观环境和微观环境的差异。后者可能包括细胞水平（如溶酶体pH值、替代底物）或染色体水平（连续基因、修饰基因、GBA中性多态性）的微环境。
Although many mutations of the GBA gene have been described as causing Gaucher disease, there is generally poor correlation between genotype and phenotype, with a few exceptions. However, most previous reports of genotype-phenotype correlation have involved unrelated individuals, who, even if they share the same mutations, are not as genetically close as siblings. We have studied 24 groups (mostly pairs) of Canadian siblings with type I (non-neuronopathic) Gaucher disease. Since most Canadian provinces have adopted similar criteria for instituting enzyme replacement therapy (ERT), the age at which ERT is begun can serve as a rough surrogate for disease severity, and concordance (or lack of concordance) can be examined between siblings. In 14 of the 24 sibling families, there was sibling concordance: either both siblings were not on ERT, or both were on ERT and had begun at roughly the same age. In these families, there was also much similarity in the clinical features of the disease between siblings. In the other 10 families there was lack of sibling concordance, with only one sibling receiving ERT (or, in one family with three affected siblings, two of three on ERT). In these families, there was also much discrepancy between siblings in the clinical features (as might be expected in a setting where the guidelines for starting ERT are relatively uniform). Possible reasons for the discordances between siblings include macro-environmental and microenvironmental differences. The latter may include micro-environments at the level of the cell (e.g. lysosomal pH, alternative substrates) or at the level of the chromosome (contiguous genes, modifier genes, neutral polymorphisms in GBA).