Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of glyoxylate metabolism caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). At the enzymic level, PH1 is usually heterogeneous. Several novel enzymic phenotypes have been identified, including the mistargeting of AGT from the peroxisomes to mitochondria, and the aggregation of AGT in the peroxisomal matrix. Seven PH1-specific point mutations, as well as a number of clinically useful normal polymorphisms, have been found so far in the AGT gene. The molecular elucidation of PH1 has led to changes in almost all aspects of its clinical management, most notably treatment. Liver transplantation as a form of enzyme replacement therapy has been used successfully in the treatment of PH1 over the last 10 years, but the long-term solution lies in gene therapy. Although PH1 is, in many respects, an ideal candidate for gene therapy, the strategies eventually adopted will need to take into account its unique metabolic and enzymic characteristics.

译文

:原发性高草酸尿症1型(PH1)是由肝脏特有的过氧化物酶体酶丙氨酸:乙醛酸氨基转移酶(AGT)缺乏引起的乙醛酸代谢的常染色体隐性先天性错误。在酶水平上,PH1通常是异质的。已经鉴定出几种新颖的酶表型,包括AGT从过氧化物酶体到线粒体的错误定位,以及AGT在过氧化物酶体基质中的聚集。迄今为止,在AGT基因中发现了七个PH1特异性点突变以及许多临床上有用的正常多态性。 PH1的分子阐明已导致其临床管理几乎所有方面的变化,尤其是治疗。在过去的十年中,肝脏移植作为一种酶替代疗法已成功用于治疗PH1,但长期的解决方案在于基因疗法。尽管在许多方面,PH1是基因治疗的理想候选者,但最终采用的策略仍需考虑其独特的代谢和酶学特征。

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