Mandrile Giorgia, Cellini Barbara, Ferraro Pietro Manuel
Genetic Unit and Thalassemia Center, San Luigi University Hospital, Orbassano.
Department of Medicine and Surgery, University of Perugia, Perugia.
Curr Opin Nephrol Hypertens. 2025 Mar 1;34(2):177-183. doi: 10.1097/MNH.0000000000001057. Epub 2024 Dec 6.
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of hepatic glyoxylate metabolism leading to nephrolithiasis and kidney failure. PH1 is caused by mutations on the AGXT gene encoding alanine:glyoxylate aminotransferase (AGT). The AGXT gene has two haplotypes, the major (Ma) and the minor (mi) alleles. This review summarizes the role of the minor allele on the molecular pathogenesis and the clinical manifestations of PH1.
PH1 shows high genetic variability and significant interindividual variability. Although the minor haplotype is not pathogenic on its own, it may be crucial for the pathogenicity of some mutations or amplify the effect of others, thus affecting both symptoms and responsiveness to Vitamin B6, the only pharmacological treatment effective in a selected group of PH1 patients.
In the last years, new drugs based on RNA-interference are available for patients nonresponsive to Vitamin B6, but no specific biomarkers are available to predict disease course and severity. Therefore, a clinical assessment of PH1 taking into account molecular analysis of the mutations and the allelic background and the possible synergism among polymorphic and pathogenic variants should be encouraged to promote approaches of personalized medicine that improve the management of available resources.
1型原发性高草酸尿症（PH1）是一种常染色体隐性遗传性肝脏乙醛酸代谢紊乱疾病，可导致肾结石和肾衰竭。PH1由编码丙氨酸：乙醛酸转氨酶（AGT）的AGXT基因突变引起。AGXT基因有两种单倍型，主要（Ma）和次要（mi）等位基因。本综述总结了次要等位基因在PH1分子发病机制和临床表现中的作用。
PH1具有高度的遗传变异性和显著的个体间变异性。虽然次要单倍型本身不具有致病性，但它可能对某些突变的致病性至关重要，或放大其他突变的效应，从而影响症状以及对维生素B6的反应性，维生素B6是唯一对部分PH1患者有效的药物治疗。
近年来，基于RNA干扰的新药可用于对维生素B6无反应的患者，但尚无特异性生物标志物可预测疾病进程和严重程度。因此，应鼓励对PH1进行临床评估，同时考虑突变的分子分析、等位基因背景以及多态性和致病性变异之间可能存在的协同作用，以推动个性化医疗方法的发展，从而改善现有资源的管理。
