背景:新发现了一种主要影响肾脏和心脏的遗传性疾病:RRAGD相关的常染色体显性肾病低镁血症伴心肌病(ADKH-RRAGD)。这种疾病的特征是镁和钾的肾脏损失,再加上不同程度的心功能不全.这些范围从心律失常到严重的扩张型心肌病,这可能需要心脏移植。与RRAGD相关的突变显著破坏mTORC1途径的非规范分支。这种破坏阻碍了转录因子EB(TFEB)的核易位和转录活性,后者是溶酶体和自噬功能的关键调节因子。
结论:所有确定的RRAGD变体都会损害肾功能,导致各种严重程度的低镁血症和低钾血症。大多数变体的肾脏表型(即S76L,I221K,P119R,P119L),通常在生命的第二个十年中表现,偶尔会出现扩张型心肌病的儿童期症状。相比之下,P88L变异体与成年后出现的扩张型心肌病有关.迄今为止,T97P变异与心脏受累无关.ADKH-RRAGD最严重的表现,特别是在儿童时期需要移植的电解质失衡和心脏功能障碍似乎与S76L有关,I221K,P119R变体。
结论:这篇综述旨在概述ADKH-RRAGD的临床表现,旨在提高意识,促进早期诊断并促进适当治疗。它还报告了利尿剂患者管理的经验有限,镁和钾补充剂,二甲双胍,或钙调磷酸酶和SGLT2抑制剂。
BACKGROUND: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function.
CONCLUSIONS: All identified RRAGD variants compromise kidney function, leading to hypomagnesemia and hypokalemia of various severity. The renal phenotype for most of the variants (i.e., S76L, I221K, P119R, P119L) typically manifests in the second decade of life occasionally preceded by childhood symptoms of dilated cardiomyopathy. In contrast, the P88L variant is associated to dilated cardiomyopathy manifesting in adulthood. To date, the T97P variant has not been linked to cardiac involvement. The most severe manifestations of ADKH-RRAGD, particularly concerning electrolyte imbalance and heart dysfunction requiring transplantation in childhood appear to be associated with the S76L, I221K, P119R variants.
CONCLUSIONS: This
review aimed to provide an overview of the clinical presentation for ADKH-RRAGD, aiming to enhance awareness, promote early diagnosis, and facilitate proper treatment. It also reports on the limited experience in patient management with diuretics, magnesium and potassium supplements, metformin, or calcineurin and SGLT2 inhibitors.