Thrombotic Microangiopathy in Inverted Formin 2–Mediated Renal Disease

Abstract

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-« have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had CharcotMarie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionallysignificant mutation in INF2. In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.

Thrombotic Microangiopathy and the Kidney

“…A polymorphism in the C5 gene (p.R885H) has been demonstrated to prevent eculizumab binding to C5 (35), and nonresponders to eculizumab should have genetic screening for this single nucleotide polymorphism and alternative treatment strategies considered. More recently, individuals presenting with a TMA with failure to respond to eculizumab have been demonstrated to have genetic variants in the noncomplement genes DGKE (36) and INF2 (37).…”

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

“…diacylglycerol kinase epsilon, DGKε) and other metabolic pathways ostensibly unrelated to complement (e.g. inverted formin 2, INF2). Yet even with comprehensive testing, a mutation is currently not found in a significant number of patients deemed to have aHUS …”

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

“…diacylglycerol kinase epsilon (DGKE)) and other metabolic pathways ostensibly unrelated to complement (e.g. inverted formin 2, INF2). Yet even with comprehensive testing, a mutation is currently not found in a significant number of patients deemed to have aHUS …”

“…Occasional therapeutic failure has been observed with eculizumab. Some patients may require higher doses, while others are unresponsive because of TMA due to STEC‐HUS, cobalamin C defect, methionine synthase deficiency, or DGKE or INF2 mutations. Drug resistance has been reported in Japanese patients with paroxysmal nocturnal haemoglobinuria resulting from a polymorphism in complement C5 that impairs eculizumab binding …”