The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase ε

Abstract

The recent discovery of mutations in the gene encoding diacylglycerol kinase (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

“…In keeping with other published cases, 1,19 we found that the predominant phenotype was the onset of TMA in early childhood, with nephrotic range proteinuria a striking feature. The proportion with a reported infectious trigger (21%) was lower than that reported by Azukaitis et al (30%) 19 and lower than that observed with complementmediated aHUS ($50%). 22 The reporting of prodromal diarrhea (29%) was similar to that reported with complement-mediated aHUS (30%).…”

“…13 Currently, DGKE nephropathy manifesting in aHUS has been reported in 35 individuals 1,14-19 and a nephrotic syndrome/MPGN-like phenotype in 9 individuals. 2 The collective characteristics were summarized recently by Azukaitis et al, 19 although without a detailed investigation of reported pathological diagnoses. The role of complement activation in DGKE nephropathy has not been definitively established.…”

“…Markers suggestive of complement activation have been observed in some patients, but relapses have occurred despite complement inhibiting therapy in 2 individuals. 19 Concurrent DGKE and C3 mutations have been reported, 15 but the consequences of DGKE loss of function appear to occur independently of complement in vitro. 20 Here we determine the incidence of DGKE aHUS and MPGN in prospective studies in the United Kingdom, review the prevalence in historic aHUS cohorts, describe the clinical presentation and long-term outcomes, and report the response to treatment and transplantation.…”

Atypical presentation of atypical haemolytic uraemic syndrome

“…However, there are reports of intronic DGKE mutation (c.888+40A>G) that segregated with disease 6. In addition, patients with DGKE mutation may not respond to eculizumab 5. Thus, our patient’s heterozygous missense variant in exon 2 of DGKE, found more commonly in Africans, has unclear relationship to aHUS.…”

“…In aHUS, pathogenic genetic variants of DGKE are usually homozygous or compound heterozygous, and the onset of aHUS is typically in the first years of life 5. However, there are reports of intronic DGKE mutation (c.888+40A>G) that segregated with disease 6.…”