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J Am Soc Nephrol. 2017 Oct;28(10):3066-3075. doi: 10.1681/ASN.2017010031. Epub 2017 May 19.

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

Author information

1
Clinic of Pediatrics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; k.azukaitis@gmail.com.
2
Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates.
3
Departments of Pediatrics and Adolescent Medicine, and.
4
Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
5
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
6
Department of Paediatrics, Seoul National University Children's Hospital, Seoul, Korea.
7
Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea.
8
Division of Pediatric Nephrology, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
9
Pediatric Nephrology Center, Klinikum Memmingen, Memmingen, Germany.
10
Department of Immunology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
11
Unité Mixte de Recherche en Santé 872, Centre de Recherche des Cordeliers, Paris, France.
12
Center for Human Genetics, Bioscientia, Ingelheim, Germany.
13
Department of Pediatrics, University of Szeged, Szeged, Hungary.
14
Department of Pediatric Nephrology, Jagiellonian University Medical College, Cracow, Poland.
15
Third Department of Internal Medicine, Research Laboratory and George Füst Complement Diagnostic Laboratory, Semmelweis University, Budapest, Hungary.
16
Nephrology Division, Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, Michigan.
17
Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Canada.
18
Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada.
19
Division of Nephrology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada; and.
20
Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, Heidelberg University, Heidelberg, Germany.

Abstract

The recent discovery of mutations in the gene encoding diacylglycerol kinase ε (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.

KEYWORDS:

DGKE; atypical hemolytic uremic syndrome; diacylglycerol kinase epsilon; membranoproliferative glomerulonephritis; thrombotic microangiopathy

PMID:
28526779
PMCID:
PMC5619969
[Available on 2018-10-01]
DOI:
10.1681/ASN.2017010031
[Indexed for MEDLINE]

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