• Users Online: 204
  • Print this page
  • Email this page

Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 101-103

Atypical hemolytic uremic syndrome with diacylglycerol kinase epsilon (DGKE) gene mutation

1 Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India
2 Division of Pediatric Nephrology, Department of Nephrology, Kidney and Urology Institute, Medanta The Medicity Hospital, Gurugram, Haryana, India

Date of Web Publication4-Dec-2019

Correspondence Address:
Arvind Bagga
Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, Division of Nephrology, All India Institute of Medical Sciences, New Delhi - 110 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_27_19

Rights and Permissions

Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury requiring dialysis in children, is caused by defects in genes encoding the alternative complement pathway. Mutations in noncomplement-related genes are rare, information of therapy and outcome of such patients is limited. We describe a 13-month-old boy with aHUS as a result of compound heterozygous mutations in diacylglycerol kinase gene, possibly triggered by enteroinvasive Escherichia coli infection, with partial response to plasma exchanges. The present case emphasizes the need for a high index of suspicion, appropriate investigation for etiology of the infective trigger, and good supportive care in the management of rare causes of aHUS.

Keywords: Acute kidney injury, diacylglycerol kinase epsilon, dialysis, plasma exchange

How to cite this article:
Sharma A, Khandelwal P, Yadav M, Sethi S, Hari P, Sinha A, Bagga A. Atypical hemolytic uremic syndrome with diacylglycerol kinase epsilon (DGKE) gene mutation. Asian J Pediatr Nephrol 2019;2:101-3

How to cite this URL:
Sharma A, Khandelwal P, Yadav M, Sethi S, Hari P, Sinha A, Bagga A. Atypical hemolytic uremic syndrome with diacylglycerol kinase epsilon (DGKE) gene mutation. Asian J Pediatr Nephrol [serial online] 2019 [cited 2020 Jul 2];2:101-3. Available from: http://www.ajpn-online.org/text.asp?2019/2/2/101/272313

  Introduction Top

Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare entity caused chiefly by inherited defects in the regulation of the alternative complement pathway. Rarely, HUS is associated with mutations in genes not related to complement regulation, such as those encoding diacylglycerol kinase epsilon (DGKE), inverted formin-2, and plasminogen (PLG).[1],[2] Defects in DGKE affect 2%–3% of patients with atypical HUS and chiefly present in infancy. While established therapies for aHUS, including complement blockade and plasma exchanges, are considered to have a limited role in the management of DGKE-associated aHUS, information on response to therapy and renal outcomes is limited due to the rarity of this entity.[3] We report a 13-month-old boy with compound heterozygous DGKE variants, who presented with aHUS following diarrhea and recovered renal function partially following plasma exchanges.

  Case Report Top

A 13-month-old boy, first-born of a nonconsanguineous marriage, presented with a history of fever and loose stools for 5 days, followed by a decline in urine output over the next 2 weeks. There was no history of dysentery, seizures, jaundice, gross hematuria, rash, or altered sensorium; family history was noncontributory. At the presentation to the hospital, he had severe pallor, anasarca, and stage 2 hypertension. Investigations showed hemoglobin 6.6 g/dl, 20% schistocytes, and lactate dehydrogenase 3255 IU/L, suggesting microangiopathic hemolytic anemia, platelet count 37,000/mm3, serum creatinine 2.7 mg/dl, proteinuria (3+ by dipstick) and microscopic hematuria. Blood C3 was 72 mg/dl (normal <90 mg/dl). Stool culture grew Escherichia coli (E. coli), and stool multiplex polymerase chain reaction showed enteroinvasive E. coli; shiga-toxin E. coli, enterohemorrhagic E. coli, and enteropathogenic E. coli were not detected. Serological tests for dengue, malaria, and leptospira were negative. Anti-factor H antibodies were negative, and flow cytometry showed normal surface expression of CD46. Serum vitamin B12 levels were 192 pg/ml (239–931 pg/ml), folate was 4 ng/ml (3.5–20.5 ng/ml), homocysteine level was 15.2 μmol/l (6.6–14.8 μmol/l), and activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 was 101% (68%–163%).

With a diagnosis of atypical HUS, in the absence of availability of eculizumab, daily plasma exchanges were begun. Despite 11 sessions of daily plasma exchanges, the child failed to attain hematological remission and remained dependent on hemodialysis. Genetic testing was ordered while switching plasma exchanges to plasma infusions. Hematological remission was attained after 2 months of the onset of the illness while on plasma infusions, however, had a relapse soon after 1 week with a fall in hemoglobin and platelet counts and was managed symptomatically with blood transfusion. Hemodialysis was discontinued after 4 months, and hypertension, initially requiring five antihypertensive agents, was controlled on two antihypertensive agents at dialysis discontinuation. At 8-month from onset, the patient has a normal renal function with an estimated glomerular filtration rate of 100 ml/1.73 m2/min, normal urinalysis, and requires one antihypertensive agent for control of blood pressure.

The next-generation sequencing by a targeted panel revealed variations at c.1009C>T (p. R337X) in exon 6 and c.1442dupG (p. V482SfsX16) in exon 11 in DGKE. Both variations result in premature truncation of the protein. In silico prediction of the nonsense variant, c.1009C>T was damaging on Mutation Taster 2 (www.mutationtaster.org), CADD score was 38 (cadd.gs.washington.edu/), and the variant was conserved across species (PhyloP5.71, Phast Cons 1.0, and GERP++3.32). The in silico prediction of the frameshift variant c.1442dupG was damaging on Mutation Taster 2 (www.mutationtaster.org), disease-associated on ENTPRISE-X (score 0.557; cssb2.biology.gatech.edu/entprise-x.) and the variant was conserved across species (PhyloP5.6 and Phast Cons 1.0). While the former variant is reported in association with disease,[4] with a frequency of 0.002% in exome aggregation consortium (ExAC) database and not reported in 1000 genomes database, the latter is a novel change, not reported in 1000 genomes and ExAC databases. Both the variants were validated by Sanger sequencing in the patient [Figure 1]. The c.1009C>T (p. R337X) variant was absent in either parent, suggesting de novo change; the other was detected in heterozygous state in the asymptomatic father [Figure 1]. Therefore, both the variants were classified as pathogenic by the American College Medical Genetics and Genomics 2015 criteria.[5]
Figure 1: Sequence chromatograms and alignment to the reference sequence showing the variation in exon 6 of diacylglycerol kinase epsilon (DGKE) gene detected in the index patient but not detected in either of the two parents. There is variation in exon 11 of the same gene detected in the patient and the father, but not in the mother

Click here to view

  Discussion Top

We describe a 13-month-old boy with atypical HUS due to compound heterozygous pathogenic frameshift variations in DGKE, including one novel and one reported change. Atypical HUS due to a DGKE defect is a rare disorder with 44 cases reported till date. While it primarily presents during infancy, onset beyond 1st year of life, like the current patient, has rarely been described.[3] Its hallmark, nephrotic range proteinuria at onset, was present in the index patient; however, proteinuria resolved during follow-up in our patient, unlike in previous reports.[6] For unclear reasons, a third of the reported cases have had features of complement dysregulation, including low blood C3 levels, as in the present patient.[4] Importantly, a viral trigger is described in 30%–50% of primary illness or relapses. Like in the present patient, a few patients have had onset following nonbloody diarrhea, the detection in the stool of enteroinvasive E. coli. highlights the need to recognize infectious triggers. Unlike enteroinvasive E. coli, infections with Shigella flexneri,[7] and Shiga-toxin producing E. coli O157: H7[8],[9] have been reported in patients with aHUS attributed to underlying complement defects.

DGKE is a protein found in endothelial cells and platelets that phosphorylates arachidonic acid-containing diacylglycerol (DAG) to phosphatidic acid.[10] DAG activates protein kinase C, which increases the production of prothrombotic factors such as PLG and tissue factor pathway inhibitor[11] and drives thrombin-induced platelet activation. Since phosphorylation of DAG to phosphatidic acid by DGKE terminates this signaling, loss of DGKE function results in a prothrombotic state.[12] Since DAG also induces endocytosis of nephrin at the slit diaphragm, the persistence of DAG causes proteinuria and kidney failure.[13],[14] The DGKE protein has catalytic and accessory domains; however, variants associated with aHUS are reported in almost all exons and intron-exon boundaries, without any “hot” spots or genotype-phenotype relationships.[3] The finding of a de novo change in the current case, as reported in one other patient previously[6] highlights the importance of parental testing, especially of novel and presumed compound heterozygous variant.

While in previously reported series, acute benefits were attributed in 10 of 16 patients to plasma therapy, the pathogenesis involves endothelial activation involving the complement cascade, and therefore, the benefit of plasma exchanges is doubtful. No response of hematological parameters to plasma exchanges and the recurrence of hemolytic anemia and thrombocytopenia during plasma infusions in the present case emphasizes the limited role of plasma exchanges/infusions in management of DGKE-associated aHUS, and underscores the need to suspect disorders that do not respond to plasma therapy such as defects in DGKE or CD46 and disorders of cobalamin metabolism. Comprehensive genetic testing should be performed in all such cases. While we do not have access to eculizumab in our country, the monoclonal's role in management requires further evaluation, especially in patients with life-threatening manifestations. The presence of an additional complement defect is an indication for complement blockade, although subsequent relapses might not be prevented.

Our case instructively highlights the need to suspect noncomplement culprits such as DGKE in young patients with atypical HUS who have severe proteinuria and do not respond promptly to plasma therapy. Investigation into the etiology of the infectious trigger and underlying genetic defect is essential in all cases of atypical HUS. Good supportive care and close long-term follow-up are cornerstones of the management of DGKE defects. Parents should be advised about the risk of relapses and progression to end-stage renal disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:1676-87.  Back to cited text no. 1
Feitz WJC, van de Kar NCAJ, Orth-Höller D, van den Heuvel LPJW, Licht C. The genetics of atypical hemolytic uremic syndrome. Med Genet 2018;30:400-9.  Back to cited text no. 2
Azukaitis K, Simkova E, Majid MA, Galiano M, Benz K, Amann K, et al. The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase ε. J Am Soc Nephrol 2017;28:3066-75.  Back to cited text no. 3
Besbas N, Gulhan B, Soylemezoglu O, Ozcakar ZB, Korkmaz E, Hayran M, et al. Turkish pediatric atypical hemolytic uremic syndrome registry: Initial analysis of 146 patients. BMC Nephrol 2017;18:6.  Back to cited text no. 4
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405-24.  Back to cited text no. 5
Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45:531-6.  Back to cited text no. 6
Brocklebank V, Wong EK, Fielding R, Goodship TH, Kavanagh D. Atypical haemolytic uraemic syndrome associated with a CD46 mutation triggered by Shigella flexneri. Clin Kidney J 2014;7:286-8.  Back to cited text no. 7
Alberti M, Valoti E, Piras R, Bresin E, Galbusera M, Tripodo C, et al. Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations. Am J Transplant 2013;13:2201-6.  Back to cited text no. 8
Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2006;17:2017-25.  Back to cited text no. 9
Shulga YV, Topham MK, Epand RM. Regulation and functions of diacylglycerol kinases. Chem Rev 2011;111:6186-208.  Back to cited text no. 10
Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 2001;70:281-312.  Back to cited text no. 11
Pettitt TR, Wakwlam MJ. Diacylglycerol kinase epsilon induced altered protein kinase C distribution in vivo. J Biol Chem 1999;264:16030-6.  Back to cited text no. 12
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G, et al. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 1999;397:259-63.  Back to cited text no. 13
Quack I, Woznowski M, Potthoff SA, Palmer R, Königshausen E, Sivritas S, et al. PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia. J Biol Chem 2011;286:12959-70.  Back to cited text no. 14


  [Figure 1]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Case Report
Article Figures

 Article Access Statistics
    PDF Downloaded89    
    Comments [Add]    

Recommend this journal