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Brief Report

Atypical Hemolytic Uremic Syndrome with Diacylglycerol

Kinase Epsilon (DGKE) Gene Mutation
Aditi Sharma, Priyanka Khandelwal, Menka Yadav, Sidharth Sethi1, Pankaj Hari, Aditi Sinha, Arvind Bagga
Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi,
1
Division of Pediatric Nephrology, Department of Nephrology, Kidney and Urology Institute, Medanta The Medicity Hospital, Gurugram, Haryana, India

Abstract
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

Introduction for 5 days, followed by a decline in urine output over the

next 2 weeks. There was no history of dysentery, seizures,
Atypical hemolytic uremic syndrome (aHUS), characterized by
jaundice, gross hematuria, rash, or altered sensorium;
microangiopathic hemolytic anemia, thrombocytopenia, and
family history was noncontributory. At the presentation
acute kidney injury, is a rare entity caused chiefly by inherited
to the hospital, he had severe pallor, anasarca, and stage
defects in the regulation of the alternative complement
2 hypertension. Investigations showed hemoglobin
pathway. Rarely, HUS is associated with mutations in genes
6.6  g/dl, 20% schistocytes, and lactate dehydrogenase
not related to complement regulation, such as those encoding
3255  IU/L, suggesting microangiopathic hemolytic
diacylglycerol kinase epsilon (DGKE), inverted formin‑2,
anemia, platelet count 37,000/mm3, serum creatinine
and plasminogen (PLG).[1,2] Defects in DGKE affect 2%–3%
2.7  mg/dl, proteinuria  (3+  by dipstick) and microscopic
of patients with atypical HUS and chiefly present in infancy.
hematuria. Blood C3 was 72 mg/dl (normal <90 mg/dl).
While established therapies for aHUS, including complement
Stool culture grew Escherichia coli  (E.  coli), and stool
blockade and plasma exchanges, are considered to have a
multiplex polymerase chain reaction showed enteroinvasive
limited role in the management of DGKE‑associated aHUS,
E. coli; shiga‑toxin E. coli, enterohemorrhagic E. coli, and
information on response to therapy and renal outcomes
enteropathogenic E. coli were not detected. Serological
is limited due to the rarity of this entity.[3] We report a
tests for dengue, malaria, and leptospira were negative.
13‑month‑old boy with compound heterozygous DGKE
Anti‑factor H antibodies were negative, and flow cytometry
variants, who presented with aHUS following diarrhea and
recovered renal function partially following plasma exchanges. Address for correspondence: Dr. Arvind Bagga,
Department of Pediatrics, ICMR Center for Advanced Research in
Nephrology, Division of Nephrology, All India Institute of Medical Sciences,
Case Report New Delhi ‑ 110 029, India.
A 13‑month‑old boy, first‑born of a nonconsanguineous E‑mail: arvindbagga@hotmail.com
marriage, presented with a history of fever and loose stools
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DOI: How to cite this article: Sharma A, Khandelwal P, Yadav M, Sethi S, Hari P,
10.4103/AJPN.AJPN_27_19 Sinha A, et al. Atypical hemolytic uremic syndrome with diacylglycerol
kinase epsilon (DGKE) gene mutation. Asian J Pediatr Nephrol 2019;2:101-3.

© 2019 Asian Journal of Pediatric Nephrology | Published by Wolters Kluwer - Medknow 101
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Sharma, et al.: Atypical hemolytic uremic syndrome with DGKE mutation
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 (Phylo P 5.71, 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 (Phylo P 5.6 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]
102 Asian Journal of Pediatric Nephrology  ¦  Volume 2  ¦  Issue 2  ¦  July‑December 2019
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
Discussion
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
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Sharma, et al.: Atypical hemolytic uremic syndrome with DGKE mutation
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
Asian Journal of Pediatric Nephrology  ¦  Volume 2  ¦  Issue 2  ¦  July‑December 2019
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
Nil.
Conflicts of interest
There are no conflicts of interest.
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