Hong Kong Med J 2023 Aug;29(4):351–4 | Epub 12 Jul 2023
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
Novel compound heterozygous mutation of the diacylglycerol kinase epsilon gene and membranoproliferative glomerulonephritis: a case report
Sharon HY Lau, MB, ChB, MRCPCH1; Eugene YH Chan, FHKAM (Paediatrics)2; Liz YP Yuen, FHKCPath, FHKAM (Pathology)3; WF Ng, FHKAM (Pathology)3; Alison LT Ma, FHKAM (Paediatrics)2
1 Department of Paediatrics, Prince of Wales Hospital, Hong Kong SAR, China
2 Paediatric Nephrology Centre, Department of Paediatrics, Hong Kong Children’s Hospital, Hong Kong SAR, China
3 Department of Pathology, Hong Kong Children’s Hospital, Hong Kong SAR, China
Corresponding author: Dr Eugene YH Chan (eugene.chan@ha.org.hk)
 Full paper in PDF
Case report
A 10-year-old Chinese boy first presented in June 2015 at the age of 4 years with steroid-resistant nephrotic syndrome. He had been taking full-dose prednisolone at 60 mg/m2/day for 4 weeks. Renal biopsy confirmed immune complex–mediated membranoproliferative glomerulonephritis (MPGN) with predominant immunoglobulin M (IgM) and scanty IgG or C3 deposits. Cyclosporin A, a calcineurin inhibitor (CNI), was introduced and successfully brought the disease into partial remission. His urine protein–to-creatinine ratio (UPCR) reduced from 13.9 mg/mg to 0.95 mg/mg after 2 months. He remained in partial remission for 4 years with cyclosporin A and low-dose prednisolone. He showed a urinary relapse following discontinuation of cyclosporin A in 2020 with a rebound in UPCR from 0.64 mg/mg to 1.57 mg/mg (Table).

Table. Blood and urine test results of the patient
Renal biopsy was repeated and revealed mild-to-moderate global mesangial cell proliferation and a few clusters of arterioles showing hyaline arteriolosclerosis with a peripheral and segmental distribution (Fig). Of note, there was evidence of mesangiolysis with loss of argyrophilic basement membrane material in a segmental pattern. The direct immunofluorescence portion showed finely granular deposits of IgA (2+), IgG (3+), IgM (2+), C1q (3+), and C3 (+) in a diffuse global and capillary distribution. Electron microscopy showed focal fusion of podocyte foot processes, splitting of glomerular basement membrane in association with mesangial cell interposition and scattered subendothelial and intramembranous dense electron deposits in keeping with immune complex. The features were indicative of immune complex–mediated MPGN with evidence of CNI toxicity. The presence of segmental mesangiolysis was suggestive of previous endothelium injury, possibly an episode of glomerular thrombotic microangiopathy (TMA).

Figure. (a) Representative glomerulus showing mesangial proliferative glomerulonephritis pattern of changes with lobular accentuation of glomerular tuft and mild global mesangial cellular proliferation and thickened capillary wall (periodic acid–Schiff stain, original magnification ×400). (b) Representative glomerulus showing mesangial proliferative glomerulonephritis pattern of changes with lobular accentuation of glomerular tuft and mild global mesangial cellular proliferation and tram-track split capillary wall (arrow) [methenamine silver stain, original magnification ×400]. (c) Occasional glomerulus showing evidence of mesangiolysis evident by loss of argyrophilic mesangial material on the right part of the glomerulus. Such mesangiolysis may indicate previous injury of thrombotic microangiopathy (TMA) as there is no active TMA (methenamine silver stain, original magnification ×400). (d) Direct immunofluorescence study showing global mesangial and capillary deposit of immunoglobulin G in a fine granular pattern (original magnification ×400). (e) Electron microscopy. An inverted u-shaped glomerular capillary is present in the centre of the field surrounded by a nucleated podocyte (P) on the left upper corner and other podocytes in the middle and right side. Focal foot process fusion, denoted as FPF in the upper centre, is noted. The lumen of the capillary tuft is denoted by the oval circle on the left side of the field and this part is occupied by the cytoplasm of the endothelial cells. The glomerular basement membrane (GBM, small white arrow on the left lower side) is normal at this region. In the upper part of the capillary loop, there are two areas of mesangial interposition (MIP) with splitted and thickened GBM (two small white arrows). Large white arrows indicate the small intramembranous and subendothelial immune-complex dense deposits. The electron microscopy features are typical of immune complex–mediated membranoproliferative glomerulonephritis
Next-generation sequencing was performed and detected two mutations in the diacylglycerol kinase epsilon (DGKE) gene, including a c.1068_1071del p.(Asn356Lysfs*6) frameshift mutation and a c.1282_1284+18del deletion. Sanger sequencing of the mother detected heterozygous DGKE gene c.1068_1071del p.(Asn356Lysfs*6). The father was unavailable for genetic analysis. In view of these results, the two DGKE variants were likely to act in trans in the patient. According to the American College of Medical Genetics/Association for Molecular Pathology classification, these two variants are considered pathogenic. Additional whole-exome sequencing revealed no significant variants in genes related to monogenic lupus.
Throughout the course of the disease, his blood tests showed no features of haemolytic uraemic syndrome (HUS). Apart from a mildly elevated lactate dehydrogenase, his complete blood count, blood smear and haptoglobin were normal. Complement function testing showed no evidence of complement activation. He was commenced on an angiotensin-converting enzyme inhibitor, prednisolone, and mycophenolate mofetil. He responded promptly with marked improvement in proteinuria: UPCR decreased to 0.36 mg/mg within 1 month. At last follow-up, his UPCR was 0.24 mg/mg with normal kidney function (estimated glomerular filtration rate = 116 mL/min/1.73 m2).
We report the first Chinese patient with DGKE nephropathy who presented as nephrotic syndrome and immune complex–mediated MPGN. Importantly, the patient responded well to immunosuppressive agents including CNI and mycophenolate mofetil. To the best of our knowledge, the pathogenic variants in this case are the first reported in DGKE-related nephrotic syndrome.
Diacylglycerol kinase epsilon gene is important in the regulation of thrombotic status and is present in podocytes, platelets, and endothelium. A loss-of-function in the DGKE gene is associated with a prothrombotic state, leading to episodes of HUS that are complement-independent.1 Interestingly, a subset of patients develop MPGN with nephrotic syndrome.2 Along with the new classification, it is believed that chronic microangiopathy often results in a form of MPGN that is neither immune complex–mediated nor complement-mediated.3 The exact mechanism of DGKE mutations leading to MPGN remains unknown.
Azukaitis et al4 reported 44 cases of DGKE nephropathies, including 33 cases with HUS, nine cases with MPGN/nephrotic syndrome, and two rare cases with a mixed HUS/MPGN presentation. Among the nine reported cases of DGKE-MPGN, three other pathogenic variants were identified. Mutations of p.Gln43*, p.IVS5-2a and p.Thr204Glnfs*6 were found in four, three and two of the patients, respectively. Interestingly, the first case of DGKE nephropathy confirmed in our territory-wide next-generation sequencing cohort had nephrotic syndrome and MPGN.
The pathology of renal biopsy in this child is particularly interesting in terms of the presence of TMA features and an immune complex–mediated MPGN picture. The presence of mesangiolysis signifies endothelial injury such as TMA. These lesions might be caused by the underlying disease process related to DGKE mutations. Of note, about half of the patients with DGKE-HUS recovered spontaneously from the initial TMA episode without any HUS-specific treatment.4 A potential explanation of this observation in our patient is that an episode of subclinical TMA had resolved on its own. Another interesting finding was the positive immunofluorescence on renal biopsy, not commonly seen in TMA-related MPGN. The immune-complex deposition in our patient could not be explained by either autoimmune disease or hepatitis. Although he had an isolated elevation of anti–double stranded DNA that occurred only on disease relapse, a confirmed diagnosis of systemic lupus could not be excluded. Whole-exome sequencing revealed no clinically significant variants in the monogenic lupus genes. Whether or not the finding of immune complex deposition at a histological level was an event secondary to the genetic mutation remains unknown. Clinicians need to be mindful of such a discrepant genetic finding and the clinical phenotype with close follow-up. There have been reported cases of patients with TMA who developed immune complex–mediated MPGN, one of whom also carried a DGKE mutation.4 5 The pathogenic and prognostic differences of this immune complex–mediated subgroup require further elucidation.
Regarding prognosis and treatment, most patients with DGKE-MPGN show some response to immunosuppressants. Nonetheless Azukaitis et al4 reported a high prevalence of chronic proteinuria in DGKE-MPGN patients. Although statistically insignificant, a trend towards a lower 10-year renal survival was also observed (50% in DGKE-MPGN vs 89% in DGKE-HUS).4 After initiation of CNI or mycophenolate mofetil, our patient showed a promising response and attained remission. At 5-year follow-up, he remained in remission with normal kidney function.
This is the first Chinese patient with DGKE nephropathy presenting as nephrotic syndrome with an MPGN picture. Of interest, our patient responded promptly to immunosuppressants, suggesting its potential role in this disease entity. This case highlights the importance of genetic testing in children with an atypical course of nephrotic syndrome. Further international collaborative studies are warranted to understand the pathogenesis and optimal management in this patient population.
Author contributions
Concept or design: SHY Lau, EYH Chan.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: SHY Lau, EYH Chan.
Critical revision of the manuscript for important intellectual content: All authors.
All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
Conflicts of interest
All authors have disclosed no conflicts of interest.
We thank the Department of Pathology, Pamela Youde Nethersole Eastern Hospital for their permission to review the patient’s first renal biopsy.
This case was accepted as poster presentation in the Joint Annual Scientific Meeting 2021 of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association and Hong Kong College of Paediatric Nursing (hybrid, 30 October 2021).
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki, with informed consent provided by the patient’s mother for treatment, procedures, and publication.
1. Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45:531-6. Crossref
2. Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013;24:377-84. Crossref
3. Masani N, Jhaveri KD, Fishbane S. Update on membranoproliferative GN. Clin J Am Soc Nephrol 2014;9:600-8. Crossref
4. Azukaitis K, Simkova E, Majid MA, et al. The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase ε. J Am Soc Nephrol 2017;28:3066-75. Crossref
5. Ankawi GA, Clark WF. Atypical haemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), different diseases or a spectrum of complement-mediated glomerular diseases? BMJ Case Rep 2017;2017:bcr2017220974. Crossref