Atypical hemolytic uremic syndrome with DGKE deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
AHUS, SUSCEPTIBILITY TO, 7, INCLUDED
AHUS7, INCLUDED
NEPHROTIC SYNDROME, TYPE 7, WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 7, INCLUDED
NPHS7
Atypical HUS with DGKE deficiency
aHUS with DGKE deficiency
D-HUS with DGKE deficiency
Hemolytic-uremic syndrome without diarrhea with DGKE deficiency
Nephrotic syndrome type 7 is an autosomal recessive renal disease characterized by onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several ... Nephrotic syndrome type 7 is an autosomal recessive renal disease characterized by onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several years. Renal biopsy typically shows membranoproliferative glomerulonephritis. Some patients may benefit from immunosuppressive therapy (summary by Ozaltin et al., 2013). Atypical hemolytic uremic syndrome-7 is characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episode, most patients develop chronic renal insufficiency. Unlike other genetic forms of aHUS, AHUS7 is not related to abnormal activation of the complement system (summary by Lemaire et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300). For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).
Ozaltin et al. (2013) reported 9 patients from 3 unrelated consanguineous families with onset of progressive clinical nephrotic syndrome in early childhood. Renal biopsy in all cases showed glomerular injury with membranoproliferative glomerulonephritis (MPGN). Most had onset in ... Ozaltin et al. (2013) reported 9 patients from 3 unrelated consanguineous families with onset of progressive clinical nephrotic syndrome in early childhood. Renal biopsy in all cases showed glomerular injury with membranoproliferative glomerulonephritis (MPGN). Most had onset in the first 5 years of life, although 2 sibs in 1 family presented at ages 8 and 17 years. At onset, all had proteinuria and most had low serum albumin. In 1 family, the proband presented with nephrotic syndrome and renal insufficiency at age 2 years and died of meningitis a year later. His brother was the most severely affected patient: he developed end-stage renal failure at age 8 years and underwent renal transplant at age 20. Another affected sib developed end-stage renal disease at age 19 years, and the fourth had no end-stage renal disease at age 30. Treatment with immunosuppressive agents failed to induce remission in the patients in this family. Two sibs from a second family showed the mildest phenotype. The sisters developed nephrotic syndrome at ages 8 and 17 years. One developed end-stage renal failure at age 23 despite immunosuppressive treatment, whereas the other responded to immunosuppressive treatment and ACE inhibitors and did not have renal failure at age 19. In the third family, 3 sibs, including a pair of twins, presented with nephrotic syndrome at age 1.5 years, but none developed end-stage renal failure by ages 2 or 12 years. These 3 patients showed partial remission in response to immunosuppressive treatment. Renal biopsies in all patients were consistent with MPGN based on the findings of hypertrophic and hypercellular glomeruli, thickening of the basement membrane with focal capillary obliteration, endothelial cell swelling, splitting of the basement membrane, effacement of podocyte foot processes, and subendothelial deposits. There was some deposition of IgM and IgG, but no C3 (120700) deposition. Renal biopsy in the patient who presented at age 17 years showed some evidence of focal and segmental glomerulosclerosis (FSGS), a nonspecific finding in advanced glomerulopathy. Serum complement components C3 and C4 (see 120810) were normal in all individuals; serum CFH (134370) was not measured. Lemaire et al. (2013) reported 13 patients from 9 unrelated families with onset of atypical hemolytic uremic syndrome within the first year of life. The infants presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Renal biopsies showed chronic thrombotic microangiopathy with glomerular hypercellularity, split basement membranes, and endothelial cell swelling without electron-dense deposits. Capillary lumens were narrowed, and there was evidence of effaced podocytes. The clinical course was characterized by relapsing episodes of aHUS before age 5 years. None of the patients had abnormalities of the complement system, and 2 patients treated with anticomplement therapy had relapses while on treatment. During follow-up, most patients developed chronic hypertension, microhematuria, and proteinuria, and 3 developed full nephrotic syndrome. Three patients received kidney transplant, none of whom had recurrence of aHUS. Twenty-two percent of sibs of index cases had aHUS, consistent with recessive transmission and high penetrance.
By homozygosity mapping combined with whole-exome analysis of a consanguineous family with early-onset nephrotic syndrome and MPGN, Ozaltin et al. (2013) identified a homozygous truncating mutation in the DGKE gene (Q43X; 601440.0001). Sequencing of this gene in 142 ... By homozygosity mapping combined with whole-exome analysis of a consanguineous family with early-onset nephrotic syndrome and MPGN, Ozaltin et al. (2013) identified a homozygous truncating mutation in the DGKE gene (Q43X; 601440.0001). Sequencing of this gene in 142 unrelated patients with a similar disorder identified 2 more consanguineous families with different homozygous truncating mutations (601440.0002 and 601440.0003). DGKE metabolizes and decreases intracellular DAG levels, thus contributing to the regulation of DAG levels. TRPC6 (603652) is a calcium-permeable cation channel expressed in the foot processes of podocytes and is known to be directly activated by DAG. In vitro functional expression studies in HEK293 cells showed that the DGKE mutants did not cause a decrease in TRPC6 current, as was observed with wildtype DGKE, consistent with a loss of DGKE function. The findings indicated that DGKE controls the intracellular concentration of DAG, which is a component of the phosphatidylinositol cycle that participates in multiple cellular functions and in lipid-mediated intracellular signaling. Perturbation of this pathway in podocytes may underlie the disorder. In 13 patients from 9 families with early-onset atypical hemolytic-uremic syndrome, Lemaire et al. (2013) identified homozygous or compound heterozygous mutations in the DGKE gene (see, e.g., 601440.0004-601440.0008). The first mutations in 4 patients from 2 families were found by exome sequencing. Sequencing the DGKE gene in 47 additional unrelated probands with pediatric-onset aHUS and 36 adult-onset aHUS probands, in whom there was no mutation in known aHUS-associated genes or CFH antibodies, identified 6 additional pediatric index cases carrying rare homozygous or compound heterozygous DGKE variants. Another family with 3 affected individuals was identified independently. The mutations included 3 premature termination codons, 2 frameshift mutations, 1 splice site mutation, and 2 missense mutations that altered conserved residues. DGKE was a frequent cause of aHUS in the first year of life (13 (27%) of 49 cases with aHUS) and accounted for 50% of familial disease in this age group (3 of 6 kindreds). This uniformly early age of onset defined a distinct subgroup of aHUS. Renal biopsy of 1 patient showed no DGKE expression, suggesting that loss of DGKE function is the underlying mechanism. Lemaire et al. (2013) noted that DGKE phosphorylates and inactivates arachidonic acid-containing diacylglycerol (AA-DAG) to the corresponding phosphatidic acid. AA-DAG is the major signaling molecule that activates protein kinase C (PKC). PKC, in turn, increases the production of various prothrombotic factors in endothelial cells. Thus, loss of DGKE may result in sustained AA-DAG signaling, causing a prothrombotic state. In addition, DAGs modify slit diaphragm function in podocytes, a disturbance of which is consistent with renal-specific effects. The findings were important because this was the first genetic cause of aHUS not related to defects in genes encoding proteins in the complement cascade pathway.