Complement factor H deficiency (CFHD) can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3 (120700), and a decrease in other ... Complement factor H deficiency (CFHD) can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3 (120700), and a decrease in other alternative pathway components, indicating activation of the alternative complement pathway. Homozygotes and heterozygotes may show increased susceptibility to meningococcal infections. In addition, a number of renal diseases have been associated with factor H defect or deficiency, including atypical hemolytic-uremic syndrome (aHUS; 235400), membranoproliferative glomerulonephritis type II (MPGN II), and nonspecific hematuria or nephritis (Ault, 2000). See also complement factor I deficiency (610984), which shows phenotypic overlap with this disorder. Welch (2002) discussed the role of complement in renal disease. - Membranoproliferative Glomerulonephritis type II Abrera-Abeleda et al. (2006) summarized features of MPGN relevant to the complement cascade. MPGN type II, also known as dense deposit disease, causes chronic renal dysfunction that progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. MPGN types I and III are variants of immune complex-mediated disease; MPGN II, in contrast, has no known association with immune complexes (Appel et al., 2005). MPGN II accounts for less than 20% of cases of MPGN in children and only a fractional percentage of cases in adults. Both sexes are affected equally, with the diagnosis usually made in children between the ages of 5 and 15 years who present with nonspecific findings such as hematuria, proteinuria, acute nephritic syndrome, or nephrotic syndrome. More than 80% of patients with MPGN II are positive for serum C3 nephritic factor (C3NeF), an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. C3NeF prolongs the half-life of C3 convertase. Patients with MPGN type II without C3NeF often have mutations in the CFH gene, which also results in prolonged activation of C3 convertase.
Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. ... Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. The mother, maternal uncle, and a cousin had depressed H levels. The second family was of English-Irish extraction living in Kentucky; 3 persons in 3 generations had H levels about half normal. The index case had depressed serum factors H and B levels and IgA nephropathy (161950) which progressed to renal failure. A sister also had IgA nephropathy and depressed serum H and C3 levels. Levy et al. (1986) reported a consanguineous Algerian family in which 2 brothers had early-onset glomerulonephritis with C3 deposits and low levels (less than 10% of normal) of complement factor H. The factor H deficiency was defined by undetectable complement hemolytic activity by the classic (CH50) and alternate (AP50) pathways, and low levels of C3 and factor B (138470). The unaffected first-cousin parents and 2 healthy sibs, presumed heterozygotes, had half-normal H values. Renal disease was discovered at 14 and 4 months of age in the elder and younger brother, respectively. The elder had recurrent episodes of macroscopic hematuria occurring during the course of infections but did not seem to have an excessive number of infections; the younger had repeated upper and lower respiratory tract infections and nearly persistent macroscopic hematuria. Electron microscopy of renal biopsies from both patients were typical for intramembranous dense deposit disease, but immunofluorescence microscopy showed an atypical pattern with abundant granular C3 deposits within the mesangium and along the capillary walls. Lopez-Larrea et al. (1987) studied a family in which 3 female sibs had undetectable levels of factor H and C3 nephritic factor, low levels of factor B, C3, and C5 (see 120500), and normal levels of C4-binding protein (120830), factor I (217030), and classic pathway factors. C4 (see 120810) levels were low in 1 patient. Two of the sibs had Neisseria meningitidis sepsis; all 3 developed membranoproliferative glomerulonephritis. Brai et al. (1988) and Misiano et al. (1993) described a consanguineous Italian family in which 3 sibs had deficiency of factor H and its spliced isoform FHL1. The proband had systemic lupus erythematosus (152700) with chronic renal failure and had highly reduced C3 serum levels and low concentrations of C5-C9. She had suffered from skin lesions (chronic discoid plaques on sun-exposed areas), with ulcerations and central nervous system involvement with psychosis. Her 2 affected brothers showed a similar serum complement profile. They had suffered from 3 and 1 episodes, respectively, of meningococcal meningitis, without autoimmune disease. Factor H was undetectable in all affected sibs, and both parents presented serum concentrations of factor H that were about 50% of normal. Western blot analysis showed the absence of both factor H and FHL1 in the affected sibs. The father and 2 of the H-deficient sibs, including the proband, also had a partial C2 deficiency (217000). Nielsen et al. (1989) described a 15-year-old girl with a complete deficiency of factor H. Both parents had half normal levels. The girl had 2 episodes of meningococcal disease. The degree of H reduction was sufficient to cause increased, spontaneous activation of the alternative complement pathway. Fijen et al. (1996) described a Dutch family in which both heterozygous and homozygous factor H deficiency was observed. The proband of the family suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis. Western blot analysis showed complete factor H deficiency. Among 21 relatives of the proband encompassing 3 generations, 10 had low factor H levels, including 2 children of the proband, indicating heterozygosity. Serum studies showed decreased levels of components of the alternative complement pathway. Vogt et al. (1995) reported a 6-year-old Native American (Sioux) boy who presented at age 13 months with hypocomplementemic hypertensive renal disease. Renal biopsy showed changes consistent with membranoproliferative glomerulonephritis, deposition of type III collagen (120180), and segmental complement C3 deposition in capillary loops. Decreased levels of serum C3 and factor B but normal levels of serum C4 and factor I were found; factor H was undetectable by radial immunodiffusion analysis. Slightly depressed levels of factor H were present in both parents; his sibs had normal levels. Ault et al. (1997) reported that the child originally described by Vogt et al. (1995) underwent renal transplantation at age 7; serum C3 concentrations remained low thereafter, as did factor H levels. Western blot analysis of the patient's plasma before and after renal transplantation showed slightly increased concentration of the 45-kD factor H and no detectable 150-kD factor H when compared with 7 normal plasma samples. Ault et al. (1997) demonstrated that the patient's fibroblasts retained 155-kD factor H protein, which was not degraded even after 12 hours, and showed that factor H was retained in the endoplasmic reticulum. Licht et al. (2006) reported 2 girls, born of consanguineous Turkish parents, with early onset of membranoproliferative glomerulonephritis type II. Renal biopsies showed thickening of the glomerular basement membrane caused by dense deposits in the lamina densa. Immunohistochemistry showed deposition of C3. Laboratory analysis showed activation of both the alternative and classical complement pathway, and both patients and their asymptomatic mother also had autoantibodies to C3 nephritic factor (C3Nef). Genetic analysis identified a homozygous mutation in the CFH gene (134370.0014) in the patients; both parents were heterozygous for the mutation. Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation, which the authors termed 'glomerulonephritis C3.' Heterozygous mutations in complement regulatory genes were identified in 4 of 6 unrelated patients with glomerulonephritis C3, including 2 patients each with mutations in the CFH (see, e.g., 134370.0017) and CFI genes (see, e.g., 217030.0007), respectively. In addition, 1 of 13 unrelated patients with glomerulonephritis with MPGN also had a heterozygous CFH mutation. The findings indicated that dysregulation of the complement alternative pathway is associated with a wide spectrum of diseases ranging from HUS to MPGN with C3 deposits.
In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene.
... In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene. In 3 affected sibs of a consanguineous Italian family with complement factor H deficiency reported by Brai et al. (1988) and Misiano et al. (1993), Sanchez-Corral et al. (2000) identified a homozygous nonsense mutation in the CFH gene (134370.0006). In 1 of the brothers reported by Levy et al. (1986), Dragon-Durey et al. (2004) identified a homozygous mutation in the CFH gene (134370.0010). Dragon-Durey et al. (2004) identified homozygous mutations in the CFH gene in 3 additional patients with MPGN, including 2 Turkish brothers (134370.0013).
Dense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II [MPGNII]) is a complex genetic disease caused by defective regulation of the alternative complement pathway in blood (as opposed to cell surface) that is rarely inherited in a simple Mendelian fashion. ...
DiagnosisClinical DiagnosisDense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II [MPGNII]) is a complex genetic disease caused by defective regulation of the alternative complement pathway in blood (as opposed to cell surface) that is rarely inherited in a simple Mendelian fashion. DDD/MPGNII is typically diagnosed in children age five to 15 years who present with one of the following: Hematuria Proteinuria Hematuria and proteinuria Acute nephritic syndrome Nephrotic syndrome TestingRenal biopsy. The definitive diagnosis of DDD/MPGNII requires electron microscopy and immunofluorescence studies of a renal biopsy [Walker et al 2007]. Light microscopy most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentric (18%), and acute proliferative and exudative (12%) patterns are also seen. Electron microscopy should demonstrate dense transformation of the glomerular basement membrane (GBM) that occurs in a segmental, discontinuous, or diffuse pattern in the lamina densa. The precise composition of these altered areas remains unknown. Immunofluorescence should be positive for C3, usually in the absence of immunoglobulin deposition. Serum C3 nephritic factor (C3NeF). Most persons with DDD/MPGNII have detectable serum levels of C3NeF. C3NeF is an autoantibody that recognizes neoantigenic epitopes on C3bBb, the C3 convertase of the alternative pathway (AP) of the complement cascade [Schwertz et al 2001]. C3 convertases cleave C3 into C3b and C3a. In the presence of C3NeF the half-life of C3 convertase is increased, and as a consequence, serum concentrations of C3 are low and serum concentrations of C3 breakdown products such as C3d are elevated. Note: (1) Serum concentrations of C3NeF can vary over time and C3NeF may be detected in the serum of persons without renal disease [Appel et al 2005]. (2) C3NeF is also present in up to 50% of individuals with MPGNI and MPGNIII (see Differential Diagnosis). Factor H autoantibodies have been reported in the serum of one woman who developed a renal disease consistent with DDD/MPGNII and MPGN type I [Jokiranta et al 1999]. One individual with DDD and a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) had low levels of factor H autoantibodies [Sethi et al 2010]. Factor B auto-antibodies (FBAA) were identified in a person with DDD without serum C3NeF. FBAA bind to and stabilize C3 convertase, enhancing the consumption of C3. C5 convertase formation from C3 convertase is prevented, thus interfering with activation of the terminal complement cascade (TCC) [Strobel et al 2010].Complement activity. Hemolytic assays using sheep erythrocytes are used to measure the activity of the alternative pathway (AP) of complement [Joiner et al 1983]. In DDD serum complement-mediated lysis of sheep erythrocytes is observed. Molecular Genetic TestingGenesCFH (the gene encoding complement factor H) has been implicated in the pathogenesis of DDD/MPGNII by molecular genetic testing and cell culture studies (see Molecular Genetics).CFHR5 (the gene encoding factor H-related 5) has been implicated in the pathogenesis of DDD/MPGNII by molecular genetic testing; however, no unequivocal disease-causing pathologic allelic variants have been reported in CFHR5 in association with DDD/MPGNII. In 7% of persons with DDD/MPGNII at least one copy of the p.Pro46Ser variant of CFHR5 is present [Abrera-Abeleda et al 2006]. (See Molecular Genetics).Other possible genes. Mutation of C3 and LMNA has been reported in one family each. To more completely define the genetics of DDD/MPGNII, molecular genetic testing of multiple complement genes is currently under investigation on a research basis. LMNA. Owen et al [2004] reported one individual with a mutation in LMNA who had both familial partial lipodystrophy type 2 (characterized by fat loss from the face and upper body) and DDD/MPGNII. C3. A heterozygous mutation in C3 (the gene encoding complement component 3) resulting in a ΔDG923 protein (a C3 protein that cannot be cleaved by C3 convertase) was reported in one familial case of DDD/MPGNII [Martinez-Barricarte et al 2010]. Table 1. Summary of Molecular Genetic Testing Used in DDD/MPGNIIView in own windowGene SymbolProportion of Inherited DDD/MGNPII Attributed to Pathologic Mutations in This GeneTest MethodMutations DetectedTest AvailabilityCFH ~10% 1Sequence analysis Sequence variants 2ClinicalCFHR5 Unknown 3Sequence analysisNone reported 3Clinical1. About 10% of persons with DDD/MPGNII have variants that are likely pathologic; these are detected by sequence analysis of CFH [Licht et al 2006, Zipfel et al 2006, Abrera-Abeleda et al 2011]. 85% of persons with DDD/MPGNII have at least one copy of the His402 variant of CFH [Abrera-Abeleda et al 2006]. (See Molecular Genetics.)2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Pathologic mutations have not yet been reported in CFHR5. However, 7% of persons with DDD/MPGNII have at least one copy of the p.Pro46Ser (see Molecular Genetics, CFHR5) variant of CFHR5 [Abrera-Abeleda et al 2006].Testing StrategyTo confirm/establish the diagnosis in a probandThe diagnosis of DDD/MPGNII must be made by renal biopsy, using electron microscopy to demonstrate dense deposits in the GBM. As a histologically defined disease, DDD/MPGNII lacks unequivocal diagnostic serologic markers of disease activity, although nearly 90% of individuals have C3NeF detectable in serum. (A subgroup of individuals with MPGNI also have C3NeF detectable in serum.) In addition, nearly 80% of individuals with DDD/MPGNII have evidence of activation of the alternative pathway of complement as reflected in the serum by low concentrations of C3 and high concentrations of C3 degradation products, including C3d [Appel et al 2005]. In persons with a histologic diagnosis of DDD/MPGNII, molecular genetic testing of CFH to detect pathologic mutations is appropriate, because identification of such a mutation helps to direct treatment. Most treatments for DDD/MPGNII are ineffective, but in individuals with pathologic mutations in CFH, plasma replacement therapy to replace factor H can control complement activation and prevent end-stage renal disease (ESRD) [Licht et al 2006]. At this time, the presence of the His402 variant of CFH (see Molecular Genetics, CFH) or of the p.Pro46Ser normal variant in CFHR5 (see Molecular Genetics, CFHR5) cannot be used to direct therapy in individuals with DDD/MPGNII. However, molecular genetic testing of CFH may be useful (a) in determining whether there is a genetic basis for the diagnosis, and if so, (b) in directing genetic counseling as well as carrier and prenatal testing for at-risk family members. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCFH. Mutations in CFH cause atypical hemolytic uremic syndrome (aHUS), which is characterized by hemolytic anemia, thrombocytopenia, and renal failure. The thrombotic microangiopathy of aHUS damages endothelial cells and causes detachment of the basement membrane. Although most typical HUS is caused by Gram-negative bacteria that produce shiga toxin (Shigella dysenteriae serotype 1; Escherichia coli serotypes O-157, O-111, O-26), atypical HUS is caused by loss-of-function or gain-of-function mutations in several genes encoding regulators (CFH, CFHR1, CFI, and MCP) or activators (C3, CFB), respectively, of the alternative pathway (AP) of complement [Goodship et al 2006, Zipfel et al 2006]. The result of these mutations is impaired protection of host surfaces against complement activation [Saunders et al 2007]. The most common mutated gene is CFH, which encodes CFH, an important regulator of the AP. CFH mutations are reported in 20%-30% of individuals with aHUS. Over 40% of the identified mutations are located in a portion of CFH that encodes SCRs 19 and 20 of the factor H protein [Saunders et al 2007]. These mutations, which affect only one allele and lead to haploinsufficiency, include: Mutations that lead to premature stop codons; Mutations that affect framework cysteine residues and prevent disulfide bond formation and the adoption of the appropriate conformational structure; Non-framework mutations that affect protein expression, result in a defective secreted protein, or severely impair capability to bind to endothelial cell surfaces. The normal allelic variant c.1204T>C (p.Tyr402His) of Factor H affects the risk of age-related macular degeneration (AMD): the c.1204C (His402) variant significantly increases the risk of (AMD) [Haines et al 2005]. CFHR5. A complex rearrangement of CFHR5 producing a mutant protein in which the first two short consensus repeats (SCRs) are duplicated (CFHR512123 9) was found in 26 individuals from Cyprus with ‘CFHR5 nephropathy’, a C3 glomerulopathy similar to DDD/MPGNII that is common in Cyprus. (See also Differential Diagnosis.)
Renal disease. Individuals with dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) typically present with one of the five following findings: ...
Natural HistoryRenal disease. Individuals with dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) typically present with one of the five following findings: Hematuria Proteinuria Hematuria and proteinuria Acute nephritic syndrome Nephrotic syndrome DDD/MPGNII affects females slightly more frequently than males. The DDD Database, a registry that currently contains information on 56 individuals with DDD/MPGNII, reports a 3:2 female:male bias [Lu et al 2007]. Spontaneous remissions of DDD/MPGNII are uncommon [Habib et al 1975, Cameron et al 1983, Marks & Rees 2000]. Although the disease can remain stable for years despite persistent proteinuria, in some individuals rapid fluctuations in proteinuria occur, with episodes of acute renal deterioration in the absence of obvious triggering events. About half of affected individuals develop ESRD within ten years of diagnosis [di Belgiojoso et al 1977, Droz et al 1982, Swainson et al 1983, McEnery 1990, Lu et al 2007], occasionally with the late comorbidity of impaired visual acuity [Colville et al 2003]. Consistent with these studies, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database reports that of the 119 children registered with DDD/MPGNII, 81 have progressed to ESRD [William Harmon, personal communication]. Progression to ESRD develops rapidly, usually within four years of diagnosis, and is the more likely outcome in individuals age ten years or younger than in older persons (p=0.006) [Smith et al 2007]. Girls may have a more aggressive disease course than boys (p=0.16). Acquired partial lipodystrophy (APL). DDD/MPGNII can be associated with APL [Eisinger et al 1972]. In persons with APL the loss of subcutaneous fat in the upper half of the body usually precedes the onset of kidney disease by several years. Misra et al [2004] reported that approximately 83% of individuals with APL have low serum concentrations of C3 and polyclonal C3NeF, and that about 20% develop DDD/MPGNII approximately eight years after the onset of lipodystrophy. Individuals who develop DDD/MPGNII have an earlier age of onset of lipodystrophy (12.6 ± 10.3 yrs vs. 7.7 ± 4.4 yrs, respectively; p<0.001) and a higher prevalence of C3 hypocomplementemia (78% vs. 95%, respectively; p=0.02), suggesting that the disease is more virulent in these individuals [Misra et al 2004].Owen et al [2004] described DDD/MPGNII in a person with Dunnigan-Kobberling syndrome, a form of partial lipodystrophy characterized by sparing of the face.The association between partial lipodystrophy and DDD/MPGNII appears to be related to the effects of dysregulation of the AP of complement on both kidneys and adipose tissue [Mathieson & Peters 1997]. The deposition of activated components of complement in adipose tissue results in the destruction of adipocytes in areas in which factor D (fD, adipsin) is high. Eye findings. Individuals with DDD/MPGNII develop drusen, often in the second decade of life. These whitish-yellow deposits lie within Bruch's membrane beneath the retinal pigment epithelium (RPE) of the retina. The distribution of drusen in individuals with DDD/MPGNII is variable [Duvall-Young et al 1989, Colville et al 2003, Holz et al 2004] and initially has little impact on visual acuity or visual fields. Over time, however, tests of retinal function such as dark adaptation, electroretinography, and electro-oculography can become abnormal, and vision can deteriorate as subretinal neovascular membranes, macular detachment, and central serous retinopathy develop [Colville et al 2003]. The long-term risk of visual problems in individuals with DDD/MPGNII is approximately 10%. Drusen are deposits similar in composition and structure to the deposits observed in the kidney [D’Souza et al 2009], reflecting similarities between the choriocapillaris-Bruch's membrane-retinal pigment epithelial interface and the capillary tuft-GBM-glomerular epithelial interface. No correlation exists between disease severity in the kidney and the eye.Autoimmune diseases. Other autoimmune diseases including diabetes mellitus type 1 and celiac disease have been observed in families with DDD/MPGNII [Sacks et al 1987, Ludvigsson et al 2006]. Pathophysiology. Fluid-phase dysregulation of the AP of the complement cascade is the triggering pathophysiologic event in DDD/MPGNII, and dysregulation of the C3 convertase alone is necessary and sufficient to result in DDD/MPGNII [Martinez-Barricarte et al 2010]. However, during disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury [Appel et al 2005, Smith et al 2007]. C3NeF persists in serum throughout the disease course [Schwertz et al 2001]. Its presence is nearly always associated with evidence of complement activation such as reduction in serum concentration of CH50, decrease in serum concentration of C3, and increase in serum concentration of C3 degradation products such as C3d. However, the relationship between C3NeF, C3, and prognosis is not clear. Some investigators have reported no correlation between C3 serum concentrations and clinical course [Eisinger et al 1972, di Belgiojoso et al 1977, Davis et al 1978, Bennett et al 1989], while others found that persistent hypocomplementemia indicates a poor prognosis [Klein et al 1983, Kashtan et al 1990]. The observed differences may be reconciled by noting that not all C3NeFs are the same, the methods for detecting the presence of C3NeFs vary, and many studies do not report titers. There is good evidence that the triggering epitopes can differ and even change over time. Ohi et al [1992] provided evidence that triggering epitopes can differ. Their report of six individuals with detectable serum concentration of C3NeF in the absence of hypocomplementemia showed that in these individuals serum C3NeF did not interfere with factor H (fH)-induced inactivation of C3bBb. Spitzer & Stitzel [1996] documented that triggering epitopes can change over time. Serum concentration of C3 in three affected persons eventually normalized despite continued C3NeF production. C3NeF isolated from these individuals and added to normal sera mediated consumption of C3, as did the addition of normal factor B (fB) to their sera, consistent with a change in the fB autoantigen in these individuals.
To date, no correlations have been reported for the DDD/MPGNII phenotype as a function of genotype. Too few cases have had pathogenic mutations of CFH to explore phenotype-genotype relationships. It is also possible that pathogenic heterogeneity exists with a final common pathway. ...
Genotype-Phenotype CorrelationsTo date, no correlations have been reported for the DDD/MPGNII phenotype as a function of genotype. Too few cases have had pathogenic mutations of CFH to explore phenotype-genotype relationships. It is also possible that pathogenic heterogeneity exists with a final common pathway.
The membranoproliferative glomerulonephritides are diseases of diverse and often obscure etiology and pathogenetic mechanisms; they account for approximately 4% and 7% of primary renal causes of nephrotic syndrome in children and adults, respectively [Orth & Ritz 1998]. ...
Differential DiagnosisThe membranoproliferative glomerulonephritides are diseases of diverse and often obscure etiology and pathogenetic mechanisms; they account for approximately 4% and 7% of primary renal causes of nephrotic syndrome in children and adults, respectively [Orth & Ritz 1998]. Based on immunopathology and ultrastructure analysis of the kidney, and of the glomerulus in particular, three subtypes of membranoproliferative glomerulonephritides are recognized. Membranoproliferative glomerulonephritis types I and III (MPGNI, MPGNIII) are variants of immune complex-mediated disease. MPGNI is characterized by the presence of subendothelial deposits and MPGNIII by the concomitant presence of subendothelial and subepithelial deposits, suggesting that MPGNIII is possibly a morphologic variant of MPGNI, given their clinical, immunologic, and immunohistologic similarities [Ferrario & Rastaldi 2004]. Of note, however, treatment outcomes following alternate-day prednisone therapy are better for those with MPGNI than for those with MPGNIII [Braun et al 1999]. DDD/MPGNII has no known association with immune complexes. In DDD/MPGNII, pathognomonic dense intramembranous deposits cause capillary wall thickening. Although the list of diseases associated with an MPGN-like pattern and capillary wall thickening is constantly growing, the differences in histology and immunology are sufficient to consider DDD/MPGNII an entity separate and discrete from either MPGNI or III. DDD/MPGNII accounts for fewer than 20% of children with MPGN and fewer than 1% of adults with MPGN [Habib et al 1975]. Other types of glomerulonephritis with deposition of C3 are:Glomerulonephritis C3 (GN-C3), characterized by the presence of isolated mesangial C3 deposits. The main difference between DDD/MPGNII and GN-C3 is the absence of intramembranous deposits within the GBM in the latter [Servais et al 2007]. Based on renal biopsy findings, GN-C3 can be divided in two types: GN-C3 with MPGN (mesangial proliferation and subendothelial C3 deposits); and GN-C3 without MPGN (no mesangial proliferation and subendothelial C3 deposits) [Servais et al 2007]. CFHR5 nephropathy, a nephropathy found in Cypriots characterized by isolated microscopic hematuria that can rapidly progress to renal failure and macroscopic hematuria following an upper respiratory tract infection. Inheritance is autosomal dominant. The cause is partial duplication of CFHR5 (CFHR512123 9) that generates a hybrid protein with two additional short consensus repeats (SCRs). The hybrid CFHR5 protein binds weakly to complement deposited in the glomerulus [Gale et al 2010]. (See Genetically Related Disorders.)Other diseases to consider in the differential diagnosis of the renal manifestations of DDD/MPGNII: Juvenile acute non-proliferative glomerulonephritis (JANG), a disease exclusively of the young (no affected individual exceeded age 12 years in the report by West et al [2000]). JANG is characterized by rapid crescent formation but no mesangial cell proliferation. Large subepithelial deposits that contain C3 and C5 but no IgG develop on the paramesangial portion of the GBM. JANG can be distinguished from DDD/MPGNII on clinical grounds as the latter is typically associated with C3NeF-induced hypocomplementemia, often with nephrotic syndrome and hypertension, while in JANG, serum concentrations of C3 remain at the lower limits of normal [West et al 2000]. Familial lecithin-cholesterol acyltransferase (LCAT) deficiency, an autosomal recessive disorder characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction that can progress to ESRD. High serum concentrations of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage and glomerular deposition of membrane-like, cross-striated structures and vacuole structures. One individual with LCAT deficiency showed glomerular histologic lesions and an immunofluorescent glomerular pattern typical of DDD/MPGNII [Sessa et al 2001]. Partial lipodystrophy (PLD) can be associated with DDD/MPGNII [Eisinger et al 1972]. In persons with PLD, the loss of subcutaneous fat in the upper half of the body usually precedes the onset of kidney disease by several years. The relationship between the two diseases reflects the effects of dysregulation of the AP of the complement cascade on kidney and adipose tissue [Mathieson & Peters 1997]. The deposition of activated components of complement in adipose tissue results in the destruction of adipocytes in areas high in content of factor D (fD, adipsin). The retinal abnormalities of DDD/MPGNII are similar to those seen in the following:Age-related macular degeneration (AMD), the most common cause of visual loss in the US in persons over age 50 years. AMD is characterized by the development of whitish-yellow deposits within Bruch's membrane beneath the RPE. In DDD/MPGNII, drusen develop at an early age and are often detectable in the second decade of life. Both AMD and DDD/MPGNII are associated with common 'at-risk' alleles of CFH [Hageman et al 2005]. Malattia leventinese and Doyne honeycomb retinal dystrophy, two autosomal dominant disorders in which drusen accumulate beneath the RPE. The two disorders are phenotypically similar to AMD [Stone et al 1999]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
After the diagnosis of dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) has been made, the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisAfter the diagnosis of dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) has been made, the following evaluations are recommended: Evaluate the complement system by measuring serum concentration of CH50, APH50, C3, C3d, C4, factor H and sMAC. (For a list of laboratories providing these tests, contact Richard Smith. See Author Notes.) Complement protein measures in DDD/MPGNII are distinctive, with most patients having only low serum concentrations of C3, while serum concentrations of properdin, C5, and other terminal proteins are within the normal range. Factor H serum concentrations can be low, as has been reported with missense mutations in the CFH coding sequence that block protein secretion from the endoplasmic reticulum [Ault et al 1997, Dragon-Durey et al 2004]. Measure autoantibodies including C3NeF, Factor H autoantibodies (FHAA) and Factor B autoantibodies (FBAA). Screen CFH for mutations using bidirectional sequencing.Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria and hematuria. Obtain a baseline ophthalmologic examination [McAvoy et al 2004]. Treatment of ManifestationsNonspecific therapies have been shown to be effective in numerous chronic glomerular diseases and should be initiated. The judicious use of these agents, along with optimal blood pressure control, may be of benefit in individuals with DDD/MPGNII. Angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor blockers decrease proteinuria in many glomerular diseases and slow the progression to renal failure [Ruggenenti et al 1999, Brenner et al 2001]. A retrospective study found that the combination of angiotensin blockers and immunosuppressants (steroids) is more effective than each therapy alone in preventing the development of renal failure [Nasr et al 2009]. Lipid-lowering agents, and in particular hydroxymethylglutaryl coenzyme A reductase inhibitors, may delay progression of renal disease as well as correct endothelial cell dysfunction and alter long-term atherosclerotic risks in the presence of hyperlipidemia [Nickolas et al 2003, Maisch & Pezzillo 2004]. These agents are not widely used in children. Renal allografts. Fewer than 200 individuals with DDD/MPGNII have undergone transplantation [Braun et al 2005]. Five-year allograft survival approximates 50%, which is significantly worse than for the NAPRTCS database as a whole (p=0.001). Living-related donor grafts fare better than deceased donor grafts (p<0.005). Allograft survival appears to be age-dependent in DDD; the survival of pediatric DDD transplant recipients is significantly worse than the rest of the pediatric transplant population [Angelo et al 2011].DDD/MPGNII recurs in nearly all grafts and is the predominant cause of graft failure in 15%-50% of transplant recipients [Appel et al 2005, Angelo et al 2011]. There are little data to suggest that any therapeutic interventions have an effect on reversing this course, although isolated reports have described the use of plasmapheresis, which appears to be of equivocal benefit [Fremeaux-Bacchi et al 1994, Kurtz & Schlueter 2002]. Prevention of Primary ManifestationsAlthough most treatment for DDD/MPGNII is ineffective, plasma replacement therapy in patients with pathologic mutations in CFH can control complement activation and prevent ESRD [Licht et al 2006]. SurveillancePeriodic funduscopic assessment is appropriate [McAvoy et al 2004]. Evaluation of Relatives at RiskIf disease-causing mutations in CFH have been identified in an affected individual, sibs can be offered molecular genetic testing to identify those who have the same mutation(s) in order to facilitate early diagnosis and management of renal disease. Penetrance rates, however, are not known. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA clinical study using eculizumab in persons with DDD/MPGN2 or C3 glomerulonephritis who are age 18 years and older is ongoing but is not recruiting new patients (ClinicalTrials.gov).A clinical study using sulodexide in persons with DDD/MPGNII who are under age 21 years was put on inactive status as no beneficial effect was noted in patients with diabetic nephropathy (ClinicalTrials.gov). Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherThe impact of genotype on graft survival has not yet been explored.Experience with intravenous immunoglobulin (IVIg) and B cell suppression is limited. The following treatment modalities are of unproven value:Plasmapheresis to remove or suppress serum C3NeF activity: In one study, one of three adults with DDD/MPGNII experienced improvement in serum creatinine during plasmapheresis [McGinley et al 1985]. Another study reported success using plasmapheresis to treat a five-year-old boy with recurrent DDD/MPGNII after transplantation. Twelve phereses were performed over 24 days, and the child continued to have improved renal function one year later [Oberkircher et al 1988]. In another report, a 15-year-old girl with rapidly progressive recurrent DDD/MPGNII in her allograft underwent 73 phereses over 63 weeks, stabilizing her creatinine and improving her creatinine clearance. Serial biopsies during this time demonstrated persistent DDD/MPGNII without development of tubular atrophy. During the course of therapy, serum C3NeF activity decreased and C3NeF activity was detected in the removed plasma. Because of the morbidity associated with repeated phereses, treatment was discontinued and graft failure ensued [Kurtz & Schlueter 2002]. In another report, two patients with a pathologic mutation in CFH were successfully treated with fresh frozen plasma [Licht et al 2006]. Prednisone. Although long-term controlled studies of prednisone therapy have suggested a possible benefit as measured by a decrease in proteinuria and prolonged renal survival in children with MPGN type I-III [West 1986, McEnery 1990], a randomized placebo-controlled study found that while evidence showed an overall benefit in individuals with MPGNI, II, and III combined, children with DDD/MPGNII had no better response to prednisone than to lactose, with treatment failure defined as a creatinine greater than 350 mmol/L (4 mg/dL) in 55.6% (5/9) and 60% (3/5) of individuals, respectively [Tarshish et al 1992]. Available data on steroid therapy in adults with DDD/MPGNII suggest a similar lack of efficacy [Donadio & Offord 1989].Note: The use of steroid therapy is extremely effective in JANG, which can be confused with DDD/MPGNII. The two diseases can be distinguished clinically, as DDD/MPGNII is typically associated with C3NeF-induced hypocomplementemia, often with nephrotic syndrome and hypertension, while in JANG, C3 levels remain at the lower limit of normal [West et al 2000].Calcineurin inhibitors. When evaluated in small numbers of individuals, the calcineurin inhibitors do not improve renal survival in DDD/MPGNII. Furthermore, in vitro studies with two calcineurin inhibitors, cyclosporin and tacrolimus, have shown that at therapeutic concentrations neither drug suppresses C3 transcription [Sacks & Zhou 2003]. Given the evidence that uncontrolled activation of the AP of the complement cascade is the basis of MPGNII/DDD, it is not surprising that these drugs are clinically ineffective immunomodulatory treatment modalities.Combined therapy with immunosuppression (IS) and renin aingotensin system (RAS) blockade. In a retrospective study, the combined use of IS (steroids) and RAS blockade (angiotensin-converting enzyme inhibitor and/or angiotensin II receptor blocker) was protective against developing end-stage renal disease (ESRD). The IS/RAS blockade therapy was superior to the use of either agent alone. These findings need to be confirmed by a prospective control study [Nasr et al 2009]. Bevacizumab. In one study, a 29-year-old woman with DDD/MPGNII and subretinal neovascular membranes was treated with monthly intravitreal injections of bevacizumab. An improvement in vision was noted; renal function remained unaltered [Farah et al 2009].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCFH1q31.3Complement factor HResource of Asian Primary Immunodeficiency Diseases (RAPID)CFHCFHR51q31.3Complement factor H-related protein 5 CFHR5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (View All in OMIM) View in own window 134370COMPLEMENT FACTOR H; CFH 608593COMPLEMENT FACTOR H-RELATED 5; CFHR5 609814COMPLEMENT FACTOR H DEFICIENCY; CFHDCFH Normal allelic variants. CFH comprises 23 exons that encode complement factor H, a protein of 1234 amino acids. Of the several alleles of CFH, the one that encodes a His at residue 402 is of particular interest because of the association of this amino acid substitution with DDD/MPGNII and AMD [Hageman et al 2005, Abrera-Abeleda et al 2006]. The c.1204T>C (p.Tyr402His) normal allelic variant is in SCR(short consensus repeat)7, one of at least three glycosaminoglycan (GAG) recognition sites in factor H. SCR7 participates in binding to C-reactive protein (CRP) and to a number of pathogens that sequester factor H as protection from complement-mediated destruction. Structural studies have shown that p.Tyr402His lies toward the center of SCR7, away from its boundaries with SCR8 and SCR9. The 3D structures of both the His402 and Tyr402 protein variants are otherwise identical [Herbert et al 2007]. In spite of this similarity, binding studies indicate that the p.Tyr402His change alters the specific types of GAGs that are recognized by SCR7. For example, binding to both human umbilical vein endothelial cells and to C-reactive protein is reduced for the His402 protein variant as compared to the Tyr402 protein variant [Laine et al 2007, Skerka et al 2007]. Pathologic allelic variants. CFH has been implicated in DDD/MPGNII by the following: A report of two sisters with DDD/MPGNII who were homozygous for the c.670_672delAAG (p.Lys224del) mutation of CFH [Licht et al 2006, Zipfel et al 2006]. As a result of this amino acid deletion in factor H, the N-terminal activities of the mutant protein (C3b binding and complement regulation) were defective, indicating that dysfunctional factor H protein is associated with the development of DDD/MPGNII [Licht et al 2006]. Studies of skin fibroblasts from a factor H-deficient child with chronic hypocomplementemic renal disease. Normal amounts of 4.3- and 1.8-kb messages were observed, but secretion of the 155-kd protein was blocked; the 45-kd protein was secreted with normal kinetics. Consistent with this finding, the affected individual's plasma lacked the 155-kd factor H protein but contained the smaller factor H-like 1 protein. The 155-kd factor H protein was retained in the endoplasmic reticulum and was not degraded even after 12 hours. Mutation screening of CFH revealed a c.1607G>A substitution on one allele and a 2949G>A substitution on the other, predicting a p.Cys536Arg change in short consensus repeat SCR9 and a p.Cys959Tyr change in SCR16, respectively. Both mutations affect conserved cysteine residues characteristic of the SCR modules of factor H and therefore predict profound changes in the higher-order structure of the 155-kd protein [Ault et al 1997]. Mutation screening results in two brothers with MPGN who were homozygous for a p.Arg127Leu amino acid change in CFH [Dragon-Durey et al 2004] Table 2. Selected CFH Allelic VariantsView in own windowClass of VariantDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1) SCR (Domain) of the Factor H Protein 2Type of MutationReferenceReference SequencesNormalc.1204C>Tp.His402Tyr 3SCR7NANM_000186.3 NP_000177.2Pathologicc.380G>Tp.Arg127Leu 4SCR2Missense, homozygousDragon-Durey et al [2004] 5c.670_672delAAGp.Lys224del 4(ΔLys224) SCR4Deletion, homozygousLicht et al [2006]c.1606T>C (1679T>C)p.Cys536Arg 4(Cys518Arg) 6SCR9 MissenseAult et al [1997]c.2876G>A (2949G>A)p.Cys959Tyr 3(Cys991Tyr)SCR16MissenseSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. SCR = short consensus repeat3. Although considered a normal allelic variant, the functional properties differ between proteins with the His402 and the Tyr402 amino acid residues.4. Signal peptide included5. This paper includes additional CFH mutations associated with other types of MPGN. 6. Signal peptide not includedNormal gene product. The normal gene product encoded by CFH is complement factor H, a plasma glycoprotein (155 kd) present in blood at concentrations ranging from approximately 500 to 800 µg/mL. It is organized in repetitive elements termed short consensus repeats (SCRs) and controls the alternative pathway (AP) of complement activation, both in fluid phase and on cellular surfaces by binding to three sites on C3b destabilizing C3bBb. In the fluid phase, this interaction results in dissociation of C3bBb into inactive fBb (ifBb) and C3bfH, which is irreversibly inactivated into iC3b by factor I [Pangburn & Muller-Eberhard 1986]. On cellular surfaces, the inactivation of bound C3b is dependent on the chemical composition of the surface to which C3b is bound [Rodriguez de Cordoba et al 2004]. Abnormal gene product. Homozygosity for the c.380G>T missense mutation is associated with absence of factor H in the serum, suggesting that this mutation results in sequestration of the protein in the endoplasmic reticulum. In contrast, the factor H with the mutation p.Lys224del is present in the serum at normal concentrations but is non-functional [Zipfel et al 2006]. CFHR5 Normal allelic variants. CFHR5 comprises ten exons that encode complement factor H related 5 (CFHR5), a protein of 551 amino acids organized into nine SCRs. Several allelic variants have been reported in the normal population, some of which are over-represented in persons with DDD/MPGNII and atypical hemolytic uremic syndrome [Abrera-Abeleda et al 2006, Monteferrante et al 2007]. One such example is the p.Pro46Ser variant (NM_030787.2:c.136C>T). Pathologic allelic variants. No unequivocally disease-causing pathologic allelic variants have been reported in CFHR5 in association with DDD/MPGNII. Normal gene product. The normal gene product encoded by CFHR5 is complement factor H-related protein 5 (CFHR5), a plasma protein organized like CFH in repetitive SCRs. CFHR5 has nine SCRs and is the only CFHR protein that is like CFH in its ability to inhibit C3 convertase in the fluid phase. CFHR5 also possesses complement factor I-dependent cofactor activity that leads to inactivation of C3b [McRae et al 2001, Rodriguez de Cordoba et al 2004, McRae et al 2005]. In 92 renal biopsies from patients with different glomerular diseases, CFHR5 was present in all complement-containing glomerular immune deposits [Murphy et al 2002], suggesting that CFHR5 plays an important role in protecting the glomerulus from complement activation. The role of CFHR5 in the physiopathology of DDD/MPGNII remains to be elucidated. Abnormal gene product. No abnormal gene product of CFHR5 has been reported in association with DDD/MPGNII.