Membranoproliferative glomerulonephritis

Recommended panel testing at Breda Genetics for this condition:

Dense deposit disease, membranoproliferative glomerulonephritis II, atypical hemolytic uremic syndrome & thrombotic thrombocytopenic purpura (ADAMTS13, C3, CD46, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFH, CFI, DGKE, LMNA, LCAT, THBD)

A classification needed first

There is a high degree of overlapping information about the genetics of membranoproliferative glomerulonephrites (MPGN) and renal insufficiency. It is therefore necessary to shed light on the subject, both for what concerns involved genes and classification/nomenclature.

MPGN classification

MPGN type I (MPGNI) is characterized by double contour appearance of the capillary walls due to mesangial cell interposition, with nonargyrophilic subendothelial deposits which are finely granular on electron microscopy.

MPGN type II (MPGNII), also known as dense deposit disease (DDD), causes chronic renal dysfunction that progresses to end-stage renal disease in about half of patients within 10 years of diagnosis.

MPGN type III (MPGNIII) represents a third variety in which there are not only subendothelial deposits but also numerous subepithelial and intramembranous deposits, associated with replication of the lamina densa and frequently disruption of the whole basement membrane.

MPGN types I and III are variants of immune complex-mediated disease; MPGN II, in contrast, has no known association with immune complexes.

MPGN genetics

Only MPGNII has been associated to genetic mutations: sequence variants have been identified in the genes CFH, CFHR5, C3, and LMNA genes. Interestingly, this disease rarely follows a pure model of Mendelian inheritance. Sequence analysis should be enough to identify genetic mutations, since no large deletions/duplcations seem to have been reported. C3 and LMNA mutations have been actually reported in just one family each.

Atypical hemolytic uremic syndrome (aHUS)

CFH mutations may also cause an allelic disorder: 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.

Atypical HUS is considered genetic when two or more members of the same family are affected or when disease-causing mutations are identified in one of the genes known to be associated with the pathogenesis of aHUS: CFH (accounting for ~30% of aHUS), CD46 (accounting for ~12% of cases), CFI (5%-10% of cases), C3, CFB, THBD, DGKE, CFHR3, CFHR1, and CFHR4 (deletions involving CFHR1 and CFHR3 or CFHR1 and CFHR4 account for ~5%-15% of aHUS).

Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a disorder to be considered within the differential diagnosis of aHUS. Atypical HUS and TTP share a common pathologic lesion (thrombotic microangiopathy) but have different clinical manifestations. TTP manifests mainly with central nervous system symptoms, but renal insufficiency has been reported. TTP is caused by mutations in the ADAMTS13 gene and is inherited in an autosomal recessive fashion. Few cases of patients harboring mutations in both the ADAMTS13 and CFH gene have been reported.

LCAT deficiency

For what concern the differential diagnosis of MPGNII, one individual with LCAT deficiency was found to show glomerular histologic lesions and an immunofluorescent glomerular pattern typical of DDD/MPGNII. Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction that can progress to end stage renal disease. LCAT deficiency is caused by  LCAT gene mutations.

Recommended testing workflow

Recommended panel testing at Breda Genetics for this condition:

Dense deposit disease, membranoproliferative glomerulonephritis II, atypical hemolytic uremic syndrome & thrombotic thrombocytopenic purpura (ADAMTS13, C3, CD46, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFH, CFI, DGKE, LMNA, LCAT, THBD)

Deletion/duplication testing for selected genes can be subsequently performed by MLPA analysis. 

References

C3 Glomerulopathy. Martín B, Smith RJH. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Jul 20 [updated 2018 Apr 5]. PMID: 20301598

Genetic Atypical Hemolytic-Uremic Syndrome. Noris M1,2, Bresin E1, Mele C1, Remuzzi G1,3,4. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Nov 16 [updated 2016 Jun 9]. PMID: 20301541

Thrombotic thrombocytopenic purpura. Knöbl P. Memo. 2018;11(3):220-226. PMID: 30220931

Dense deposit disease and C3 glomerulopathy. Barbour TD1, Pickering MC, Terence Cook H. Semin Nephrol. 2013 Nov;33(6):493-507. PMID: 24161036

Update on C3 glomerulopathy. Barbour TD, Ruseva MM, Pickering MC. Nephrol Dial Transplant. 2016 May;31(5):717-25. PMID: 25326473

Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies. Rudnicki M. Biomed Res Int. 2017;2017:2180508. PMID: 28573137

Inherited renal diseases. Leung JC. Curr Pediatr Rev. 2014;10(2):95-100. PMID: 25088262

OMIM: 235400