Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life

Abstract

Collagen IV nephropathies (COL4Ns) comprise benign familial microscopic hematuria, thin basement membrane nephropathy (TBMN), X-linked Alport syndrome (AS) and also autosomal recessive and dominant AS. Apart from the X-linked form of AS, which is caused by hemizygous mutations in the COL4A5 gene, the other entities are caused by mutations in the COL4A3 or COL4A4 genes. The diagnosis of these conditions used to be based on clinical and/or histological findings of renal biopsies, but it is the new molecular genetics approach that revolutionised their investigation and proved particularly instrumental, especially, in many not so clear-cut cases. More recently, the spectrum of COL4N has expanded to include late onset focal segmental glomerulosclerosis (FSGS) that develops on top of TBMN in later life. Also, other reports showed that some patients with a primary diagnosis of familial FSGS proved to have variants in COL4 genes. In the presence of a renal biopsy picture of FSGS and in the absence of either electron microscopy studies or molecular genetic studies that point to TBMN and COL4N, the patient and his family may be mistakenly diagnosed with hereditary FSGS leading to unnecessary further investigations, erroneous family counselling and improper corticosteroid treatment. TBMN is a frequent finding in the general population, and according to several recent reports, it may be the underlying cause and the explanation for many familial and sporadic cases of late-onset FSGS with non-nephrotic proteinuria. This is an important new finding that needs widespread recognition. It is anticipated that the molecular genetic analysis with next generation sequencing will certainly offer timely correct diagnosis.

A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population

“…The phenotypic heterogeneity observed among patients with inherited monogenic disorders, including AS, TBMN and CFHR5 nephropathy, prompted us to hypothesize that the full spectrum of the phenotype behaves as a multifactorial condition, implicating primary genes, modifier genes and environmental factors [34, 37]. Here we considered that excellent candidates to act as genetic modifiers could be non-synonymous SNPs located in specific genes of the SD.…”

Focal segmental glomerulosclerosis associated with mitochondrial disease

“…Therefore, the presence or absence of hematuria may help to distinguish between MDs and Alport’s syndrome. Of note, patients with Alport’s syndrome can present with FSGS on kidney biopsy and therefore, this cannot be used as a feature to distinguish between the two conditions [16, 17]. Mutations in the COL4A3-5 genes that encode α-chains of glomerular basement membrane collage type IV are classically associated with Alport’s syndrome, and recent studies have shown that these mutations can be associated with FSGS [18].…”

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

“…Whether the above-described cases of FSGS should be considered to be familial FSGS or rather a secondary effect of undiagnosed TBMN is a matter of debate 36 . FSGS occurs in at least 5% of patients…”

“…Across disease categories COL4A3-5 FSGS (AD) [33][34][35] FSGS could arise secondary to unrecognized TBMN through complex mechanisms involving cross-talk between components of the glomerular filtration barrier, through defects in the GBM that result in podocyte foot-process effacement and GBM scarring, and through the actions of modifier genes 36,38 TBMN (AD) 122,123 Alport syndrome (AD, AR, XL) 124,125 DGKE MPGN (AR) 39 • aHUS could arise secondary to MPGN and vice versa because loss of DGKE function and complement activation both cause sustained diacylglycerol signalling 39,44 , which induces glomerular epithelial cell injury, proteinuria, upregulation of prothrombotic factors and platelet activation 20,44,46,47 , and increases TRPC6 channel activity, which is associated with podocyte foot-process effacement and nephrotic syndrome 44,48 • In DGKE-mediated aHUS, the main prothrombotic effect is mediated through upregulation of the pro-inflammatory p38-MAPK pathway that causes impaired endothelial cell proliferation and angiogenesis 45 aHUS (AR) [20][21][22]40 TTC21B Ciliopathies (AR) 51 • Most patients with TTC21B-related glomerulopathy reported to date carry biallelic p.Pro209Leu mutations. This mutation has also been identified in patients with nephronophthisis 51-53 • Glomerulopathies could result from TTC21B-mediated alterations in cytoskeletal architecture in mature podocytes, which affects cell size and migration, actin and microtubule networks and cell nucleation 52 • Tubular lesions characteristic of nephronophthisis suggest a concomitant ciliary defect in glomerulopathy patients 52,53 Glomerulopathies (AR) 52,53 PAX2 RCS (AD) 126 • Truncating PAX2 mutations are more frequently associated with RCS, while missense mutations are more frequently associated with isolated CAKUT or FSGS 128 • Location of the mutation within the gene is associated with the phenotype 128 • FSGS could develop secondary to subtle renal developmental anomalies or through dysregulat...…”

“…In the studies described above [33][34][35] , most patients were diagnosed with FSGS well into adulthood; the possibility of these patients having secondary FSGS cannot, therefore, be excluded 38 . As an erroneous diagnosis of primary FSGS can lead to inaccurate counselling and unwarranted corticosteroid treatment 36 , the value of redefining the COL4A phenotypic spectrum to include both Alport syndrome and FSGS warrants serious discussion 34 . An alternative proposal is to redefine the Alport spectrum by including benign familial haematuria and TBMN (caused by heterozygous COL4A3/4 mutations) at the mild end, secondary FSGS and late ESRD in the middle and early ESRD with extrarenal features (caused by biallelic COL4A3/4 mutations or hemizygous COL4A5 mutations) at the severe end of the spectrum 38 (FIG.…”