Alport Syndrome and Thin Basement Membrane Nephropathy

Abstract

Both Alport syndrome and thin basement membrane nephropathy (TBMN) can be considered as genetic diseases of the GBM involving the α3/α4/α5 network of type IV collagen. Mutations in any of the COL4A3, COL4A4 or COL4A5 genes can lead to total or partial loss of this network. Males with mutations in the X-linked COL4A5 gene develop Alport syndrome with progressive renal disease and sometimes extra-renal disease. Females who are heterozygous for a COL4A5 mutation are considered to be carriers for X-linked Alport syndrome. Although their clinical course and GBM ultrastructural changes can sometimes mimic TBMN, more often it tends to be more progressive than usually seen in TBMN. Males or females who are heterozygous for COL4A3 or COL4A4 mutations usually manifest as TBMN, with nonprogressive hematuria, while those who are homozygous or combined heterozygotes develop autosomal-recessive Alport syndrome. Thus, individuals with TBMN can be considered to be carriers for autosomal-recessive Alport syndrome, but there remain some exceptions in which patients heterozygous for COL4A3 or COL4A4 mutations develop autosomal-dominant Alport syndrome. Distinguishing between all these groups of patients requires a combination of family history and a renal biopsy for electron microscopic examination of the GBM and immunohistochemical staining of the GBM for the α3, α4 and α5 chains of type IV collagen. Mutational analysis of the COL4A3, COL4A4, and COL4A5 genes, whenever it becomes available, will be a valuable adjunct to the diagnostic workup in these patients. Novel therapeutic approaches may one day provide a treatment or cure for these patients, avoiding the need for transplantation and dialysis.

Diagnosing Alport Syndrome: Lessons from the Pediatric Ward

“…Carrier status may be underestimated and pediatric nephrologists may be less aggressive in diagnosing Alport syndrome in case of a negative family history or when parents have no hematuria. Mutations in Alport syndrome have been reported to occur de novo in 10% of genetically tested patients [8,9]; in our cohort, we did not find any.…”

“…Currently, at least 1,422 different pathogenic mutations have been identified, most (976) of them in the COL4A5 gene (The Human Gene Mutation Database (HGMD, Cardiff, 2018.1). De novo mutations have been reported in approximately 10% of patients [8,9].…”

Basement membranes in development and disease

“…The most common collagen IV-associated renal disease is Alport syndrome, of which there are three types: X-linked, autosomal recessive, and autosomal dominant (Thorner, 2007;Gubler, 2008). Symptoms can vary but usually present as hematuria, hearing loss, and ocular lesions.…”

The Power of Molecular Genetics in Establishing the Diagnosis and Offering Prenatal Testing: The Case for Alport Syndrome

“…According to some older publications, these patients occasionally progress to proteinuria and chronic kidney disease (CKD) while a small percentage reach end-stage kidney disease (ESKD) on long follow-up [5][6][7][8] . In a paper we published in 2007, we presented our initial experience in investigating 116 patients of 13 Cypriot families, where 20 renal biopsies had the dual diagnosis of focal segmental glomerulosclerosis (FSGS) and TBMN.…”