Mild Forms of Alport Syndrome: Hereditary Nephropathy in the Absence of Extra-Renal Features

The type IV collagen nephropathies comprise a spectrum of abnormalities predominantly affecting the glomerular basement membrane (GBM) in the kidney, but also involving other organs such as the ear and eye. Type IV collagen nephropathies result from genetic mutations causing loss or deficiency of type IV collagen synthesis, and have been associated with Alport syndrome at one end of the spectrum, where individuals who are the most severely affected experience end-stage renal failure (ESRF) in their early teen-age years together with hearing loss and vision abnormalities. At the other end of the spectrum type IV collagen nephropathies are associated with mild defects, such as thin basement membrane nephropathy (TBMN) or benign familial hematuria where individuals may experience mild kidney abnormalities involving episodic hematuria but retain relatively normal renal function and show no extra-renal abnormalities. There are six different type IV collagen genes located on multiple chromosomes, and three of these genes (COL4A3, COL4A4, and COL4A5) are associated with X-linked, autosomal recessive or autosomal dominant inheritance patterns of Alport syndrome. In addition the type IV collagen genes are associated with the TBMN phenotype, involving heterozygous mutations of the COL4A3 and COL4A4 genes, with an autosomal dominant pattern of inheritance. The main focus of this chapter is the mild forms of Alport syndrome, and so in the following pages we review mild presentations of Alport syndrome, and illustrate this with a unique New Zealand family segregating mild X-linked Alport syndrome, some of whom display features of TBMN.