The collagen IV nephropathies

Inherited disorders of type IV collagen account for a significant percentage of patients with persistent hematuria. The two major forms of familial hematuria, Alport syndrome and thin basement membrane nephropathy, arise from mutations that affect a glomerular basement network composed of α(alpha)3, α(alpha)4, and α(alpha)5 type IV collagen chains. Patients with Alport syndrome exhibit a progressive nephropathy associated with sensorineural deafness and ocular anomalies, while the symptoms of thin basement membrane nephropathy are confined to the kidney and progressive nephropathy is unusual. Approximately 80 % of patients with Alport syndrome have X-linked disease due to mutations in COL4A5, which encodes the α(alpha)5(IV) chain. About 15 % have autosomal recessive disease due to mutations in both alleles of the COL4A3 or COL4A4 gene, which encode the α(alpha)3(IV) and α(alpha)4(IV) chains, respectively. Thin basement membrane nephropathy is typically an autosomal dominant disorder; heterozygous mutations in COL4A3 or COL4A4 are found in about 50 % of affected families. A less common form of familial hematuria, hereditary angiopathy associated with nephropathy, aneurysms, and muscle cramps (HANAC syndrome), is caused by mutations that affect another basement membrane type IV collagen network that consists of α(alpha)1(IV) and α(alpha)2(IV) chains. HANAC syndrome arises from mutations in the COL4A1 gene. This chapter discusses the natural history of these disorders as well as what is known or hypothesized about the pathways from mutations to structural changes to clinical symptoms. Diagnostic approaches and therapy are also reviewed.