Alport syndrome (AS) is a heritable kidney disease characterized by persistent hematuria (blood in the urine), chronic renal failure, and progression to end-stage renal disease. In addition, AS is frequently associated with sensorineural hearing loss and specific ocular defects, including anterior
lenticonus (a cone-shaped bulging of the anterior surface of the lens), perimacular flecks (white or yellow flecks surrounding the macula), and recurrent corneal erosions. The reported prevalence of AS ranges from 1 in 5000 to 1 in 50,000 individuals, depending on the study. It has been estimated
that AS accounts for up to 1% of patients with end-stage renal disease and 1% to 2% of patients with kidney transplants. AS results from defects in type IV collagen, a heterotrimeric molecule composed of a variable combination of three alpha chains. Three forms of AS have been described, each distinguished by the manner in which it is inherited. Approximately 80% to 85% of individuals with AS have the X-linked form of the condition (XLAS), which results from variants in the COL4A5 gene. COL4A5 is located on the X chromosome at band q22.3 and encodes the alpha ()5 chain of type IV collagen (5[IV]). The remaining patients have either the autosomal recessive form (ARAS) or the autosomal dominant form (ADAS). Both ARAS and ADAS result from variants in either COL4A3 or COL4A4. COL4A3 and COL4A4 are both located on chromosome 2 at bands q36 to q37 and encode the 3 and 4 chains of type IV collagen (3[IV] and 4[IV]), respectively. Patients with XLAS or ARAS have chronic microhematuria, progressive renal failure, and eventually, end-stage renal disease, often in combination with high-frequency sensorineural hearing loss and/or the ASrelated ocular findings. Patients with end-stage renal disease before age 31 are said to have juvenile AS, while those with later-onset end-stage renal disease have adult AS. Heterozygous carriers of XLAS- or ARAS-related gene variants (i.e., the female relatives of males with XLAS or the close relatives of ARAS patients) often have asymptomatic microhematuria. Female carriers of XLAS gene variants may also develop additional symptoms of AS, including renal failure and endstage renal disease, but their phenotype is more variable and often less severe than their affected male family members. The phenotype associated with ADAS, the least common form of AS, is variable and ranges from isolated microhematuria to the progressive phenotype seen among patients with XLAS or ARAS. All three types of AS are associated with specific changes in the glomerular basement membrane (GBM), most often, thickening, thinning, splitting, and lamellation detectable on ultrastructural examination of renal biopsy specimens. In addition, affected patients may have altered expression of the collagen type IV alpha chains in the GBM, which is detectable by immunohistochemistry. Since the three types of AS have overlapping phenotypes, they have been referred to as a spectrum of diseases known as collagen type IV–related nephropathies. Another condition within this spectrum is known as thin basement membrane nephropathy (TBMN), which is characterized by isolated, asymptomatic microhematuria. TBMN is considered an autosomal dominant condition and results from variants in either COL4A3 or COL4A4.