Alport's Syndrome

Classically, patients with Alport's syndrome develop hematuria, thinning and splitting of the GBMs, mild proteinuria (<1–2 g/24 h), and chronic glomerulosclerosis, leading to renal failure in association with sensorineural deafness. Some patients develop lenticonus of the anterior lens capsule and, rarely, mental retardation or leiomyomatosis.

 Approximately 85% of patients with Alport's syndrome have an X-linked inheritance of mutations in the alpha 5(IV) collagen chain on chromosome Xq22–24. Female carriers have variable penetrance depending on the type of mutation or the degree of mosaicism created by X inactivation. Fifteen percent of patients have autosomal recessive disease of the 3(IV) or 4(IV) chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in 3(IV) or 4(IV) chains.
Pedigrees with this syndrome are quite variable in their rate and frequency of tissue damage leading to organ failure. Patients with nonsense or missense mutations, reading frame shifts, or large deletions generally develop renal failure and sensorineural deafness by age 30 (juvenile form), while patients with splice variants, exon skipping, or missense mutations of -helical glycines generally deteriorate after the age of 30 (adult form) with mild or late deafness. Early severe deafness or lenticonus suggest a poorer prognosis. 
Alport's patients early in their disease typically have thin basement membranes on renal biopsy , which thicken over time into multilamellations surrounding lucent areas that often contain granules of varying density—the so-called split basement membrane. In any Alport kidney there are areas of thinning mixed with splitting of the GBM. Tubules drop out, glomeruli scar, and the kidney eventually succumbs to interstitial fibrosis.

Primary treatment is control of systemic hypertension and use of ACE inhibitors to slow renal progression. Although patients who receive renal allografts usually develop anti-GBM antibodies directed toward the collagen epitopes absent in their native kidney, overt Goodpasture's syndrome is uncommon and graft survival is good.

Thin Basement Membrane Disease


Some variants of Alport's syndrome are now recognized as a subpopulation of patients with thin basement membrane disease. Thin basement membranes are found in 5–10% of the so-called normal population. These subclinical patients have normal blood pressure and little proteinuria, and they rarely progress to renal failure. If they present with hematuria, they are often given the diagnosis of benign familial hematuria. Many of these patients have mutations in the same 3(IV) or 4(IV) collagen genes associated with autosomal recessive or dominant Alport's syndrome. Clearly, the boundary between nonprogressive Alport's syndrome and benign familial hematuria is quite variable, as there is a spectrum of clinical penetrance.