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Diagnosis: X-linked Alport Syndrome

Electron microscopy study demonstrated irregular thickening of the GBM, with splitting and fragmentation of the lamina densa (Figure 16).

Figure 16. Electron microscopy photography showing irregular thickening of the GBM, with splitting and fragmentation of the lamina densa (X 6,000).

Type IV collagen, the major structural component of the GBM is a multimeric protein composed of three α chains coiled around one another to form a triple-helical molecule or protomer. Six genetically distinct, but closely related, α(IV) chains have been so far identified (α-1 to α-6). Many type IV molecules could potentially be formed, however, only three protomers have been discovered: α1.α1.α2(IV), α3.α4.α5(IV), and α5.α5.α6(IV). The three networks are not equally distributed within basement membrane. The most abundant, α1.α1.α2(IV)-α1.α1.α2(IV), is ubiquitous and found in all basement membranes. However, in the glomerular tuft, the strong mesangial expression of the α1(IV) and α2(IV) chains contrasts with their faint GBM distribution, limited to the subendothelial aspect of the basement membrane. The other networks have restricted and specific distributions. In the mature kidney, the α3.α4.α5(IV)-α3.α4.α5(IV) network is present within the GBM, the distal tubule basement membrane, and focally in Bowman's capsule basement membrane. However, in human GBM development, there is a switch from the exclusive α1.α1.α2(IV) network detected at the early capillary-loop stage, to the α3.α4.α5(IV) network present in the mature glomerulus. The α3.α4.α5(IV) network is also present in the alveolar basement membrane and the specialized basement membrane of the eye and the cochlea. The α1.α1.α2(IV)-α5.α5.α6(IV) network is expressed in Bowman's capsule and the collecting duct basement membrane and in epidermal and smooth muscle cell basement membrane. The α6 chain is consistently absent from the GBM (Jennette JC et al. Heptinstall's Pathology if the Kidney, 6° ed. Wolters Klumer - Lippincott Williams & Wilkins, Philadelphia, 2007, p. 492).

α3 and α5 normally stain the entire thickness of the glomerular basement membrane (global and diffuse) as well as the distal tubular BM. In Alport families with X-linked disease the α3 and α5 staining are usually absent in males and have a discontinuous distribution in females (mosaic staining pattern). In autosomal recessive patients staining of α5 is seen only along Bowman’s capsule and collecting ducts basement membrane while α3 is totally negative.

See the Chapter Hereditary Diseases of our Tutorial (only Spanish version)

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References

• Adam J, Connor TM, Wood K, Lewis D, Naik R, Gale DP, Sayer JA. Genetic testing can resolve diagnostic confusion in Alport syndrome. Clin Kidney J. 2014;7(2):197-200. [PubMed link] [Free full text]
• Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K.Natural history of genetically proven autosomal recessive Alport syndrome. Pediatr Nephrol. 2014 Mar 15. [Epub ahead of print] [PubMed link]
• Hashimura Y, Nozu K, Kaito H, Nakanishi K, Fu XJ, Ohtsubo H, Hashimoto F, Oka M, Ninchoji T, Ishimori S, Morisada N, Matsunoshita N, Kamiyoshi N, Yoshikawa N, Iijima K. Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain. Kidney Int. 2014;85(5):1208-13.  [PubMed link]
• Lin X, Suh JH, Go G, Miner JH. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. J Am Soc Nephrol. 2014;25(4):687-92. [PubMed link]
• Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J. Clinical and genetic features in autosomal recessive and X-linked Alport syndrome. Pediatr Nephrol. 2014;29(3):391-6. [PubMed link]
• Liapis H, Jain S. The interface of genetics with pathology in alport nephritis. J Am Soc Nephrol. 2013;24(12):1925-7.  [PubMed link]

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