The skins elastic fiber system consists of elastin (which is normally non-glycosylated) and glycosylated proteins (fibulin, fibronectin, and collagen). It is speculated that either abnormal glycosylation and/or impaired secretion of proteins caused by ATP6V0A2 dysfunction lead to WSS. The ATP6V0A2 pump is highly expressed within the Golgi apparatus. ATP6V0A2 is primarily found within the medial-Golgi and the trans-Golgi. ATP6V0A2 acidifies the medial- and trans-Golgi so that their resident enzymes (e.g. glycosidases and glycosyltransferases) function properly. Therefore, mutations in the ATP6V0A2 gene reduce the ability of ATP6V0A2 to produce the necessary pH gradient for these glycosylation enzymes, which results in abnormal N- and O-linked glycosylation. Because the physical properties of skin rely heavily on the structural proteins of the elastic fiber system of epidermal cells, abnormal glycosylation can lead to structural defects in the elastic fibers, and therefore lead to the inelastic skin seen in WSS. WSS patients may also have defective secretion of another ECM component of the skin called tropoelastin. The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles. It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle. The process of coacervation is thought to be essential for proper elastin assembly in the ECM. Coacervation must occur outside of the cell within the ECM ( the ECM has a more alkaline environment than the vesicle) for proper elastic fiber assembly.
In young children, episodes of visible (macroscopic) haematuria may occur. Protein begins to appear in urine as the disease progresses. This is now regarded as an indication for treatment with ACE inhibitors. Progressive loss of kidney function (reflected clinically by increases in serum creatinine or decreases in estimated glomerular filtration rate) can occur and may require treatment with renal replacement: dialysis or a kidney transplant. Hearing loss
Alport syndrome can also cause hearing loss although some patients are not affected. Hearing in Alport syndrome patients is normal at birth. Hearing loss in affected patients develops progressively, usually at the stage when kidney function is normal, but there is substantial proteinuria. However, in some patients, hearing loss is only noted after kidney function has been lost. Characteristically the early changes are reduced ability to hear high-frequency sounds, sensorineural deafness. This becomes more severe and affects lower frequencies too. Hearing loss is not usually complete in Alport syndrome; good communication is almost always possible with the use of hearing aids. Eye changes
Various eye abnormalities are often seen including lenticonus, keratoconus, cataracts and corneal erosion as well as retinal flecks in the macula and mid-periphery. These rarely threaten vision. Lenticonus (cone-shaped lens) can be treated by replacement of the lens, as for cataracts. Mild keratoconus can be managed with hard, scleral, piggy-back or other specialty medical contact lenses; progressive cases may be halted with corneal collagen cross linking; and severe cases may require a corneal transplant.