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Alport syndrome, also known as familial or hereditary nephritis, is a genetic disease of the kidneys that also may involve the eyes, ears, and other organ systems. Although patients who have severe forms of this disease develop deafness and end-stage renal disease (ESRD) by young adulthood, the earliest detectable abnormality in the child who has Alport syndrome is isolated hematuria. Therefore, knowledge of the etiology, pathology, and diagnosis of this disorder is important to pediatricians who encounter hematuria frequently Familial Nephritis, Alport Syndrome, Alport's syndrome, Alports syndrome.
The earliest clinical finding in the child who has Alport syndrome is isolated, persistent microscopic hematuria. Intermittent gross hematuria also may be observed, particularly with upper respiratory tract infections. The hematuria is related to ultrastructural abnormalities in the renal basement membranes (Figure ). The glomerular basement membrane (GBM) appears thin on electron microscopy, and it is believed that attenuation or rupture of the abnormal GBM permits passage of red blood cells into the urine. Males who have X-linked Alport syndrome or children of either gender who
Evidence of extrarenal involvement is rare in the very young child, but auditory abnormalities are common as the patient who has Alport syndrome grows older. Sensorineural hearing loss occurs in approximately 50% of Alport kindreds and is more common among males. Most affected boys develop deafness by adolescence, and females who have X-linked disease may suffer hearing impairment in later life. Little is known of the
The older child who has familial nephritis and deafness also may develop unique ocular abnormalities. Most common is anterior lenticonus, a disorder in which the lens protrudes into the anterior chamber through a thinned lens capsule. Specific changes in retinal pigment and corneal endothelium also have been described. Megathrombocytopenia has been associated with Alport syndrome in a few case reports, and the rare disorder of diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in several families who had X-linked Alport syndrome.
There is considerable heterogeneity in clinical phenotype between kindreds who have X-linked dominant Alport syndrome, but if pertinent family
It is now known that Alport syndrome is a disease of basement membranes, which are specialized aggregates of unique extracellular proteins that provide structural and functional support to epithelial and endothelial cell layers throughout the body. The most abundant protein constituent of basement membranes
The genes for six different type IV collagen alpha chains have been identified in recent years. Biochemical nomenclature designates these collagen chains as alpha1(IV) through alpha6(IV). Each trimeric collagen molecule typically consists of two different alpha chains in a 2:1 ratio (eg, two alpha1(IV) chains and one alpha2(IV) chain). The six chains differ not only in their protein sequence, but also in their distribution among basement membranes of the body. Biochemical analyses and indirect immunofluorescence microscopy with antibodies specific for the different type IV alpha chains have demonstrated that type IV collagen alpha1 and alpha2 chains appear to be ubiquitous in all basement membranes. However, presence of the other alpha chains is restricted and varies according to organ site, structure, and function of the basement membrane. For example, alpha3(IV), alpha4(IV), and alpha5(IV) chains are present in the GBMs of the kidney, the lens capsule of the eye, and the stria vascularis of the cochlea. The basement membrane at the dermalepidermal junction, however, contains only alpha5(IV) and alpha6(IV) chains in addition to the ubiquitous alpha1(IV) and alpha2(IV) chains. Bowman capsule and the distal tubular basement membrane of the nephron are composed of all six of the known collagen IV alpha chains.
Gene defects in patients who have Alport syndrome have been traced to DNA coding and regulatory sequences for the alpha3(IV), alpha4(IV), and alpha5(IV) collagen chains. The mutations differ for each family kindred and include large and small deletions, missense mutations, and splice-site mutations. The gene frequency for Alport syndrome is estimated to be 1/5,000 to 1/10,000. The majority of mutations involve the gene for the
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