July 2018 Case
Gabriel Giannini, MD (Resident) and Jean Hou, MD (Faculty)
Adolescent Caucasian male with proteinuria and persistent microscopic hematuria. Urinalysis reveals 2+ protein, and 2+ blood. Serum creatinine is 1.78 mg/dl.
IgG, IgA, IgM, C1q, C3, albumin, fibrin and kappa and lambda, all negative
Ultrastructural glomerular basement membrane abnormalities and absence of glomerular and tubular basement membrane staining for alpha-5 subunit of type IV collagen, consistent with X-linked Alport syndrome. Discussion Alport syndrome (AS) is a rare genetic disorder which is clinically characterized by progressive renal dysfunction, sensorineural hearing loss, and ocular abnormalities. AS results from a defect in basement membrane structure caused by mutations in the genes encoding alpha-3, alpha-4, and alpha-5 subtypes of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively). This results in defective assembly of the collagen heterotrimer subunits that are necessary for functional basement membrane production, structure, and function in the kidney, eye, and cochlea.
There are three main genetic variants of AS. X-linked AS (XLAS) is the most common, accounting for approximately 80% of cases, and is associated with mutations in the locus encoding the alpha-5 chain of type IV collagen, located on the long arm of the X chromosome. Rarer, autosomal forms of AS are caused by mutations in the genes encoding for the collagen IV alpha-3 and alpha-4 chains, COLA3 and COLA4, respectively, which are located on chromosome 2. Autosomal recessive Alport syndrome (ARAS) is associated with mutations in both alleles of COL4A3 and COL4A4, and accounts for approximately 15% of cases. In comparison, autosomal dominant Alport syndrome (ADAS) is caused by heterozygous mutations of these genes and accounts for only 5% of AS cases.
In XLAS, maternal inheritance of the defective gene in males typically results in severe disease, with early onset proteinuria and progressive renal dysfunction. Approximately 50% of untreated males with XLAS develop end stage renal disease (ESRD) before age 25, and nearly all male patients will have progressed to ESRD by the age of 60. In comparison, females who harbor one maternally inherited defective gene can have quite variable clinical presentations due to random X chromosome inactivation. The rate of progression to end stage renal disease and deafness in XLAS appears to be mutation dependent, exhibiting a genotype-phenotype correlation. There is evidence that certain types of mutations in the COL4A5 gene such as large rearrangements/deletions and nonsense or frameshift mutations may confer higher risk of developing ESRD at a relatively younger age.
Histologic changes in early stages of the disease may be quite subtle and include: mesangial hypercellularity, interstitial foamy macrophages (foam cells), and thin glomerular basement membranes (GBM's) observed by EM. With disease progression, thickened capillary loops with irregular contours, focal segmental and/or global glomerulosclerosis, and tubular atrophy and interstitial fibrosis can be observed. Electron microscopy is diagnostic and can reveal irregular GBM thickening and thinning, and eventually the typical GBM changes including subepithelial scalloping, basket-weaving, and multilamellation.
Typically, there is no immunofluorescence staining for usual immune reactants in glomeruli. However, faint granular staining for IgG, C3, and IgM may be observed along capillary walls early in disease. Indirect immunofluorescence for type IV collagen alpha chains can confirm the complete absence of the alpha-5 subunit in male X-linked Alport's patients. This is in contrast to the patchy, mosaic pattern of staining in carrier females (due to random X-inactivation). Patients with autosomal recessive AS demonstrate staining for the alpha-5 subunit only in Bowman’s capsule and distal tubules but not in GBMs. Carriers of autosomal recessive Alport have normal immunostaining for type IV collagen alpha chains, as well as a subset of AS patients with rare mutations causing residual truncated type IV collagen chains which can show normal immunostaining patterns. As a less-invasive alternative to renal biopsy, skin biopsy and immunofluorescence staining can also be a diagnostic tool for XLAS.
Genetic testing in this patient eventually confirmed the presence of a mutation in COL4A5, and the patient is currently being evaluated for renal transplant.
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