Alport Syndrome 

In 1927, Cecil A. Alport described 3 generations of a family with combinations of progressive hereditary nephritis and deafness. Alport also noted that hematuria was the most common presenting symptom, and that males were affected more severely than females. Subsequently, many more families were described, and the eponym Alport syndrome (AS) was coined in 1961.

Since that time, identification of genetic loci involved in Alport syndrome has confirmed that the disease is genetically heterogeneous and is caused by defects in one of several subunits of type IV collagen, a major component of basement membranes. In most patients, the disease is inherited as an X-linked trait; however, some families have autosomal recessive and autosomal dominant forms. Furthermore, different mutations in type IV collagen genes can lead to a broad spectrum of disease phenotypes. For example, some families with Alport syndrome may have normal hearing or minimal hearing defects despite advanced renal disease.

Ultrastructural findings are diagnostic and consist of profound glomerular basement membrane (GBM) abnormalities. No specific treatment exists for patients with Alport syndrome. Patients who develop end-stage renal disease (ESRD) are offered renal transplantation and usually have excellent allograft survival rates.

The GBM is a sheetlike structure between the capillary endothelial cells and the visceral epithelial cells of the renal glomerulus. Type IV collagen is the major constituent of the GBM. Each type IV collagen molecule is composed of 3 subunits, called alpha (IV) chains, which are intertwined into a triple helical structure. Two molecules interact at the C-terminal end, and 4 molecules interact at the N-terminal end to form a "chicken wire" network. Six isomers of the alpha (IV) chains exist and are designated alpha-1 (IV) to alpha-6 (IV). The genes coding for the 6 alpha (IV) chains are distributed in pairs on 3 chromosomes (see Table 1), as follows:

• The alpha-1 (IV) and alpha-2 (IV) chains are encoded by genes COL4A1 and COL4A2, respectively, and are located on chromosome 13.
• The alpha-3 (IV) and alpha-4 (IV) chains are encoded by a similar pair of genes (ie, COL4A3, COL4A4, respectively) and are located on chromosome 2.
• Genes COL4A5 and COL4A6 on the X chromosome encode alpha-5 (IV) and alpha-6 (IV) chains, respectively (see Table 1).

Table 1. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in Alport Syndrome (Open Table in a new window)

The alpha-1 (IV) and alpha-2 (IV) chains are ubiquitous in all basement membranes (see Table 2); however, the other type IV collagen chains have more restricted tissue distribution. The basement membranes of the glomerulus, cochlea, lung, lens capsule, and Bruch and Descemet membranes in the eye contain alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains, in addition to alpha-1 (IV) and alpha-2 (IV) chains. The alpha-6 (IV) chains are present in epidermal basement membranes (see Table 2).

Table 2. Tissue Distribution of Alpha (IV) Chains (Open Table in a new window)

Alport syndrome is caused by defects in the genes encoding alpha-3, alpha-4, or alpha-5 chains of type IV collagen of the basement membranes. The estimated gene frequency ratio of Alport syndrome is 1:5000, and the disorder is genetically heterogeneous. Three genetic forms of Alport syndrome exist: XLAS, which results from mutations in the COL4A5 gene and accounts for 85% of cases; ARAS, which is caused by mutations in either the COL4A3 or the COL4A4 gene and is responsible for approximately 10-15% of cases; and, rarely, autosomal dominant Alport syndrome (ADAS), which is caused by mutations in either the COL4A3 or the COL4A4 gene in at least some families and accounts for the remainder of cases (see Table 1).

In the COL4A5 genes from the families with XLAS, more than 300 gene mutations have been reported. Most COL4A5 mutations are small and include missense mutations, splice-site mutations, and small (ie, < 10–base pair [bp]) deletions. Approximately 20% of the mutations are major rearrangements at the COL4A5 locus (ie, large-sized and medium-sized deletions). A particular type of deletion spanning the 5' ends of the COL4A5 and COL4A6 genes is associated with a rare combination of XLAS and diffuse leiomyomatosis of the esophagus, tracheobronchial tree, and female genital tract.

In patients with Alport syndrome, no mutations have been identified solely in the COL4A6 gene. To date, only 6 mutations in the COL4A3 gene and 12 mutations in the COL4A4 gene have been identified in patients with ARAS. Patients are either homozygous or compound heterozygous for their mutations, and their parents are asymptomatic carriers. The mutations include amino acid substitutions, frameshift deletions, missense mutations, inframe deletion, and splicing mutations. ADAS is more rare than XLAS or ARAS. Recently, a splice site mutation resulting in skipping of exon 21 in the COL4A3 gene was found in ADAS.

Despite remarkable advances in delineating the molecular genetics of Alport syndrome, the pathogenesis of renal failure in patients with this disease remains poorly understood. The primary abnormality in patients with Alport syndrome results from aberration of basement membrane expression of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen. These chains are usually underexpressed or absent from the basement membranes of patients with Alport syndrome.

The primary abnormality in patients with Alport syndrome lies in the noncollagenous (NC1) domain of the C-terminal of the alpha-5 (IV) chain in XLAS and that of alpha-3 (IV) or alpha-4 (IV) chains in ARAS and ADAS. Incidentally, the antigen involved in the pathogenesis of Goodpasture syndrome resides in the NC1 domain of the alpha-3 (IV) chain.

In the early developmental period of the kidney, alpha-1 (IV) and alpha-2 (IV) chains predominate in the GBM. With glomerular maturation, alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains become preponderant by a process called isotype switching. Evidence shows that alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains combine to form a unique collagen network. Abnormality of any of these chains, as observed in patients with Alport syndrome, limits formation of the collagen network and prevents incorporation of the other collagen chains.

Recent evidence demonstrates that isoform switching of type IV collagen becomes developmentally arrested in patients with XLAS. This leads to retaining of the fetal distribution of alpha-1 (IV) and alpha-2 (IV) isoforms and absence of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) isoforms. The cysteine-rich alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains are thought to enhance the resistance of GBM to proteolytic degradation at the site of glomerular filtration; thus, anomalous persistence of alpha-1 (IV) and alpha-2 (IV) isoforms confers an unexpected increase in susceptibility to proteolytic enzymes, leading to basement membrane splitting and damage.

How the defect of collagen chains results in glomerulosclerosis remains unclear. Evidence now suggests that accumulation of types V and VI collagen (along with alpha-1 [IV] and alpha-2 [IV]) chains in the GBM occurs as a compensatory response to the loss of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains. These proteins spread from a normal subendothelial location and occupy the full width of GBM, altering glomerular homeostasis and resulting in GBM thickening and impairment of macromolecular permselectivity with subsequent glomerular sclerosis, interstitial fibrosis, and renal failure.

Experimental studies implicate transforming growth factor beta (TGF-beta) and matrix metalloproteinases in the progression of renal disease in Alport syndrome. Further studies are needed to define their precise pathogenetic role and their potential relevance as therapeutic targets.

Frequency

United States

Alport syndrome is a rare disease and accounts for approximately 3% of children and 0.2% of adults with ESRD.

International

In Europe, Alport syndrome accounts for 0.6% of patients with ESRD.

Mortality/Morbidity

Alport syndrome is a progressive disease that ultimately leads to renal failure. Prognosis depends on the type of inheritance, the sex of the patient, and the type of mutations in type IV collagen genes.

• Approximately 90% of patients with Alport syndrome develop ESRD by age 40 years. Approximately 75% of patients younger than 30 years develop ESRD (ie, juvenile type).
• Renal prognosis depends on the kind of mutation. The probability of ESRD occurring in patients younger than 30 years is significantly higher (90%) when they have a large rearrangement of the COL4A5 gene compared to those with minor mutations (50-70%). Furthermore, the rate of progression of renal disease is fairly constant among patients within a particular family but shows significant variability between different families.
• Prognosis in females with XLAS is usually benign, and they rarely develop ESRD. The reported probability of females with XLAS developing ESRD is 12% by age 40 years and 30% by age 60 years. Risk factors for progression to ESRD are episodes of gross hematuria in childhood, nephrotic range proteinuria, and diffuse GBM thickening visible with electron microscope.

Sex

In patients with XLAS, the disease is consistently severe in males and is much less severe in females. ARAS is equally severe in male and female homozygotes.

Age

• Hematuria is usually discovered during the first years of life in males with Alport syndrome. If individuals do not have hematuria during the first decade of life, they are unlikely to have Alport syndrome.
• Proteinuria is usually absent in childhood, but this condition eventually develops in males with XLAS and in both males and females with ARAS.
• Hearing loss and ocular abnormalities are never present at birth and usually become apparent by late childhood or early adolescence, generally before the onset of renal failure.