Introduction
Background
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.
Pathophysiology
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
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Table
| Alpha (IV) Chain | Genes | Chromosomal Location | Mutation |
| Alpha-1 (IV) | COL4A1 | 13 | Unknown |
| Alpha-2 (IV) | COL4A2 | 13 | Unknown |
| Alpha-3 (IV) | COL4A3 | 2 | ARAS* |
| Alpha-4 (IV) | COL4A4 | 2 | ARAS |
| Alpha-5 (IV) | COL4A5 | x | XLAS † |
| Alpha-6 (IV) | COL4A6 | x | Leiomyomatosis ‡ |
| * Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes) † X-linked Alport syndrome ‡ Autosomal recessive Alport syndrome |
| Alpha (IV) Chain | Genes | Chromosomal Location | Mutation |
| Alpha-1 (IV) | COL4A1 | 13 | Unknown |
| Alpha-2 (IV) | COL4A2 | 13 | Unknown |
| Alpha-3 (IV) | COL4A3 | 2 | ARAS* |
| Alpha-4 (IV) | COL4A4 | 2 | ARAS |
| Alpha-5 (IV) | COL4A5 | x | XLAS † |
| Alpha-6 (IV) | COL4A6 | x | Leiomyomatosis ‡ |
| * Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes) † X-linked Alport syndrome ‡ Autosomal recessive Alport syndrome |
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
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Table
| Alpha (IV) Chain | Tissue Distribution |
| Alpha-1 (IV) | Ubiquitous |
| Alpha-2 (IV) | Ubiquitous |
| Alpha-3 (IV) | GBM, distal TBM*, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-4 (IV) | GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-5 (IV) | GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-6 (IV) | Distal TBM, epidermal basement membrane |
| * Tubular basement membrane |
| Alpha (IV) Chain | Tissue Distribution |
| Alpha-1 (IV) | Ubiquitous |
| Alpha-2 (IV) | Ubiquitous |
| Alpha-3 (IV) | GBM, distal TBM*, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-4 (IV) | GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-5 (IV) | GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
| Alpha-6 (IV) | Distal TBM, epidermal basement membrane |
| * Tubular basement membrane |
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.
Clinical
History
Clinical features are best described in patients with XLAS. In these patients, the disease is consistently severe in males and is much less symptomatic in females. In patients with ARAS, the disease is equally severe in male and female homozygotes. Occasionally, mild clinical manifestations are observed in the carriers (heterozygotes) of ARAS.
- Renal manifestations
- Hematuria: Gross or microscopic hematuria is the most common and earliest manifestation of Alport syndrome. Microscopic hematuria is observed in all males and in 95% of females. This condition is usually persistent in males, whereas it can be intermittent in females. Like immunoglobulin A (IgA) nephropathy, approximately 60-70% of patients experience episodes of gross hematuria, often precipitated by upper respiratory infection, during the first 2 decades of life. Hematuria is usually discovered during the first years of life in males. If a male patient does not present with hematuria during the first decade of life, he is unlikely to have Alport syndrome.
- Proteinuria: Proteinuria is usually absent in childhood but eventually develops in males with XLAS and in both males and females with ARAS. Proteinuria usually progresses with age and can occur in the nephrotic range in as many as 30% of patients. Significant proteinuria is infrequent in females with XLAS, but it may occur.
- Hypertension: This condition is usually present in males with XLAS and in males and females with ARAS. Incidence and severity increases with age and degree of renal failure.
- Hearing defects: Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with Alport syndrome. Some families with Alport syndrome have severe nephropathy but normal hearing. Hearing loss is never present at birth. Usually, hearing loss becomes apparent by late childhood or early adolescence, generally before the onset of renal failure. Hearing impairment is always associated with renal involvement.
- Ocular manifestations
- Anterior lenticonus: This condition occurs in approximately 25% of patients with XLAS and is not present at birth, but it worsens with increasing age. Anterior lenticonus is the pathognomonic feature of Alport syndrome and manifests by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently. This condition is not accompanied by eye pain, redness, or night blindness. No defect in color vision occurs.
- Dot-and-fleck retinopathy: The most common ocular manifestation of patients with Alport syndrome, that is, dot-and-fleck retinopathy, occurs in approximately 85% of males with XLAS. This condition is rarely observed in childhood, and it usually becomes apparent at the onset of renal failure. Dot-and-fleck retinopathy is usually asymptomatic with no associated visual impairment or night blindness.
- Posterior polymorphous corneal dystrophy: This condition is a rare ocular manifestation in patients with Alport syndrome. Most patients are asymptomatic; however, some patients may develop slowly progressive visual impairment.
- Leiomyomatosis: Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography scanning or magnetic resonance imaging.
- ARAS: ARAS is much less common than XLAS, accounting for 10-15% of all patients with Alport syndrome. ARAS is usually observed in consanguineous marriages. The parents are asymptomatic or mildly affected, while their children (ie, both boys and girls) are often equally and severely affected. The clinical features are usually identical to those observed in patients with XLAS. Renal failure may have an earlier onset. Dot-and-fleck retinopathy and anterior lenticonus also occur in patients with ARAS.
- ADAS: This form of Alport syndrome is rare and is present in successive generations. Males and females are often equally and severely affected. Renal manifestations and deafness are usually identical to those occurring in patients with XLAS, but renal failure may occur at a later age. Clinical features confined to ADAS include bleeding tendency, macrothrombocytopenia, abnormalities of platelet aggregation (Epstein syndrome), and, occasionally, neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechner syndrome).
Physical
Initially, the findings on physical examination may be unremarkable, but, with time, patients develop progressive renal failure manifested by hypertension, edema, and anemia. Moreover, various extrarenal features may also be observed, as follows:
- Sensorineural deafness
- In the early stages, hearing impairment is detectable only by audiometry, with bilateral hearing loss to high tones in frequency ranging from 2000-8000 hertz (Hz).
- In males with XLAS and in both males and females with ARAS, the hearing deficit is progressive and eventually involves lower frequencies, including those of conversational speech.
- In females with XLAS, hearing loss occurs less frequently and late in life. The risk of developing hearing loss by age 40 years is approximately 90% in males and 10% in females with XLAS. Approximately 60% of patients with ARAS usually develop hearing loss when they are younger than 20 years. In patients with Alport syndrome, studies of brainstem auditory-evoked responses indicate the cochlea as the site of the lesion involved with hearing impairment. Animal studies reveal marked thickening of the basement membranes of the strial vessels of the cochlea; however, only limited information is available of the inner ear histology in humans with Alport syndrome. Striking alterations of the stria vascularis of the cochlea are described.
- Characteristic ocular abnormalities
- Anterior lenticonus: This condition is the conical protrusion of the lens surface into the anterior chamber of the eye because of a thin and fragile basement membrane of the lens capsule. The lenticonus is most marked anteriorly because the capsule is thinnest there, the stresses of accommodation are more marked, and the lens is least supported. Anterior lenticonus occurs in approximately 25% of patients with XLAS. This condition is not present at birth but worsens with age. Anterior lenticonus is the pathognomonic feature of patients with Alport syndrome, and its presence in any individual is highly suggestive of Alport syndrome. This condition is a valuable marker of disease severity and is almost invariably accompanied by progressive renal failure and hearing loss. Diagnosis of anterior lenticonus is made by slit lamp examination. Minor degrees of lenticonus are difficult to detect but are suggested by distinctive oil droplet appearance on the red reflex on slit lamp examination.
- The diagnosis is confirmed when the central part of the lens projects anteriorly 3-4 mm in an axial projection on biomicroscopic examination. The condition is usually bilateral, causes a slowly progressive axial myopia, and rarely may progress to anterior capsular cataract, for which surgical extraction is required.
- Ultrastructure analysis of the anterior lens capsule by electron microscopy confirms the diagnosis of Alport syndrome.1 This condition rarely progresses to spontaneous rupture of the lens capsule, and posterior lenticonus is very uncommon.
- Dot-and-fleck retinopathy: This condition is the most common ocular manifestation in patients with Alport syndrome, occurring in approximately 85% of males with XLAS. Dot-and-fleck retinopathy is rarely observed in childhood and usually becomes apparent at the onset of renal failure. This condition comprises numerous, bilateral, white and yellow perimacular dots and flecks. These spare fovea but can spread to the periphery. No associated visual impairment or night blindness occurs. Typically, this condition does not fluoresce with angiography. These dots are thought to be located at the level of the retinal pigment epithelium–Bruch membrane–choriocapillaris complex. The abnormal basement membrane proteins in patients with Alport syndrome may result in enhanced permeability of the Bruch membrane and the underlying choriocapillaris, allowing accumulation of lipofuscin and other undefined substances in the retinal pigment epithelium or in the Bruch membrane.
- Posterior polymorphous corneal dystrophy: A rare ocular manifestation of patients with Alport syndrome, this condition appears as clear vesicles alone or in groups (string of pearls) on the endothelial surface of the cornea. This condition is usually bilateral but can be unilateral or asymmetric. Posterior polymorphous corneal dystrophy is attributed to the lamellation and thickening of the outer layer of the Descemet membrane. The demonstration of posterior polymorphous corneal dystrophy in any individual is highly suggestive of Alport syndrome.
- Leiomyomatosis
- Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in about 20 families with Alport syndrome. All patients with Alport syndrome diffuse leiomyomatosis complex have been found to have deletions that span the 5' ends of the COL4A5 and COL4A6 genes.
- Females in these families typically exhibit genital leiomyomas with clitoral hypertrophy and variable involvement of the labia majora and uterus. Bilateral posterior subcapsular cataracts also frequently occur in the affected individuals.
Causes
Alport syndrome is caused by defects in the genes encoding alpha-3 (IV), alpha-4 (IV), or alpha-5 (IV) chains of type IV collagen of the basement membranes.
The 3 genetic forms of Alport syndrome are as follows:
- XLAS - The most common form (85%) that results from mutations in the encoding of the alpha-5 (IV) chain of type IV collagen
- ARAS - Caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains and is responsible for approximately 10-15% of cases
- ADAS - Rare form that is caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains
Overview: Alport Syndrome