Alport syndrome (AS) is a hereditary glomerular disease characterized primarily by hematuria, proteinuria, and progressive renal dysfunction. It may be accompanied by or occur without extrarenal manifestations such as sensorineural hearing loss and ocular abnormalities.
Etiology and Pathogenesis
Alport syndrome results from mutations in the COL4A3–COL4A6 genes, which encode the α3–α6 chains of type IV collagen. Mutations in COL4A6 are very rare. The inheritance patterns of Alport syndrome are shown in Table 1. X-linked Alport syndrome (XLAS) is the most common, accounting for approximately 85% of cases. Autosomal recessive Alport syndrome (ARAS) constitutes about 10%–15% of cases, while autosomal dominant Alport syndrome (ADAS) is rare. In addition, digenic inheritance has been identified in recent years.
Table 1 Inheritance patterns of Alport syndrome
Clinical Manifestations
The clinical manifestations of Alport syndrome exhibit heterogeneity depending on the inheritance pattern.
Renal Manifestations
Hematuria
Hematuria is the most common clinical feature. It may present as asymptomatic and persistent microscopic hematuria during childhood, with episodes of gross hematuria following upper respiratory tract infections. Nearly 100% of males with XLAS or patients with ARAS exhibit microscopic hematuria, while more than 90% of females with XLAS also have microscopic hematuria.
Proteinuria
Males with XLAS and patients with ARAS typically develop proteinuria as they age and as hematuria persists, occasionally progressing to nephrotic syndrome. Proteinuria is also relatively common in females with XLAS and patients with ADAS.
Progressive Decline in Renal Function
Males with XLAS or digenic inheritance, as well as patients with ARAS, often experience early onset and severe disease, with progression rates varying among families. About 50% of these individuals progress to end-stage renal disease (ESRD) during adolescence. Females with XLAS and patients with ADAS tend to have later onset and milder disease, but they still carry a risk of progression to ESRD.
Extrarenal Manifestations
Hearing Loss
Sensorineural hearing loss is a characteristic feature, typically bilateral but potentially asymmetric. Hearing impairment begins in the high-frequency range and gradually affects the entire frequency range with age, detectable using pure-tone audiometry.
Ocular Abnormalities
Ocular abnormalities are relatively common and include anterior lenticonus, perimacular dot-and-fleck retinopathy, and retinal changes near the equatorial region. These usually do not significantly affect vision but may progress as renal function deteriorates.
Other Symptoms
Some patients with Alport syndrome may develop diffuse leiomyomatosis and cardiovascular or cerebrovascular complications, such as aortic dilation, dissection, or aneurysms, mitral valve prolapse, ventricular septal abnormalities, and cerebral aneurysms.
Diagnosis
The diagnosis of Alport syndrome primarily relies on clinical manifestations, histopathological findings, family analysis, and genetic testing.
Histopathological Examination
Renal Biopsy
In light microscopy, glomeruli often show minimal changes in early stages. As the disease progresses, pathological changes such as segmental or diffuse mesangial cell proliferation and focal segmental glomerulosclerosis may appear. Immunofluorescence is often negative. A hallmark pathological change is seen in electron microscopy, where the glomerular basement membrane (GBM) is diffusely thickened or shows irregular thickening and thinning, often accompanied by splitting of the lamina densa. The lamina densa of the GBM may thicken up to 1,200 nm (normal thickness is 100–350 nm), with irregular internal and external contours, sometimes exhibiting a "basket-weave" appearance.
Immunofluorescence for Type IV Collagen α Chains
Immunofluorescence detection of type IV collagen α chains in kidney and skin tissues is used for diagnosis. Under normal conditions, type IV collagen α3 and α4 chains are deposited in the GBM and distal tubular basement membrane (dTBM), while the α5 chain is deposited in the GBM, Bowman's capsule (BC), dTBM, and epidermal basement membrane (EBM). Immunofluorescence appears as continuous linear deposits. Patients with X-linked or autosomal recessive inheritance patterns show abnormalities in α3–α5 chain deposition.
Table 2 Type IV collagen α chain immunofluorescence results in Alport syndrome patients
Genetic Testing
Genetic testing has high sensitivity and specificity and is considered the preferred diagnostic method. Because the type of mutation determines disease progression, genetic testing provides better prognostic insights compared to histopathology. Whole-exome sequencing or targeted gene panel sequencing is commonly used to identify mutations in the COL4A3–COL4A6 genes. Additionally, genetic testing or validation of genetic variants in first-degree relatives of diagnosed patients should be performed.
Alport syndrome can be definitively diagnosed in patients with persistent glomerular hematuria or hematuria with proteinuria if they exhibit any of the characteristic histopathological changes or mutations in the COL4A3–COL4A6 genes.
Differential Diagnosis
Alport syndrome needs to be differentiated from thin basement membrane nephropathy (TBMN), focal segmental glomerulosclerosis (FSGS), and IgA nephropathy. GBM ultrastructural changes, immunofluorescence detection of type IV collagen α chains in kidney and skin tissues, and genetic testing are useful for differentiation.
Treatment
There is currently no specific treatment for Alport syndrome. The treatment strategy focuses on early intervention to slow disease progression. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are recommended to reduce proteinuria and inhibit renal interstitial fibrosis. ACEI or ARB therapy should be initiated promptly in males with X-linked inheritance, patients with autosomal recessive or digenic inheritance, and patients with unclear inheritance patterns who present with hematuria and proteinuria. Additionally, timely screening and evaluation for hearing and ocular abnormalities are essential for hearing and vision preservation. If the disease progresses to end-stage renal disease (ESRD), renal replacement therapy is required.