Alport's syndrome is progressive hereditary hematuric glomerulonephritis that generally affects males much more severely than females. There is a juvenile form of the disease in which boys develop renal failure at a mean age of 18 years, and an adult type in which renal failure occurs in men around the age of 35. Alport's syndrome is often associated with progressive hearing loss and occasionally with other nonrenal defects.

Genetics

Inheritance in the largest and best-studied kindreds is X-linked dominant. Nearly 100 different mutations of the COL4A5 gene that codes for the a5 chain of type IV collagen have been described. COL4A5 is located on the X chromosome at Xq22. In occasional families with early development of renal failure in both genders, autosomal recessive Alport's syndrome results from mutations of COL4A3 or COL4A4, both on chromosome 2 at 2q36. However, other families, particularly those with associated thrombopathy, display autosomal dominant inheritance, with as yet obscure mutations.

Pathogenesis

The fundamental lesion in most variants of Alport's syndrome is a defect in one of the genes coding for the a3, 4, or 5 chains of type IV collagen in the glomerular basement membrane (GBM). If one a chain is defective, normal assembly of a chain heterotrimers cannot occur. This is believed to lead to formation of imperfect collagen, apparent ultrastructurally as thickening and lamellation of the GBM and other basement membranes.

Incidence and Epidemiology

Alport's syndrome occurs worldwide. The true incidence is probably 1 in 5000 of the population, but many cases go unrecognized.

Clinical Features

With X-linked disease, all hemizygous males have uninterrupted microscopic hematuria from birth, as do affected males and females with autosomal disease. In contrast, most heterozygous females with an X-linked gene show early but milder signs, and a few are clinically normal.
In childhood, hematuria may be episodically macroscopic, often after minor infections, and this may encourage confusion with postinfectious and other forms of glomerulonephritis. Microscopy of the urine sediment shows dysmorphic erythrocytes with occasional tubular cells and erythrocytic, blood, and granular casts. Proteinuria is variable.
Some families with Alport's syndrome have associated abnormalities; the most common is high-frequency sensorineural hearing loss. This was true of Alport's original kindred, but hearing loss is not found in all families. When present, premature hearing loss in many family members is a valuable clue to the diagnosis, but requiring it as a condition for diagnosing Alport's syndrome causes many cases to be overlooked. Hearing impairment worsens roughly in step with increasing renal dysfunction and becomes profound in severe cases. Tinnitus troubles some patients.
Less common than hearing loss, but nearly pathognomonic of Alport's syndrome, is anterior lenticonus. It occurs in families with juvenile-type Alport's syndrome and is readily apparent if the examiner uses a series of strong convex lenses in the ophthalmoscope to examine the anterior structures in the eye through a dilated pupil. The “oil drop” seen on the anterior surface of the lens explains the severe refractive error that impairs vision and prevents a clear view of the fundus. In some families, white or yellowish retinal flecks are seen, particularly near the macula.

Laboratory Findings

Renal biopsy shows a mixture of glomerular and tubular lesions, with progressive scarring as the disease advances. Foam cells may be prominent but are not diagnostic, and glomerular crescents can occur in juvenile-type nephritis. Routine immunofluorescence is negative, but examination of the biopsy with fluoresceinated anti-GBM sera reveals striking findings: the normal distinct linear staining of the GBM is often absent in males who are hemizygous for an X-linked gene, and often shows interrupted staining in heterozygous females. Electron microscopy of early cases may show thinning of the GBM. More advanced cases show a characteristic thickening of the GBM, which is frayed into several lamellae, often separated by small electron-dense granules. Basement membrane splitting is not pathognomonic of Alport's syndrome because similar appearances can occur in many glomerular diseases; however, only in Alport's syndrome is the splitting prominent and widespread at a time when there are few other changes in the kidney. A renal biopsy is unnecessary for diagnosis in a patient with hematuria who has an extensive family history of hematuria and of renal failure in male relatives.
The blood in advanced cases shows the findings expected with renal insufficiency. Rare families have thrombocytopenia with giant platelets or cytoplasmic Fechtner inclusions in granulocytes.
Specific genetic tests are available for identifying the over 100 known mutations of COL4A5. At present, these are of value to perhaps 10% to 20% of known families with Alport's syndrome. The number of identified mutations will probably increase rapidly, and it is likely that genetic screening and diagnosis will soon become practicable. Some adult-type families, both with and without overt hearing loss, contain many hundreds of known gene carriers, and there are likely many more undiscovered. Tests for the more common mutations may be appropriate in adults with familial or unexplained glomerulonephritis.

Course and Prognosis

All affected males eventually develop renal failure, at varying ages in different kindreds. The few women who develop renal failure are mostly elderly. Boys and girls with homozygous autosomal recessive disease commonly develop renal failure during grade school.

Treatment

There is no specific treatment. Control of hypertension is important, and modest protein restriction could be advised when renal function begins to deteriorate. Appropriate plans should be made for dialysis or transplantation. Rarely, anti-GBM nephritis may develop in the renal allograft of a patient with Alport's syndrome, but this is not a bar to transplantation unless other members in the same family have lost grafts to anti-GBM nephritis. As in any familial nephropathy, great care should be taken in the selection of living donors.
Hearing aids help the hearing loss to some degree. If vision becomes severely impaired by lenticonus, intraocular lens implantation is feasible. Genetic counseling is vital but complicated by the genetic heterogeneity of Alport's syndrome. For this reason, it is desirable to assemble as complete a pedigree as possible and perhaps to attempt molecular diagnosis before counseling the patient.