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.