Dr. MJ Bazos MD,
Alport Syndrome (AS) is an inherited disorder of
the basement membranes of the kidney, eye and ear. People who inherit defective
genes for the "collagen" proteins in these basement membranes may develop
progressive loss of renal function, deafness and abnormalities of the eye. In
the kidneys, glomerular basement membranes normally act like filters, allowing
fluid to move from blood vessels to urine while retaining protein and red blood
cells within the bloodstream. Thus, one of the early signs of Alport syndrome
may be leakage of small amounts of blood or protein into the urine during
childhood. Collagen-containing membranes are also important for the shape of the
lens of the eye and the structure of the inner ear.
In 1927, Dr. Alport wrote his classic report on
a British family with the syndrome. He drew attention to the fact that affected
males in this family uniformly developed progressive renal failure and deafness,
whereas females were less affected. This pattern of inheritance is termed
"X-linked". The normal copy of the gene onto the other X chromosome relatively
protects female "carriers" who inherit an abnormal Alport gene on one X
chromosome. Some females may develop renal insufficiency, but in general this
occurs late in life. In contrast, every male receives one Y chromosome from his
father and one X chromosome from his mother; thus, if he happens to inherit an
X-chromosome bearing a mutant Alport gene, the boy is unprotected and develops
the full-blown Alport Syndrome as a young adult.
In the 1970s, electron microscopic studies of
kidney biopsy tissue proved that the primary problem lies in the kidney's
basement membrane; at an early stage, its collagen fibers are visibly ragged,
rendering it thin, fragile and easily ruptured. In 1990, it was finally shown
that classical X-linked Alport Syndrome (XLAS) is caused by mutations of a
specialized collagen gene ("Col 4A5") located on the X-chromosome. Female
"carriers" pass the defective gene to 50% of their sons; these boys invariably
develop Alport Syndrome. Affected males pass the defective gene to all their
daughters and never to their sons (to whom they pass the Y chromosome).
A rare variant of X-linked Alport Syndrome has
been described in association with abnormal muscle of the esophagus (interfering
with swallowing). This condition is due to mutations of another collagen gene
("Col 4A6") located on the X- chromosome.
About 85% of Alport Syndrome (AS) cases have the
classical X-linked pattern of inheritance similar to the family described by Dr.
Alport. However, about 15% of cases follow a different genetic pattern. Basement
membranes are actually a meshwork of many types of collagens and the genes for
some of these other collagens are not located on the X-chromosome.
Patients with Autosomal Recessive Alport
Syndrome (ARAS) have inherited a pair of abnormal collagen genes, one from each
parent. In some families, the syndrome is caused by two mutant copies of a
collagen gene termed "Col 4A3"; in other families, the "Col 4A4" genes are
defective. We now know that both of these collagen genes are located on
chromosome #2, rather than on the X-chromosome. Consequently, both males and
females are fully affected. Both these genes are important for integrity of the
basement membrane; if either one is eliminated, there is progressive
deterioration of renal function, deafness and changes in the eye, just as in
X-linked Alport syndrome. ARAS cannot be distinguished from classical X-linked
Alport syndrome (XLAS) on clinical grounds or standard assessments of renal
biopsy tissue. One or more children in a family may be affected, but renal
failure does not usually occur in subsequent generations unless there is
marriage between family members or marriage into another affected family.
Parents of a child with ARAS are "carriers".
Each has one normal, as well as one abnormal copy of the gene. Similarly, half
of the patient's siblings may be carriers who are relatively protected by the
normal copy of the gene. Although their basement membranes may be thin and urine
tests may show small amounts of blood or protein in the urine, ARAS carriers
generally do not develop progressive kidney dysfunction.
In some families, a single copy of the abnormal
collagen gene on chromosome #2 is passed on to 50% of each successive
generation. Each carrier may have blood in the urine but no one in the family
develops kidney failure. In the past, such families were said to have "Benign
Familial Hematuria", but the cause was not fully understood. Kidney biopsies
often showed thin basement membranes, prompting physicians to coin the term
"Thin Glomerular Basement Membrane Disease" to describe the situation.
In rare instances, (<1%) the typical symptoms
of Alport Syndrome follow an autosomal dominant pattern (ADAS). In other words,
kidney failure and deafness may be seen in successive generations, affecting
males and females equally. In one such family, Dr. Antignac (Paris) discovered
an unusual mutation of the Col 4A3 gene. Although damage to the Col 4A3 gene
usually causes ARAS, Dr. Antignac suggested that this particular mutation
actually produces a disruptive form of 4A3 collagen. Affected individuals from
this family do not seem to be protected by their one normal copy of the gene.
Instead, the abnormal, disruptive collagen is somehow able to interfere with
basement membrane structure even in the presence of some normal 4A3 collagen.
Another unusual form of Alport Syndrome has been described in association with
giant platelets in the blood, but the genetic basis for this variant is unknown.
symptoms in classical Alport Syndrome (XLAS)
The first subtle manifestations of classical
Alport Syndrome (XLAS) usually appear early in life. Blood in the urine
(hematuria) may be detectable by one year of age in about 15% of cases, and by
six years of age in about 70% of cases. Occasionally, there may be brief
episodes lasting for days during which the blood is visible to the eye; pain or
other symptoms do not accompany these episodes. Leak of protein in the urine is
not usually evident in infancy, but increases during the first two decades. If a
renal biopsy is performed in the first few years of life, segments of the renal
basement membranes may be somewhat thin, but the characteristic unraveled
appearance of basement membrane collagen may not be evident until several years
later. As time goes by, the basement membranes become progressively thickened or
fibrosed in parallel with decreasing overall function of the kidney.
Progressive loss of kidney function in Alport
Syndrome is variable. In some families, affected males may require dialysis as
early as 20 years and invariably by 31 years of age; in others, dialysis is not
needed until about 40 years. Deafness is bilateral, but may be subtle in
childhood. Formal audiometric studies detect some level of hearing abnormality
in about 85% of affected boys by age 15 and many require hearing aids by the age
of 25. About 25-30% of patients have a characteristic abnormality of the shape
of the lens, as well as changes in the retina at the back of the eye. Although
useful in diagnosis, these problems are not usually associated with severe loss
Transplantation in Alport Syndrome
In general, long-term results of renal
transplantation in Alport Syndrome are satisfactory and comparable to
transplantation for other conditions. However, there are two important concerns
which must be addressed. If a family member wishes to serve as a kidney donor,
special care must be taken to ensure that the donor is unaffected. Often this
may require a renal biopsy and/or consultation with a genetics specialist.
Secondly, there are a small number of males with classical X-linked Alport
Syndrome whose Col 4A5 gene is entirely absent (deleted as opposed to modified).
When these patients are transplanted with a normal kidney, their immune system
recognizes the normal Col 4A5 collagen as a new, foreign (unaccustomed) protein
and mounts an unusually strong response. Often the transplanted kidney is
rapidly rejected in such cases.
As outlined above, the genetics of Alport
Syndrome is complex. Diagnosis in young children may be tricky, even with the
help of a renal biopsy. Some centers are able to perform specialized analysis
(immunohistochemistry) of renal biopsy tissue or molecular genetic testing
(linkage analysis) to identify the form of Alport Syndrome involved. However,
these studies are usually performed on a research basis and are not available as
a routine clinical test. Thus, there is a strong case to be made for genetic
counselling of families with young children at risk, anticipated pregnancies or