Alport Syndrome

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.

History

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.

Non-classical Alport Syndrome

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.

Progression of 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 of vision.

Renal 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.

Genetic Counselling

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 transplantation.


With acknowledgement to Dr. Paul Goodyer, Professor of Pediatric Nephrology at the McGill University Health Center, Montreal, QC, for his assistance in compiling this information.

© 2002





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