NORD gratefully acknowledges Clifford Kashtan, MD, FASN, Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota Medical School; Executive Director, Alport Syndrome Treatments and Outcomes Registry, for assistance in the preparation of this report.
Alport syndrome is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the inner ear and the eye. There are three genetic types. X-linked Alport syndrome (XLAS) is the most common; in these families affected males typically have more severe disease than affected females. In autosomal recessive Alport syndrome (ARAS) the severity of disease in affected males and females is similar. There is also an autosomal dominant form (ADAS) that affects males and females with equal severity. The hallmark of the disease is the presence of blood in the urine (hematuria) early in life, with progressive decline in kidney function (kidney insufficiency) that ultimately results in kidney failure, especially in affected males. About 50% of untreated males with XLAS develop kidney failure by age 25, increasing to 90% by age 40 and nearly 100% by age 60. Females with XLAS usually do not develop kidney insufficiency until later in life. They may not develop kidney insufficiency or failure at all, but the risk increases as they grow older. Both males and females with ARAS develop kidney failure, often in the teen-age years or early adulthood. ADAS tends to be a slowly progressive disorder in which renal insufficiency does not develop until well into adulthood. Individuals with Alport syndrome can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision. XLAS is caused by variants in the COL4A5 gene. ARAS is caused by variants in both copies of either the COL4A3 or the COL4A4 gene. ADAS is caused by variants in one copy of the COL4A3 or COL4A4 gene. Alport syndrome is treated symptomatically and certain medications can potentially delay the progression of kidney disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required.
The disease we now know as Alport syndrome was first described in the British medical literature in the early years of the 20th century. In 1927 Dr. Cecil Alport published a paper describing the association of kidney disease and deafness in affected individuals. Many additional cases were described in the literature and the disorder was named after Dr. Alport in 1961. Alport syndrome is often discussed with a related disorder known as thin basement membrane nephropathy (TBMN), in which the predominant pathologic abnormality is thinning of glomerular basement membranes. Many people diagnosed with TBMN have variants in the same genes that cause Alport syndrome. People diagnosed with TBMN have persistent microscopic blood in the urine (hematuria) in a similar pattern as seen in individuals with Alport syndrome. Patients given a diagnosis of TBMN are less likely to have symptoms outside of the kidney (extrarenal abnormalities) than patients with Alport syndrome, and additional kidney findings such as protein in the urine (proteinuria), high blood pressure (hypertension), kidney insufficiency, and kidney failure are less common than in Alport syndrome. Patients who have hematuria and variants in the COL4A3, COL4A4 or COL4A5 genes should be given a diagnosis of Alport syndrome, while those with thin glomerular basement membranes but no variants in these genes should be diagnosed with hematuria with thin glomerular basement membranes. Differentiating Alport syndrome and TBMN can be challenging, especially in young patients and in women. For more information on this topic see the Related Disorders section of this report.
The onset, symptoms, progression, and severity of Alport syndrome can vary greatly from one person to another due, in part, to the specific subtype and gene variant present. Some individuals may have a mild, slowly progressive form of the disorder, while others have earlier onset of severe complications.
The first sign of kidney disease is blood in the urine (hematuria). Hematuria is usually not visible to the naked eye, but can be seen when the urine is examined under a microscope. This is referred to as microscopic hematuria. Sometimes, blood may be visible in the urine (i.e. the urine may be brown, pink, or red) for a few days, usually when an affected individual has a cold or the flu. This is referred to as an episode of gross hematuria. Males with XLAS usually exhibit persistent microscopic hematuria early in life. About 95% of females with XLAS syndrome have microscopic hematuria, but it may come and go (intermittent). Both males and females with ARAS develop hematuria during childhood. Males and females with ADAS also have hematuria.
With time many affected individuals exhibit elevated levels of albumin and other proteins in the urine (albuminuria and proteinuria), which are indications that kidney disease is progressing. The next stage in progression is gradual loss of kidney function, frequently associated with high blood pressure (hypertension), until, ultimately, the kidneys fail to work (end stage renal disease or ESRD). The kidneys have several functions including filtering and excreting wastes products from the blood and body, creating certain hormones, and helping maintain the balance of certain minerals in the body such as potassium, sodium, chloride, and other electrolytes. A variety of symptoms can be associated with ERSD including weakness and fatigue, changes in appetite, puffiness or swelling (edema), poor digestion, excessive thirst and frequent urination.
As noted above, the rate of progression of kidney disease varies greatly. Many males with XLAS develop ERSD by their teen-age years or early adulthood, although some will not develop kidney failure until their 40s or 50s. Most females with XLAS do not develop kidney insufficiency until later in life. Kidney failure is less common than in males with XLAS but still a significant risk – about 15% by age 45 and 20-30% by age 60.
Progressive hearing loss (sensorineural deafness) occurs frequently in people with Alport syndrome. Sensorineural deafness results from impaired transmission of sound input from the inner ears (cochleae) to the brain via the auditory nerves. The hearing loss is bilateral, meaning it affects both ears. Diminished hearing is usually evident by late childhood in males with XLAS although it may be mild or subtle. In males with XLAS the frequency of hearing loss is approximately 50% by age 15, 75% by age 20 and 90% by age 40. Hearing loss is progressive and may require hearing aids as early as the teen-age years. Hearing aids are typically very helpful in people with deafness caused by Alport syndrome.
The onset, progression and severity of hearing loss in Alport syndrome varies greatly due to, in part, the specific genetic variant present in each individual. Hearing loss in females with XLAS occurs less frequently than in males and usually occurs later in life, although a smaller percentage of females will develop hearing loss in their teen-age years. Both males and females with ARAS develop hearing loss, usually during late childhood or early adolescence. Individuals with ADAS may develop hearing loss, although this occurs much later during life, usually as older adults.
Individuals with Alport syndrome may also develop abnormalities in several parts of the eyes including the lens, retina and cornea. Eye abnormalities in XLAS and ARAS are very similar in presentation. Eye abnormalities are uncommon in ADAS.
Anterior lenticonus is a condition in which the lenses of the eyes are shaped abnormally, specifically the lens bulges forward into the space (anterior chamber) behind the cornea. Anterior lenticonus can result in the need for glasses and sometimes leads to cataract formation. Anterior lenticonus occurs in about 20% of males with XLAS and often becomes apparent by late adolescence or early adulthood.
The retina, which is the nerve-rich, light-sensitive membrane that lines the back of the eyes, may also be affected, usually by pigmentary changes caused by the development of yellow or white flecks superficially located on the retina. These changes do not appear to affect vision. Rare patients develop progressive thinning of the retina that can result in holes (macular holes) that can impair vision.
The cornea, which is the clear (transparent) outer layer of the eyes, may also be affected, although the specific abnormalities can vary. The effects on the cornea may be slowly progressive. Recurrent corneal erosions in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly may occur. Recurrent corneal erosions can cause discomfort or severe eye pain, an abnormal sensitivity to light (photophobia), blurred vision, and the sensation of a foreign body (such as dirt or an eyelash) in the eye. Posterior polymorphous corneal dystrophy may also occur. Effects on the cornea may be slowly progressive. Both eyes may be affected; one eye can be more severely affected than the other. In severe cases, posterior polymorphous corneal dystrophy can cause swelling (edema) of a specific layer of the cornea, photophobia, the sensation of a foreign body (such as dirt or an eyelash) in the eye, and decreased vision.
Additional symptoms can occur in certain individuals with Alport syndrome. In a small number of males, aneurysms of the chest or abdominal portions of the aorta, the main artery that carries blood away from the heart, have occurred. Aneurysms occur when the walls of blood vessels balloon or bulge outward, potentially rupturing causing bleeding within the body.
Alport syndrome is caused by disease-causing variants in the DNA sequences of specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a disease-causing variant in the DNA sequence of genes of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The COL4A5 gene is located on the X chromosome. The COL4A3 and the COL4A4 genes are located on chromosome 2. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
X-linked Alport syndrome is caused by disease-causing variants in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females. Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.
Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.
Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be heterozygous because they inherit a normal copy of the gene from their mothers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female who is heterozygous for an X-linked disorder has a 50% chance with each pregnancy of having a heterozygous daughter, a 50% chance of having a daughter with two normal copies of the gene, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Approximately 10-15% of males with XLAS have a variant that occurs randomly (spontaneously) for no known reason. In these cases, the mutation was not inherited from the mother.
Autosomal recessive Alport syndrome is caused by disease-causing variants in both copies of either the COL4A3 or the COL4A4 genes. Autosomes are the non-sex chromosomes that carry most of our genes. There are 22 autosomes and cells have two copies of each autosome, one inherited from the mother and the other inherited from the father. Each cell has two copies (alleles) of every autosomal gene. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be heterozygous for the disease, and may or may not show symptoms. The risk for two heterozygous parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is heterozygous like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Autosomal dominant Alport syndrome is caused by disease-causing variants in one copy of either the COL4A3 gene or the COL4A4 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new variant (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Researchers have determined that the progression and severity of Alport syndrome tend to vary based upon the specific variant present in a gene as well as the specific location of the variant in the gene. This is known as genotype-phenotype correlation and allows physicians to predict individuals who are at risk of early-onset kidney failure or more likely to develop extra-renal abnormalities. More than 1000 different disease-causing variants have been identified in XLAS.
Some individuals with Alport syndrome have loss of genetic material (microdeletion) and loss of function of several adjacent genes (contiguous gene syndrome) on the long arm of the X chromosome, which affects both the COL4A5 and COL4A6 genes. In addition to the classic symptoms of Alport syndrome, affected individuals can develop leiomyomatosis (tumors of smooth muscle that are not malignant). This is known as Alport syndrome with diffuse leiomyomatosis. Another disorder involving a contiguous gene syndrome associated with X-linked Alport syndrome is the AMME complex. For more information on these disorders, see the Related Disorders section below.
The COL4A3, COL4A4, and COL4A5 genes create (encode) proteins known as alpha chains of collagen IV, a protein family that serves as the major structural component of basement membranes, specifically those of the kidneys, ears and eyes. Basement membranes are delicate protein matrices that separate the thin outer layer of tissue (epithelium) of a structure from the underlying tissue. The basement membrane anchors the epithelium to the loose connective tissue beneath it and also serves as a barrier. The COL4A3 gene encodes the collagen IV alpha-3 chain. The COL4A4 gene encodes the collagen IV alpha-4 chain. The COL4A5 gene encodes the collagen IV alpha-5 chain. Disease-causing variants in these genes impair the production of functional copies of the corresponding proteins, leading in turn to the improper health and maintenance of collagen IV. The negative effects of collagen IV abnormalities result in the progressive damage to the basement membranes and ultimately the signs and symptoms of Alport syndrome.
For example, in the kidneys the glomerular basement membrane (GBM) is a vital component of the walls of the small blood vessels (capillaries) that make up glomeruli. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. Collagen IV acts to strengthen and hold the GBM together. In individuals with Alport syndrome the GBM is initially thin and can develop microscopic ruptures that allow blood cells to leak into the urine, causing hematuria. The cells of the glomeruli respond to the abnormal collagen IV by laying down other proteins that lead to thickening of the GBM while impairing the GBM’s ability to keep protein out of the urine. This results in proteinuria. Further damage such as the formation of scar tissue (fibrosis) in the kidneys may also occur. Damage to the GBM and the kidneys is progressive, causing worsening kidney function and, in many cases, eventually kidney failure.
Alport syndrome is estimated to affect approximately 1 in 5,000-10,000 people in the general population in the United States, which means that approximately 30,000-60,000 people in the United States have the disorder. Alport syndrome is estimated to account for 3% of children with chronic kidney disease and 0.2% of adults with end-stage renal disease in the United States. In XLAS, males are affected more severely than females. In the autosomal forms of Alport syndrome, males and females are affected with equal severity.
A diagnosis of Alport syndrome is suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The likelihood of diagnosis increases in individuals with a family history of Alport syndrome, kidney failure without known cause, early hearing loss or hematuria. A variety of specialized tests can help to confirm a suspected diagnosis.
Clinical Testing and Workup
The diagnostic approach to confirming a suspected diagnosis of Alport syndrome has been evolving over the past decade. While tissue studies (kidney or skin biopsy) are very useful tools in the evaluation of patients with hematuria, early genetic testing is becoming increasingly important. When clinical information and family history strongly suggest a diagnosis of Alport syndrome, genetic testing, using the techniques of next generation or whole exome sequencing, can confirm the diagnosis, establish the inheritance pattern and provide useful prognostic information. Genetic testing for Alport syndrome is offered by several commercial laboratories as well as some hospital laboratories, but there is wide variation in insurance coverage.
When genetic testing is unavailable or inaccessible, studies of tissue specimens (biopsies) are performed. A suspected diagnosis of XLAS may be confirmed by skin biopsy. A specific test known as immunostaining is performed on the sample. With immunostaining, an antibody that reacts against collagen type IV alpha-5 chain proteins is added to the skin sample. This allows physicians to determine whether a specific protein is present and in what quantity. Normally, alpha-5 chains are found in skin samples, but in males with XLAS they are nearly completely absent. Alpha-3 and alpha-4 chains are not present in the skin and, therefore, skin biopsies cannot be used to diagnose ARAS or ADAS.
A kidney biopsy may be also performed. A kidney biopsy can reveal characteristic changes to kidney tissue including abnormalities of the glomerular basement membrane (GBM) that can be detected by an electron microscope. Immunostaining can also be performed on a kidney biopsy sample. In addition to detecting alpha-5 chains, kidney samples can be assessed to determine whether type IV collagen alpha-3 or alpha-4 chains are present and in what quantity.
Examination of urine samples (urinalysis) can reveal microscopic or gross amounts of blood (hematuria) in the urine. Hematuria may come and go (intermittent) in some cases, especially females with XLAS or individuals with ADAS. If kidney disease has progressed, elevated levels of protein can also be detected in urine samples.
Individuals diagnosed with Alport syndrome should undergo hearing tests that determine a person’s audible range for tones and speech (audiometry) and a complete eye (ophthalmological) exam.
In cases where a parent has a known genetic abnormality (i.e. heterozygous mothers) prenatal diagnosis or pre-implantation genetic diagnosis (PGD) may be options. Prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of the fluid that surrounds the developing fetus is removed and studied.
PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
The treatment of Alport syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, nephrologists, audiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Due to the rarity of Alport syndrome, treatment trials that have been tested on a large group of patients are lacking until recently. Clinical practice recommendations based on empiric findings have been published (Kashtan C., et al. 2013 and Savige J., et al. 2013) and discuss the treatment of Alport syndrome, including information on identifying and treating children with a high risk of developing early-onset renal failure.
Medications known as angiotensin-converting enzyme (ACE) inhibitors have been used to treat individuals with Alport syndrome. Historical (retrospective) data strongly suggests that early treatment with ACE inhibitors can delays progression to end-stage renal disease in males and females with Alport syndrome. This off-label use may not be appropriate for all affected individuals and several factors must be considered before starting the therapy such as baseline kidney function, family history, and specific symptoms present. ACE inhibitor therapy should be considered in all patients with Alport syndrome who have elevated levels of protein in the urine (overt proteinuria). These drugs are blood pressure medications that prevent (inhibit) an enzyme in the body from producing angiotensin II. Angiotensin II is a chemical that acts to narrow blood vessels and can raise blood pressure. ACE inhibitors in individuals with Alport syndrome have been shown to reduce proteinuria and slow the progression of kidney disease, delaying the onset of renal failure.
Some individuals do not respond to or cannot tolerate ACE inhibitors. These individuals may be treated with drugs known as angiotensin receptor blockers (ARBs). ARBs prevent angiotensin II from binding to the corresponding receptors on blood vessels.
In the medical literature, ACE inhibitor therapy or ARB therapy is recommended in individuals with Alport syndrome who show overt proteinuria. These therapies may also be considered in affected individuals who have small amounts of albumin in the urine (microalbuminuria), but have not yet developed overt proteinuria. Albumin is a marker for kidney disease because the kidney may leak small amounts of albumin when damaged.
Although treatment may slow the progression of kidney disease in Alport syndrome, there is no cure for the disorder and no treatment has thus far been shown to completely stop kidney decline. The rate of progression of kidney decline in individuals with Alport syndrome is highly variable. In many affected individuals kidney function eventually deteriorates to the point where dialysis or a kidney transplant is required.
Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney — filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals such as potassium. End-stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant.
A kidney transplant is preferred for individuals with Alport syndrome over dialysis and has generally been associated with excellent outcomes in treating affected individuals. Some individuals with Alport syndrome will require a kidney transplant in adolescence or the teen-age years, while others may not require a transplant until they are in their 40s or 50s. Most females with XLAS and some individuals will ADAS syndrome never require a transplant. If a kidney transplant is indicated, great care must be taken in selecting living related kidney donors to ensure that affected individuals are not chosen. Alport syndrome does not recur in kidney transplants. However about 3% or less of transplanted Alport patients make antibodies to the normal collagen IV proteins in the transplanted kidney, causing severe inflammation of the transplant (anti-GBM nephritis).
Specific symptoms associated with Alport syndrome are treated by routine, accepted guidelines. For example, hearing aids are used to treat hearing loss when appropriate. Hearing aids are usually effective in people with Alport syndrome because they do not lose the ability to distinguish the various sounds of speech from each other another, as long as the sounds are amplified. Surgery to remove cataracts is performed when necessary.
Alport syndrome registries have been established in several countries. Two of the largest Alport syndrome registries are in the United States, the Alport Syndrome Treatments and Outcomes Registry (http://alportregistry.org/) and in Europe, the European Alport Registry (http://www.alport.de/englishindex.html). Registries have also been established in the United Kingdom, France, Italy, Australia, China and other countries. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. Medical practitioners are encouraged to submit data from their treatment of patients with Alport syndrome.
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