Alport syndrome
Encyclopedia
Alport syndrome or hereditary nephritis is a genetic disorder
characterized by glomerulonephritis
, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes (lenticonus). The presence of blood
in the urine
(hematuria
) is almost always found in this condition.
It was first identified in a British family by Dr. Cecil A. Alport
in 1927, though William Howship Dickinson
is considered by some to have made contributions to the characterization.
s in COL4A3
, COL4A4
, and COL4A5
, collagen
biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney
, inner ear
, and eye
. Basement membrane
s are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein
into the urine.
The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.
The use of eye examinations for screening has been proposed.
All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either the glomerular or the renal tubular basement membrane.
Of these three alpha chains, only alpha5 is normally expressed in the skin, so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.
that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.
Once kidney failure has developed, patients are given dialysis
or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.
Gene therapy
as a possible treatment option has been discussed.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
characterized by glomerulonephritis
Glomerulonephritis
Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys...
, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes (lenticonus). The presence of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
(hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
) is almost always found in this condition.
It was first identified in a British family by Dr. Cecil A. Alport
Cecil A. Alport
Arthur Cecil Alport, M.D. was an English physician who first identified the Alport syndrome in a British family in 1927.-Biography:...
in 1927, though William Howship Dickinson
William Howship Dickinson
William Howship Dickinson was a British doctor.He was involved in the early characterization of what came to be known as Alport syndrome.He worked at Great Ormond Street Hospital.-Further reading:...
is considered by some to have made contributions to the characterization.
Causes
Alport syndrome is caused by mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in COL4A3
COL4A3
Collagen alpha-3 chain is a protein that in humans is encoded by the COL4A3 gene.-Further reading:...
, COL4A4
COL4A4
Collagen alpha-4 chain is a protein that in humans is encoded by the COL4A4 gene.-Further reading:...
, and COL4A5
COL4A5
Collagen alpha-5 chain is a protein that in humans is encoded by the COL4A5 gene.-Disease Database:-Further reading:...
, collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, inner ear
Ear
The ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....
, and eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
. Basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
s are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
into the urine.
The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.
Inheritance patterns
Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.- In most people with Alport syndrome, the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosomeX chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure. - Alport syndrome can be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2Chromosome 2 (human)Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second largest human chromosome, spanning more than 237 million base pairs and representing almost 8% of the total DNA in cells.Identifying genes on each...
, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. - Past descriptions of an autosomal dominant form are now usually categorized as other conditions, though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.
Criteria for the clinical diagnosis
Gregory et al., 1996, gave the following 10 criteria for the diagnosis of Alport syndrome; Four of the 10 criteria must be met:- Family history of nephritisNephritisNephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
of unexplained haematuria in a first degree relative of the index case or in a male relative linked through any numbers of females. - Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney diseasePolycystic kidney diseaseAutosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
or IgA nephropathyIgA nephropathyIgA nephropathy is a form of glomerulonephritis...
. - Bilateral sensorineural hearing lossSensorineural hearing lossSensorineural hearing loss is a type of hearing loss in which the root cause lies in the vestibulocochlear nerve , the inner ear, or central processing centers of the brain....
in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years. - A mutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in COL4An (where n = 3, 4 or 5). - ImmunohistochemicalImmunohistochemistryImmunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
evidence of complete or partial lack of the Alport epitopeEpitopeAn epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
in glomerular, or epidermal basement membranes, or both. - Widespread GBMGBM-Medicine:* Glioblastoma multiforme, a type of brain tumor* Glomerular basement membrane, a part of the glomerulus which helps separate urine from blood-Other:* Game Boy Micro, a portable video game system from Nintendo...
ultrastructural abnormalities, in particular thickening, thinning and splitting. - Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
- Gradual progression to ESRD in the index case of at least two family members.
- Macrothrombocytopenia or granulocytic inclusions, similar to the May-Hegglin anomaly.
- Diffuse leiomyomatosis of esophagusEsophagusThe esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
or female genitalia, or both.
The use of eye examinations for screening has been proposed.
Immunohistochemistry
Immunohistochemical (IHC) evidence of the X-linked form Alport syndrome may be obtained from biopsies of either the skin or the renal glomerulus. In this processes, antibodies are used to detect the presence or absence of the alpha3, alpha4, and alpha5 chains of collagen type 4.All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either the glomerular or the renal tubular basement membrane.
Of these three alpha chains, only alpha5 is normally expressed in the skin, so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.
Treatment
As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure and the proteinuriaProteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.
Once kidney failure has developed, patients are given dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.
Gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
as a possible treatment option has been discussed.
Disease database
COL4A5 gene variant databaseSee also
- Samoyed hereditary glomerulopathySamoyed hereditary glomerulopathyIn canines, Samoyed hereditary glomerulopathy [glo-mer″u-lop´ah-the] is an hereditary noninflammatory disease, of the renal glomeruli occurring in the Samoyed breed of dog. The disease has been shown to be a model for hereditary nephritis in humans in that the disease resembles that of the human...
, a disease shown to be a model for Alport syndrome.