Alport's Syndrome
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Alport syndrome is a
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
affecting around 1 in 5,000–10,000 children, characterized by
glomerulonephritis Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal.
Proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
is a feature as kidney disease progresses. The disorder was first identified in a British family by the physician Cecil A. Alport in 1927. Alport syndrome once also had the label hereditary nephritis, but this is misleading as there are many other causes of hereditary kidney disease and 'nephritis'. Alport syndrome is caused by an inherited defect in
type IV collagen Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...
—a structural material needed for the normal function of different body parts. Since type IV collagen is found in the ears, eyes, and kidneys, this explains why Alport syndrome affects different seemingly unrelated parts of the body (ears, eyes, kidneys, etc.). Depending on where the mutation is located in the genome, Alport syndrome can present itself in many forms. This includes X-linked Alport syndrome (XLAS), autosomal recessive Alport syndrome (ARAS), and autosomal dominant Alport syndrome (ADAS).


Signs and symptoms

These descriptions refer to 'classic' Alport syndrome, which usually causes significant disease from young adult or late childhood life. Some individuals, usually with milder mutations or 'carrier' status, develop disease later, or show only some of the features of classic disease.


Chronic kidney disease

Blood in urine is a usual feature of Alport syndrome from early infancy, identifiable on urine dipsticks. In young children, episodes of visible (macroscopic)
haematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...
may occur. Protein begins to appear in urine as the disease progresses. This is now regarded as an indication for treatment with
ACE inhibitors Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as ...
. Progressive loss of kidney function (reflected clinically by increases in serum
creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...
or decreases in estimated
glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearance (medicine), clearing toxins; absorption of glucose, amino acids, and other small molecules; reg ...
) can occur and may require treatment with renal replacement:
dialysis Dialysis may refer to: * Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...
or a
kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...
.


Hearing loss

Alport syndrome can also cause hearing loss although some patients are not affected. Hearing in Alport syndrome patients is normal at birth. Hearing loss in affected patients develops progressively, usually at the stage when kidney function is normal, but there is substantial
proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
. However, in some patients, hearing loss is only noted after kidney function has been lost. Characteristically the early changes are reduced ability to hear high-frequency sounds,
sensorineural deafness Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...
. This becomes more severe and affects lower frequencies too. Hearing loss is not usually complete in Alport syndrome; good communication is almost always possible with the use of hearing aids.


Eye changes

Various eye abnormalities are often seen including lenticonus,
keratoconus Keratoconus is an eye disorder in which the cornea, the transparent front part of the eye, gradually thins and bulges outward into a cone shape. This causes distorted vision, including blurry vision, double vision, increased nearsightedness, ...
,
cataract A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...
s and corneal erosion as well as retinal flecks in the
macula The macula (/ˈmakjʊlə/) or macula lutea is an oval-shaped pigmented area in the center of the retina of the human eye and in other animals. The macula in humans has a diameter of around and is subdivided into the umbo, foveola, foveal avas ...
and mid-periphery. These rarely threaten vision. Lenticonus (cone-shaped lens) can be treated by replacement of the lens, as for cataracts. Mild keratoconus can be managed with hard, scleral, piggy-back or other specialty medical
contact lenses Contact lenses, or simply contacts, are thin lens (optics), lenses placed directly on the surface of the Human eye, eyes. Contact lenses are ocular prosthetic devices used by over 150 million people worldwide, and they can be worn to correct ...
; progressive cases may be halted with corneal collagen cross-linking; and severe cases may require a
corneal transplant Corneal transplantation, also known as corneal grafting, is a surgical procedure where a damaged or diseased cornea is replaced by Corneal button, donated corneal tissue (the graft). When the entire cornea is replaced it is known as penetrating ...
. Macular abnormalities such as incomplete
foveal hypoplasia The ''fovea centralis'' is a small, central pit composed of closely packed cones in the eye. It is located in the center of the ''macula lutea'' of the retina. The ''fovea'' is responsible for sharp central vision (also called foveal vision), w ...
or staircase foveopathy are common in Alport syndrome. It may also be associated with
retinitis pigmentosa Retinitis pigmentosa (RP) is a member of a group of genetic disorders called inherited retinal dystrophy (IRD) that cause loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visua ...
.


Leiomyomatosis

Diffuse leiomyomatosis of the oesophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography (CT) scanning or magnetic resonance imaging (MRI).


Other abnormalities

Aortic dissection Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of agonizing ches ...
has been described very rarely in patients with early-onset disease.
Leiomyoma A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due ...
s, tumours of smooth muscle affecting the oesophagus and female genital tract, may occur in a rare overlap syndrome involving the adjacent ''COL4A5'' and ''COL4A6'' genes.


Pathophysiology

Alport syndrome is a relatively common
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
affecting around 1 in 5,000-10,000 children.


Genetics

Alport syndrome is caused by
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in ''COL''4A3, ''
COL4A4 Collagen alpha-4(IV) chain is a protein that in humans is encoded by the ''COL4A4'' gene. This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, ho ...
'', and ''
COL4A5 Collagen alpha-5(IV) chain is a protein that in humans is encoded by the ''COL4A5'' gene. This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated ...
'', three of six human genes involved in
basement membrane The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...
(type IV) collagen biosynthesis. Mutations in any of these genes prevent the proper production or assembly of the specialised
type IV collagen Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...
'345' network which is an important structural component of basement membranes in the
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
, inner
ear In vertebrates, an ear is the organ that enables hearing and (in mammals) body balance using the vestibular system. In humans, the ear is described as having three parts: the outer ear, the middle ear and the inner ear. The outer ear co ...
, and
eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...
. It is also found in other locations, including the alveoli of the lungs. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. Type IV collagen '112' type is found in both vertebrates and invertebrates and is the major isoform in most human basement membranes. When mutations prevent the formation of 345 type IV collagen network in the glomerulus, the 112 network, which is formed in fetal development but usually replaced by 345, persists into adult life.


Inheritance patterns

Alport syndrome can have different inheritance patterns depending on which specific mutation is present. * In most people with Alport syndrome (about 85%), the condition is inherited in an
X-linked Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...
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 chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
. 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 also be inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern if both copies of the ''COL4A3'' or ''COL4A4'' gene, located on
chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost ei ...
, 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
form are now usually categorized as other conditions. Notably, conditions associated with giant platelets and associated with mutations of '' MYH9'' are no longer considered to be Alport variants. However apparent autosomal dominant transmission of disease associated with mutations in ''COL4A3'' and ''COL4A4'' does occur. Clinical utility gene card for: Alport syndrome.


Diagnosis

The diagnosis can usually be made on a combination of clinical, family history, and biopsy criteria.


Biopsy of kidneys or skin

To be helpful, kidney biopsies need to be taken before the disease is too advanced. Changes in conventional (light) microscopy are not characteristic, and the possibility of other diagnoses, particularly
focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. This process damages the filtration function of the kidney, resulting in protein presence in the urine du ...
(FSGS), may be raised. Electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane (GBM), developing into areas of thinning and thickening, and finally into a complex appearance with apparent splitting, often described as a 'basketweave' appearance. Early or very localised changes on this spectrum are not diagnostic, but the later changes are considered diagnostic. Immunohistochemistry or immunofluorescence studies to identify the COL3-4-5 proteins in GBM can be helpful. However, these studies may be normal in some patients with Alport syndrome, especially milder variants. The skin contains type IV collagen in a '556' network. Skin biopsies have been used to show the absence of the ''COL4A5'' gene product, but these techniques are not straightforward, only apply to patients with severe ''COL4A5'' mutations, and are not widely available.
Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
is now a better alternative if kidney biopsy is not possible.


Family history

A family history of end-stage renal disease with hearing impairment is suggestive of Alport syndrome, but other conditions can cause this combination of abnormalities. Most can be distinguished by clinical features. The finding of haematuria in relatives is suggestive. While X-linked inheritance is the most common pattern, genetic testing is revealing that atypical presentations may be more common than currently thought.


Genetic testing

Genetic testing plays an increasingly important role in confirming the diagnosis where the clinical features do not amount to proof.


Other tests

The use of eye examinations for screening has been proposed. Other tests may include a urine or blood test.


Treatment


Kidney disease and kidney failure

In addition to measures for
chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
(CKD) of any cause, there is evidence that
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...
s can slow the deterioration of kidney function in Alport syndrome, delaying the need for dialysis or transplantation. The development of proteinuria has been recommended as an indication for commencing treatment. Once kidney failure has developed, patients usually do well on
dialysis Dialysis may refer to: * Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...
or with a
kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...
. Transplantation can rarely be associated with the formation of antibodies to type IV collagen in the donor kidney resulting in progressive graft failure as a result of
Goodpasture syndrome Goodpasture syndrome (GPS), also known as anti–glomerular basement membrane disease, is a Rare disease, rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs, glomeru ...
('Alport post-transplant anti-GBM disease').
Gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...
has been frequently discussed, but delivering it to the
podocyte Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...
s in the glomerulus that normally produce the type IV collagen in the glomerular basement membrane is challenging.


Hearing loss

It is not known whether ACE inhibitors or other treatments affect hearing loss. For those with classic Alport syndrome, hearing aids are often required in teenage or young adult years.


Prognosis

Studies of the life expectancy of patients with Alport syndrome are rare, but one 2012 study found that Alport patients receiving renal replacement therapy (dialysis or kidney transplantation) exhibited, on average, better survival compared with matched controls who had other kidney diseases (and who also received renal replacement therapy).


See also

* AMMECR1 * Samoyed hereditary glomerulopathy, a disease shown to be a model for Alport syndrome. * Fechtner syndrome *
Thin basement membrane disease Thin basement membrane disease (previously referred to as "benign familial hematuria") is, along with IgA nephropathy, the most common cause of hematuria without other symptoms. The only abnormal finding in this disease is a thinning of the basemen ...


References


External links


GeneReview/NIH/UW entry on Alport syndrome
{{DEFAULTSORT:Alport Syndrome Kidney diseases Collagen disease Syndromes affecting the kidneys Syndromes affecting hearing Syndromes with tumors Rare syndromes Diseases named after discoverers