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Alport syndrome

This is part of Rare diseases.

Diagnosis: Alport syndrome

Synonyms: --

Innehåll


Date of publication: 2014-06-16
Version: 2.0

ICD 10 code

Q87.8A

The disease

Alport syndrome is a hereditary kidney disease, which also affects hearing and sometimes sight. The condition develops gradually and takes different forms. The most common and most severe form of Alport syndrome is hereditary nephritis with impaired hearing, which has an X chromosome-linked dominant inheritance pattern. It is this form which is described in this text.

Alport syndrome was described for the first time in 1902 by the American physician Robert Guthrie, but was named after the English doctor Arthur Cecil Alport. In 1927 he concluded that symptoms other than those associated with kidney disease could be linked to the syndrome.

Occurrence

In Sweden, Alport syndrome in all its forms occurs in between 15 and 20 individuals per 100,000, meaning that between 1,400 and 1,800 people in the country have the disease. Around 80 per cent of them, between 1,100 and 1,400 people, have the form associated with the pattern of inheritance linked to the X chromosome.

Cause

Alport syndrome is caused by a mutation in one of several genes which controls the production of the collagen IV protein.

Collagen is an important constituent of the body’s supportive tissue. It is found, for example, in skin, bone, tendons, cartilage, the cornea, the vitreous humour of the eye and in supportive tissue in the internal organs. There are different types of collagen and they are made up of at least six different chains of proteins (polypeptide chains).

In collagen IV, chains 1 and 2 are the main components, and chains 3, 4, 5 and 6 are less important. The gene which codes for chain 5 is often called the Alport gene (COL4A5) and it is located on the long arm of the X chromosome (Xq22). This is the gene responsible for 80 per cent of cases of Alport syndrome. Mutations in COL4A3 and COL4A4, both of which are found on chromosome 13, can also cause Alport syndrome.

The basement membrane is a thin membrane which separates the outer layer of cells that in turn separates skin and mucous membranes from interstitial fluid (or tissue fluid). Collagen IV is present in all types of basement membranes. In Alport syndrome the glomerular basement membrane, which envelopes the capillary network (glomeruli) in the kidneys, is damaged. (See figure below.)

 

Diagram: Cross-section of kidney

Figure: Cross-section of the kidney.

The most important function of the kidneys is to purify the blood and produce urine, but they also play an important role in the regulation of other functions such as balancing salt, fluid and calcium levels, regulating blood pressure and producing red blood cells. The glomerular basement membrane acts as a filter for the blood that passes through it. The urine produced at this stage is called primary urine. During its passage through the tubuli (a system of narrow tubes in the kidneys) primary urine changes and becomes more concentrated as substances vital to the body are re-absorbed, at the same time that the correct acid-base balance, and salt-liquid balance, are maintained. In Alport syndrome this process does not function correctly.

All individuals with the syndrome show characteristic changes in the glomerular basement membrane, which can be established with the help of an electron microscope. These changes lead to progressive kidney disease and the development of chronic kidney failure.

If collagen is defective, this can affect the basement membranes in the cochlea in the inner ear. Sound-sensitive hair cells are located on the membrane, and if they are damaged hearing is impaired. If the collagen protein is defective, the lens and retina of the eye can also be affected.

Heredity

Inheritance patterns vary. Generally, the pattern of inheritance is X-linked dominant, as the Alport gene (COL4A5) on the X chromosome has mutated. As women have two X chromosomes they inherit a milder form of the disease as the healthy X chromosome compensates to a large extent for the mutated gene on the other X chromosome. Men, who have only one X chromosome, do not experience this compensatory effect, so the disease develops fully.

A woman who carries the mutated gene has a 50 per cent chance of passing it on to her children. Boys who inherit the gene become seriously ill, while girls with one mutated gene develop the milder form, like their mothers. A man who has Alport syndrome always passes on the mutated gene to his daughters but never to his sons.

Figure: X-linked dominant inheritance via a female carrier with the disease

 

Figure: X-linked dominant inheritance via a male carrier with the disease

Sometimes chromosomes 2 or 13 have mutations on collagen genes (COL4A3 and COL4A4), in which case the syndrome is inherited via the autosomal recessive pattern (15 per cent). An autosomal dominant inheritance pattern can also occur (5 per cent). In both these forms, girls are just as severely affected as boys.

An autosomal recessive inheritance pattern means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

When the inheritance pattern of Alport disease is autosomal dominant this means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

Symptoms

The first sign of Alport syndrome is usually traces of blood in the urine, but in such small quantities that the urine does not turn red (microscopic haematuria). Haematuria is present at birth in all males with the condition and in most girls with the mutation but is first discovered in a special examination, for example following the diagnosis of someone in the family with the syndrome. Often protein is also found in the urine (proteinuria). As the disease progresses, blood is visible in the urine (macroscopic haematuria) especially in boys. In children and some women, blood in the urine is the only symptom of kidney disease. Loss of kidney function in boys with the disease is usually discovered first during puberty, when blood pressure is found to be elevated. Kidney function then deteriorates progressively, leading to kidney failure before the age of thirty. Reduced kidney function during childhood is very unusual.

Children may be born with impaired hearing, or hearing may deteriorate later in life. In the case of X chromosome-linked inheritance, boys’ hearing deteriorates progressively. The rate of deterioration varies, depending on the scale of the damage to the cochlea in the inner ear (sensorineural hearing loss). Loss of hearing is often most pronounced at high registers, (a frequency of between 3 000 and 6 000 Hz), which makes it difficult to distinguish speech and makes for increased sensitivity to loud noises. It can also affect the hearing range between high and low pitched sounds (middle frequency loss), which produces a characteristic hammock-like curve in an audiogram.

All newborns in Sweden are screened for hearing loss, which involves tests for otoacoustic emissions (OAE). If hearing impairment is indicated, additional tests are made and hearing impairment can usually be confirmed before the child is three months old. Congenital hearing loss is established by this examination. The degree of impairment varies greatly, as does the rate at which hearing deteriorates.

Men with Alport syndrome usually have a more severe form of kidney disease than women with the syndrome. Most women retain satisfactory kidney function until an advanced age. One third of women develop high blood pressure, usually after middle age, and a few develop kidney failure. The syndrome can increase the risk of pre-eclampsia, and kidney function may deteriorate during pregnancy.

Vision is affected in between 20 and 30 per cent of men with the X chromosome-linked form of Alport syndrome. Changes to the lens, such as conical projections of its anterior or posterior surfaces (lenticonus) and certain changes to the retina (retinal maculopathy) may occur, but they are not usually serious. Sometimes, however, they may cause cataracts.

All family members with the syndrome have the same genetic mutation, and the form of progression is similar. However, symptoms vary greatly between different families.

Diagnosis

Diagnosis is based on a specific combination of kidney disease and impaired hearing and is usually made initially when the individual is a teenager or older. In school age children, particularly in the case of boys who present with blood in the urine from no known cause, an audiogram should be carried out to check hearing.

An analysis of kidney tissue with an electron microscope is the most conclusive diagnostic method. Using a narrow needle a small sample is taken from the kidney (kidney biopsy). The test shows that the glomerular basement membrane is thickened and split, which confirms the diagnosis. Analysis of a skin sample (skin biopsy) is also a useful diagnostic test. An examination of the basement membrane of the epidermis using immunofluorescence can establish the absence of the polypeptide chain 5 in collagen type IV. The absence of polypeptide chain 5 confirms the diagnosis, but a kidney biopsy may still be necessary. The presence of polypeptide chain 5 in the basement membrane of the epidermis does not rule out the diagnosis.

DNA-based diagnosis is possible. To date, mutations in the Alport gene have been established in several hundred families around the world who have the inherited X chromosome-linked form of the syndrome. At the time of diagnosis it is important that the family is offered genetic counselling and the relevant tests. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is currently no medical treatment which will cure Alport syndrome.

Paediatric medical follow-up should be continued through childhood so that renal malfunction or hearing impairments can be detected as early as possible. Once it has been established that kidney function is impaired, the disease progresses and may lead to kidney failure. For this reason, children and adults with the disease should have early contact with a renal unit for systematic monitoring of the levels of blood salts (sodium, potassium, calcium, phosphate and bicarbonate), urine volume and blood pressure. Medication to lower blood pressure (ACE, inhibitor angiotensin converting enzyme) extends the time the kidneys can function.

Often dialysis is a temporary solution before a kidney transplant is carried out. There are two types of dialysis, haemodialysis and peritoneal dialysis. In haemodialysis, blood is pumped out of the body and is then passed through a machine which cleans it and removes impurities before returning it to the body. Treatment takes approximately four hours and most individuals require three treatments a week. In peritoneal dialysis, the blood never leaves the body, but it is cleaned by the dialysis fluid in the abdomen while it circulates through the patient’s own peritoneum. Peritoneal dialysis can be carried out in the patient’s home.

If an individual has the syndrome and has a kidney transplant there is a certain risk of developing antiglomerular basement membrane disease, which means that the transplanted kidney stops functioning. As patients with Alport syndrome lack elements of collagen IV, after a kidney transplant the immune system may treat the new, undamaged collagen IV as a foreign substance and produce antibodies to attack the elements of collagen IV which the body does not recognise (the Goodpasture antigens). The antibodies attach themselves to the basement membranes and damage them.

As most people with Alport syndrome experience progressive hearing loss, which in some becomes severe, hearing should be checked every year in childhood. People with the disease are affected from a young age. Regular contact with an ENT specialist is important. The hearing impairment team provides hearing aids and other auditory devices and offers support and treatment of a medical, educational, psychological, social and technical nature. The team includes teachers of the hearing impaired, psychologists and social workers. Today there are hearing aids for all degrees of hearing impairment.

If hearing loss leads to deafness in adulthood, a cochlear implant can restore hearing. A cochlear implant consists of a speech processor (a small computer) that is worn behind the ear and an implant under the skin, also located behind the ear. The cochlear implant converts sound into coded electrical impulses. Signals are transferred via electrical impulses to the auditory nerve, with the help of an electrode inserted in the cochlea, enabling the brain to interpret the signals as sound.

A thorough eye examination should be carried out when the diagnosis is made as changes to both the lens and retina may occur.

Growing up with both kidney disease and a hearing impairment can be very difficult for a young person, particularly as the diagnosis is often made when the individual is at a sensitive period in life. For this reason it is important to provide both psychological and social support for the whole family. Children and young people with the syndrome should also be offered continuous psychological support adapted to their age and maturity. It can also be beneficial to meet others with similar experiences.

Practical advice

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National and regional resources in Sweden

Specialists with knowledge and experience of the disease work at Swedish university hospitals. Kidney transplants are carried out in transplant clinics at Swedish university hospitals.

Resource personnel

Paediatric kidney specialists

Associate Professor Gianni Celsi, Uppsala University Children's Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: gianni.ennio.celsi@akademiska.se.

Associate Professor Sverker Hansson, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Kidney specialists

Associate Professor Peter Barany, Renal Clinic, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

ENT specialists

Professor Claes Möller, Audiology Clinic, University Hospital Örebro, SE-701 05 Örebro, Sweden. Tel: +46 19 602 10 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

The Swedish Kidney Association, Sturegatan 4 A, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 546 40 500, fax: +46 8 546 40 504, email: info@njurforbundet.se, www.njurforbundet.se.

HRF, The Swedish Association of the Hard of Hearing, Gävlegatan 16, Box 6605, SE-113 84 Stockholm, Sweden. Tel: +46 8 457 55 00, text telephone: +46 8 457 55 01, fax: +46 8 457 55 03, email: hrf@hrf.se, www.hrf.se.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

The Alport Syndrome Foundation, www.alportsyndrome.org.

Courses, exchanges of experience for personnel

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Research and development

International research is under way to identify genetic anomalies in families with Alport syndrome. Evaluations of existing medical treatments are also being carried out, as is research into whether anti-inflammatory medication can extend the period that a kidney is functional. Research is also being carried out to develop gene and stem cell therapies.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, "Mer hos oss" in the column on the right-hand side.

Alport syndrome. Information is available at the Centre for Rare Disorders, Oslo University Hospital HF, Rikshospitalet, PO Box 4950 Nydalen, NO-0424 Oslo, Norway. Tel: +47 23 07 53 40, fax: +47 23 07 53 50, email: sjeldnediagnoser@oslo-universitetssykehus.no, www.sjeldnediagnoser.no.

Literature

Alport AC. Hereditary familial congenital haemorrhagic nephritis. BMJ 1927; 1: 504-506.

Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B et al. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol 2013; 28: 5-11.

Kruegel J, Rubel D, Gross O. Alport syndrome—insights from basic and clinical research. Nat Rev Nephrol 2013; 9, 170-178.

Palmgren B, Jin Z, Rosenhall U, Duan U. Genterapi vid genetiskt orsakad hörselnedsättning. Läkartidningen 2008; 105: 2406-2410.

Persson U, Hertz JM, Wieslander J, Segelmark M. Alport syndrome in southern Sweden. Clin Nephrol 2005; 64: 85-90.

Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinte F. Expert Guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 2013; 24: 364-375.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: alport syndrome

Orphanet, europeisk databas
www.orpha.net
Sökord: alport syndrome

Gene and Disease
www.ncbi.nlm.nih.gov/books/NBK22183 
Sökord: alport syndrome

Genetics Home Reference
www.ghr.nlm.nih.gov 
Sökord: alport syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the original draft of this information material is Helmut Hecht, Jönköping.

The revision of the material was carried out by Associate Professor Gianni Celsi, Uppsala University Children's Hospital.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-06-16
Version: 2.0
Publication date of the Swedish version: 2013-12-18

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.