Alport syndrome

Alport syndrome is a genetic disorder[1] affecting around 1 in

Alport syndrome
5,000-10,000 children[2], characterized by glomerulonephritis,
end-stage kidney disease, and hearing loss.[3] Alport syndrome can
also affect the eyes, though the changes do not usually affect sight,
except when changes to the lens occur in later life. Blood in urine
is universal. Proteinuria is a feature as kidney disease progresses.

The disorder was first identified in a British family by the

physician Cecil A. Alport in 1927.[4][5] 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'. Hearing loss effect of Alport syndrome in 13-
year-old boy
Alport syndrome is caused by an inherited defect in type IV
Specialty Medical genetics
collagen—a structural material that is needed for the normal
function of different parts of the body. 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.).

Contents
Signs and symptoms
Hematuria and proteinuria
Hearing loss
Leiomyomatosis
Eye changes
Other abnormalities
Pathophysiology
Genetics
Diagnosis
Biopsy of kidneys or skin
Family history
Genetic testing
Other tests
Treatment
Kidney disease and renal failure
Hearing loss
Prognosis
See also
References
External links
Signs and symptoms
These descriptions refer to 'classic' Alport syndrome, which usually causes significant disease from young adult or late childhood
life.[6] Some individuals, usually with milder mutations or 'carrier' status, develop disease later, or show only some of the features
of classic disease.

Hematuria and proteinuria

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 may occur. Protein begins to appear in urine as the disease progresses. This is now
regarded as an indication for treatment with ACE inhibitors.

Hearing loss
Alport syndrome can also cause hearing loss although some patients are not affected.[7] 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. 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, 'high-tone hearing loss'. 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.

Leiomyomatosis
Diffuse leiomyomatosis of the esophagus 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).[8]

Eye changes
Various eye abnormalities are often seen including lenticonus, keratoconus, cataracts as well as retinal flecks in the macula and
mid-periphery.[9] 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; progressive
cases may be halted with corneal collagen cross linking; and severe cases may require a corneal transplant.

Other abnormalities
Aortic dissection has been described very rarely in patients with early-onset disease.[6] Leiomyomas, 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.[10]

Pathophysiology

Genetics
Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, three of six human genes involved in basement
membrane (type IV) collagen biosynthesis. Mutations in any of these genes prevent the proper production or assembly of the
specialised type IV collagen '345' network which is an important structural component of basement membranes in the kidney,
inner ear, and eye. 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 pattern,[11] 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. 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 pattern if both copies of the COL4A3 or
COL4A4 gene, located on chromosome 2, 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.[12] 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.[13][14]
Clinical utility gene card for: Alport syndrome.[15]

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 on conventional (light) microscopy
are not characteristic, and the possibility of other diagnoses, particularly focal segmental glomerulosclerosis (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.

Skin contains type IV collagen in a '556' network. Skin biopsies have been used to show 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 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.[16]

Treatment

Kidney disease and renal failure

In addition to measures for chronic kidney disease (CKD) of any cause, there is evidence that ACE inhibitors can slow the
deterioration of kidney function in Alport syndrome, delaying the need for dialysis or transplantation.[17] The development of
proteinuria has been recommended as an indication for commencing treatment.[6]

Once kidney failure has developed, patients usually do well on dialysis or with a kidney transplant. 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 ('Alport post-transplant anti-GBM disease').[18][19]

Gene therapy has been frequently discussed, but delivering it to the podocytes in the glomerulus that normally produce the type
IV collagen in the glomerular basement membrane is challenging.[20]

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 of 456 male patients from across
Europe who received a kidney transplant found that they had somewhat increased life expectancy compared to matched controls
(the controls were "randomly selected from the same age, year, and modality categories").[21]

See also
AMMECR1
Samoyed hereditary glomerulopathy, a disease shown to be a model for Alport syndrome.[22]
Fechtner syndrome

References
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Syndrome. NCBI Gene Reviews. NCBI. Retrieved 17 February 2016.
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MF, Saus J, Antignac C, Smeets H, Gubler MC (2003). "X-linked Alport syndrome: natural history and genotype-
phenotype correlations in girls and women belonging to 195 families: a 'European Community Alport Syndrome
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H, Hachicha J (2006). "Autosomal dominant Alport's syndrome: study of a large Tunisian family" (http://www.sjkd
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COL4A4 gene". Kidney International. 65 (5): 1598–603. doi:10.1111/j.1523-1755.2004.00560.x (https://doi.org/1
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15. Hertz JM, Thomassen M, Storey H, Flinter F (2012). "Clinical utility gene card for: Alport syndrome" (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC3355248). European Journal of Human Genetics. 20 (6): 713.
doi:10.1038/ejhg.2011.237 (https://doi.org/10.1038%2Fejhg.2011.237). PMC 3355248 (https://www.ncbi.nlm.nih.
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16. Zhang KW, Colville D, Tan R, Jones C, Alexander SI, Fletcher J, Savige J (2008). "The use of ocular
abnormalities to diagnose X-linked Alport syndrome in children". Pediatric Nephrology. 23 (8): 1245–50.
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18. http://www.edren.org/pages/edreninfo/alport-syndrome.php
19. Name, Your. "EdRen - Edinburgh Royal Infirmary Renal Unit - Alport anti-GBM disease" (http://www.edren.org/pa
ges/edreninfo/alport-syndrome/alport-anti-gbm-disease.php). www.edren.org. Retrieved 2016-02-17.
20. Tryggvason K, Heikkilä P, Pettersson E, Tibell A, Thorner P (1997). "Can Alport syndrome be treated by gene
therapy?". Kidney International. 51 (5): 1493–9. doi:10.1038/ki.1997.205
(https://doi.org/10.1038%2Fki.1997.205). PMID 9150464 (https://www.ncbi.nlm.nih.gov/pubmed/9150464).
21. Temme, Johanna; Kramer, Anneke; Jager, Kitty J.; Lange, Katharina; Peters, Frederick; Müller, Gerhard-Anton;
Kramar, Reinhard; Heaf, James G.; Finne, Patrik (2012-12-01). "Outcomes of Male Patients with Alport
Syndrome Undergoing Renal Replacement Therapy" (http://cjasn.asnjournals.org/content/7/12/1969). Clinical
Journal of the American Society of Nephrology. 7 (12): 1969–1976. doi:10.2215/CJN.02190312 (https://doi.org/1
0.2215%2FCJN.02190312). ISSN 1555-9041 (https://www.worldcat.org/issn/1555-9041). PMC 3513741 (https://
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the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model".
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12595505).

This article incorporates public domain material from the United States National Library of Medicine document "Alport
syndrome" (https://ghr.nlm.nih.gov/condition/alport-syndrome) (Genetics Home Reference).

External links
GeneReview/NIH/UW entry on Alport syndrome (https://www.ncbi.nlm.
Classification ICD-10: Q87.8 (htt D
nih.gov/books/NBK1207/)
p://apps.who.int/cla
ssifications/icd10/br
owse/2016/en#/Q8
7.8) · ICD-9-CM:
759.89 (http://www.i
cd9data.com/getIC
D9Code.ashx?icd9
=759.89) · OMIM:
301050 (https://omi
m.org/entry/30105
0) 104200 (https://w
ww.omim.org/entry/
104200) 203780 (ht
tps://www.omim.or
g/entry/203780)
300195 (https://ww
w.omim.org/entry/3
00195) · MeSH: y
 D009394 y (https://
www.nlm.nih.gov/cg
i/mesh/2015/MB_cg
i?field=uid&term=D
009394) ·
DiseasesDB: 454
(http://www.disease
sdatabase.com/ddb
454.htm)
External MedlinePlus:
resources 000504 (https://ww
w.nlm.nih.gov/medli
neplus/ency/article/
000504.htm) ·
eMedicine:
med/110 (https://em
edicine.medscape.c
om/med/110-overvi
ew) · Patient UK:
Alport syndrome (ht
tps://patient.info/doc
tor/Alports-Syndrom
e) · GeneReviews:
Collagen IV-Related
Nephropathies
(Alport Syndrome
and Thin Basement
Membrane
Nephropathy) (http
s://www.ncbi.nlm.ni
h.gov/books/NBK12
07/)

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