| Alport syndrome | |
| Effect of hearing loss from Alport syndrome in a 13-year-old boy | |
| Speciality | Medical genetics |
Alport syndrome
is a genetic disorder[1] affecting approximately 1 in 5,000–10,000 children,[2] glomerulonephritis, end-stage renal disease and hearing loss have been characterized.[3] Alport syndrome can also affect the eyes, although the changes usually do not affect vision unless changes to the lens occur later in life. Blood in urine is universal. Proteinuria is a sign of progression of kidney disease.
The disease was first discovered in a British family by a doctor. Cecil A. Alport in 1927[4][5] Alport syndrome was once also labeled hereditary nephritis
, but this is misleading because there are many other causes of hereditary kidney disease and nephritis.
Alport syndrome is caused by a hereditary defect in type IV collagen, a structural material necessary for the normal functioning of various parts of the body. Since type IV collagen is found in the ears, eyes, and kidneys, this explains why Alport syndrome affects various seemingly unrelated parts of the body (ears, eyes, kidneys, etc.).
Content
- 1 Signs and symptoms 1.1 Hematuria and proteinuria
- 1.2 Hearing loss
- 1.3 Leiomyomatosis
- 1.4 Eye changes
- 1.5 Other deviations
- 2.1 Genetics 2.1.1 Patterns of inheritance
- 3.1 Kidney or skin biopsy
- 4.1 Kidney diseases and kidney failure
Signs and symptoms
These descriptions refer to "classic" Alport syndrome, which usually causes serious illness in young adults or late childhood.[6] Some people, usually those with milder mutations or carrier status, develop the disease later or exhibit only some of the features of the classic disease.
Hematuria and proteinuria
Blood in the urine is a common feature of Alport syndrome from early childhood, which can be identified by urine dipsticks. In young children, episodes of visible (macroscopic) hematuria may occur. As the disease progresses, protein begins to appear in the urine. This is now considered an indication for treatment with ACE inhibitors.
Hearing loss
Alport syndrome can also cause hearing loss, although some patients are not affected.[7] Patients with Alport syndrome have normal hearing at birth. Hearing loss progresses in affected patients, usually to the point where renal function remains normal but there is significant proteinuria. However, some patients experience hearing loss only after loss of kidney function. Typically, early changes are characterized by a decrease in the ability to hear high-frequency sounds, “high-tone hearing loss.” This becomes more severe and affects lower frequencies as well. In Alport syndrome, hearing loss is usually not complete; good communication is almost always possible with the use of hearing aids. [8][ quote needed
]
Leiomyomatosis
Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually begin in late childhood and include dysphagia, postprandial vomiting, chest or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography (CT) or magnetic resonance imaging (MRI).[9]
Eye changes
Various ocular abnormalities are frequently observed, including: lenticonus, keratoconus, cataracts, and macular and midperipheral retinal spots.[10] They rarely threaten vision. Lenticone (cone-shaped lens) can be treated by replacing the lens, as with cataracts. Mild keratoconus can be treated with solid, scleral, combination, or other specialized medical treatments. contact lenses; progressive cases can be stopped by corneal collagen cross-linking; and in severe cases a corneal transplant may be required.
Other deviations
Aortic dissection is very rarely described in patients with early onset disease.[6] Leiomyomas, smooth muscle tumors affecting the esophagus and female genital tract, can occur in a rare overlap syndrome involving adjacent COL4A5
and
COL4A6
genes.[11]
Alport syndrome - treatment
Currently, it is not possible to cure Alport syndrome. Therapy is limited to controlling symptoms and stopping the progression of the disease. Depending on the degree of chronic renal failure, special supportive therapy is included; and at an advanced stage - complete replacement of damaged kidneys - so-called renal replacement therapy, such as dialysis.
a kidney transplant may be considered . However, due to the family burden of Alport syndrome (the possibility of latent forms of the disease in relatives), the choice of a kidney donor for transplantation is very careful. In case of elevated blood pressure, antihypertensive drugs are used.
Gene therapy techniques are in the experimental phase, providing hope for the possibility of treating abnormalities in the genetic material that cause Alport syndrome.
Pathophysiology
Genetics
Alport syndrome is caused by mutations in COL
4A3,
COL4A4
, and
COL4A5
, three of six human genes involved in basement membrane (type IV) collagen biosynthesis.
Mutations in any of these genes interfere with the proper production or assembly of the specialized type IV collagen "345" network, which is an important structural component of the basement membranes in the kidney, inner ear, and eye.[12] 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 "112" collagen is found in both vertebrates and invertebrates, and is the major isoform in most human basement membranes. When mutations prevent the formation of the 345 type IV collagen network in the glomerulus, the 112 network, which forms during fetal development but is usually replaced by 345, persists into adult life.[ citation needed
]
Inheritance patterns
Alport syndrome can have different patterns of inheritance depending on which specific mutation is present.
- For most people with Alport syndrome (about 85%), the disease runs in families. X-linked pattern[13] due to mutations in the COL4A5
gene.
A condition is considered X-linked if the gene involved in the disease is located on the X chromosome. In men who have only one X chromosome, one altered copy of the COL4A5
gene is enough to cause severe Alport syndrome, which explains why most affected men eventually develop kidney failure.
In women who have two X chromosomes, a mutation in one copy of the COL4A5
gene usually results in blood in the urine, but most affected women do not develop kidney failure. - Alport syndrome can also be inherited as an autosomal recessive pattern if both copies of the COL4A3
or
the COL4A4
gene, located on chromosome 2, have been mutated.[12]
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.[ citation needed
] - Previous descriptions of the autosomal dominant form are now generally classified as other conditions.[14] In particular, conditions associated with giant platelets and associated with MYH9
are no longer considered Alport variants.
However, apparent autosomal dominant transmission of the disease associated with mutations in COL4A3
and
COL4A4
does occur.[15][16]
Clinical useful gene map for: Alport syndrome.[17]
Pathophysiology[edit]
Genetics
Alport syndrome is caused by mutations in COL
4A3,
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 specialized 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.[ citation needed
]
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, due to mutations in the COL4A5
gene.
A condition is considered X-linked if the gene is 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 the most affected males will 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 the 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.[ citation needed
] - Past descriptions of an autosomal dominant 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.
Diagnostics
Diagnosis can usually be made based on a combination of clinical criteria, family history criteria, and biopsy.
Kidney or skin biopsy
Kidney biopsy should be helpful before the disease becomes too widespread. Changes on conventional (light) microscopy are uncommon, and the possibility of other diagnoses, especially focal segmental glomerulosclerosis (FSGS), may be increased. Electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane (GBM), to areas of thinning and thickening, and finally to a complex appearance with obvious clefting, often described as a "wicker basket" appearance. Early or very localized changes in this spectrum are not diagnostic, but later changes are considered diagnostic.[ citation needed
]
Immunohistochemical or immunofluorescence studies to identify COL3-4-5 proteins in GBM may be useful. However, these studies may be normal in some patients with Alport syndrome, especially in milder forms.
The skin contains type IV collagen in the 556 network. Skin biopsy was used to show absence of COL4A5
gene product, but these methods are not simple, apply only to patients with severe
COL4A5
mutations, and are not widely available.
Genetic testing is now the best alternative if kidney biopsy is not possible.[ citation needed
]
Family history
A family history of end-stage renal disease with hearing loss is suggestive of Alport syndrome, but other conditions may cause this combination of abnormalities. Most of them can be distinguished by clinical signs. The discovery of hematuria in relatives is suggestive.[ citation needed
]Although X-linked inheritance is the most common pattern, genetic testing suggests that atypical presentations may be more common than currently believed.
Genetic testing
Genetic testing is playing an increasingly important role in confirming a diagnosis when clinical signs are not proof.[ citation needed
]
Other tests
The use of eye examination for screening has been suggested.[18]
Features of the clinical picture and treatment of Alport syndrome in children
You can suspect the presence of a pathology in a baby immediately after its birth. Children have characteristic changes and deformations of the facial skull in the form of a cleft upper lip (cleft lip) and a funnel-shaped hard palate (cleft palate), increased head size, as well as a typical facial expression with a wandering gaze. Other mutations may manifest as hearing and vision impairment. Such a child does not even react to loud sounds and sudden movements of the environment, which is discovered even in the maternity hospital.
To eliminate external defects, young patients undergo plastic surgery. I had the opportunity to participate in suturing the upper lip of a child with such a problem. After surgery, a small scar remains, which fades over time and becomes almost invisible. Surgeries are performed within a few weeks after the birth of the child, which reduces the risk of secondary complications.
To prevent damage to kidney tissue, young patients are prescribed a special diet. Newborns and infants are breastfed or receive a formula that is most adapted to the composition of human milk. This eliminates the risk of developing immune deficiency. The main means for the treatment of symptomatic signs of the disease are introduced at 5–7 years of life (earlier - as needed) and practically do not differ from the treatment that an adult receives. To adapt blind and deaf children, society uses hearing aids and corrective surgeries. For the first few years, the child must attend special schools or receive additional training from a specialist in order to catch up with peers.
Care
Kidney disease and kidney failure
In addition to interventions for chronic kidney disease (CKD) of any cause, there is evidence that ACE inhibitors may slow the decline in kidney function in Alport syndrome, delaying the need for dialysis or transplantation.[19] The development of proteinuria is recommended as an indication for initiation of treatment.[6]
Once kidney failure develops, patients usually do well. dialysis or kidney transplantation. Transplantation may rarely be associated with the formation of antibodies to type IV collagen in the donor kidney, leading to progressive graft failure resulting in Goodpasture's syndrome ("Post-transplant Alport disease versus GBM").[20][21]
Gene therapy has often been discussed, but delivering it to glomerular podocytes, which normally produce type IV collagen in the glomerular basement membrane, is challenging.[22]
Hearing loss
It is not known whether ACE inhibitors or other treatments affect hearing loss. People with classic Alport syndrome often require hearing aids during adolescence or young adulthood.[ citation needed
]
Alport syndrome - complications
Symptoms of nephrotic syndrome, caused by excessive loss of protein from damaged glomeruli, appear later (at about 10-15 years of age) and affect half of patients. Impaired blood flow through damaged kidneys leads to the development of arterial hypertension (blood pressure > 140/90 mmHg in adults).
Chronic renal failure progresses over time , leading to severe impairment of kidney function (end-stage renal disease). In girls, if symptoms develop, it is transient hematuria, excessive protein loss from the kidneys (proteinuria) is less common, the disease is mild, and symptoms of severe kidney damage develop later in life (50-75 years).
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- Lagona E., Tsartsali L., Costaridou S., Skiatitu A., Georgaki E., Sociou F. (April 2008). "Skin biopsy for the diagnosis of Alport syndrome." Hippocracy
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UK Alport Group (25 July 2013).
"Information for the doctor on Alport syndrome." Rare
. Rare Kidney Disease Registry. Retrieved February 17, 2021. - Zhou J, Hertz JM, Tryggvason K (June 1992). "Mutation in the alpha 5 (IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular involvement: detection by denaturing gradient gel electrophoresis of a PCR product." American Journal of Human Genetics
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This article includes public domain material from the US National Library of Medicine document: "Alport syndrome." (Home Guide to Genetics)
