Generality
Alport syndrome is a rare hereditary genetic disorder that causes progressive loss of renal function, hearing loss and eye anomalies.
The cause of Alport syndrome is the mutation of genes involved in the production of a protein essential for the proper functioning of the kidneys, inner ear and eyes.
The diagnosis of Alport syndrome is based on physical examination, medical history, renal biopsy and a genetic test.
Currently, those suffering from Alport syndrome can only rely on symptomatic treatments, that is to say that they alleviate symptoms and postpone complications.
What is Alport Syndrome?
Alport syndrome is a rare genetic disorder that causes severe kidney problems, hearing loss and ocular abnormalities in those who carry them.
Alport syndrome is an inherited condition, where the term "hereditary" means "transmitted by one or both parents".
Epidemiology: how common is Alport syndrome?
According to statistics, one individual every 50, 000 would be born with Alport syndrome.
Synonyms
Due to its inherited nature and due to its renal involvement, Alport syndrome is also known, in the medical field, as hereditary nephritis .
Causes
The Alport syndrome is due to a mutation - that is an abnormal change - in one or more of the 3 human genes named with the letters COL4A3, COL4A4 and COL4A5 .
Where do the genes responsible for Alport syndrome reside?
While for the genes COL4A3 and COL4A4 the localization is for both the chromosome 2 of the human genome, for the gene COL4A5 it is on the chromosome X of the human genome.
Chromosome 2 is an autosomal chromosome ; the X chromosome, on the other hand, is a sex chromosome, which is a chromosome on which the sex of an individual depends.
The effects of mutations
Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.
When they are free of mutations (therefore in a healthy person), the 3 genes associated with Alport syndrome produce a fundamental protein component for the correct generation, processing and final structuring of type IV collagen that is prevalent in the kidneys, in the inner ear and in the eyes .
When instead they are victims of mutations, the 3 genes related to Alport syndrome lose the ability to generate the protein component indispensable for the realization of the aforementioned type IV collagen and this involves a tissue alteration of the kidneys, inner ear and eyes, with consequent dysfunctions by these organs.
Did you know that ...
The involvement of type IV collagen, by Alport syndrome, makes it a connective tissue disease, such as Ehlers Danlos syndrome or Marfan syndrome .
FISIOPATOLGIA: SOME ADDITIONAL DETAILS
The genes related to Alport syndrome contribute to the formation of a type IV collagen variant, which is essential for:
- The correct filtering action of the renal glomeruli against the blood.
Explanation. Located in the kidneys, the renal glomeruli are particular agglomerates of blood vessels, capable of removing (as if they were filters) the waste substances from the blood and creating urine.
With the alteration of their type IV collagen these kidney structures fail in their filtering and urine creation actions.
- The work of translation, made by the organ of Corti of the inner ear, of sound waves in nerve impulses.
Explanation. The organ of Corti is the structure of the inner ear responsible for transforming the sound waves perceived by the ear into "readable" and "interpretable" nerve signals from the human brain.
The alteration of type IV collagen combined with the organ of Corti undermines the process of translation of sound into the language of the human nervous system.
- Maintaining the right shape of the lens, the adequate stiffness of the cornea, and the normal color of the pigment epithelium of the retina.
Explanation. The shape of the crystalline lens and the rigidity of the cornea are indispensable for visual function and ocular health (the color of the pigment epithelium of the retina, on the other hand, seems to have no importance in these areas).
The presence in the eyes of an altered type IV collagen modifies the shape of the crystalline lens, the corneal rigidity and the color of the retinal pigment epithelium.
All this information explains why the Alport syndrome is associated with a certain symptomatology.
Inheritance of Alport syndrome
To understand...
- Each human gene is present in two copies, called alleles, one of maternal origin and one of paternal origin.
- An inherited disease is autosomal dominant when, to occur, the mutation of only one copy of the gene that causes it is sufficient.
- An inherited disease is autosomal recessive when mutation of both copies of the gene that causes it is required to occur.
Alport syndrome presents 3 different models of inheritance .
According to the most common pattern of inheritance (80% of cases), Alport syndrome is a so-called hereditary disease linked to the X chromosome (such as haemophilia or color blindness), as it depends on the mutation of the COL4A5 gene located on the chromosome sexual X.
According to the second most common model of inheritance (approximately 10% of cases), the Alport syndrome behaves like a so-called autosomal recessive inherited disease, as due to its presence a specific mutation is needed in both alleles of one of the COL4A3 genes and COL4A4, located on chromosome 2.
Finally, according to the less common model of inheritance (approximately 5% of cases), Alport syndrome represents an example of an autosomal dominant inherited disease, since a specific mutation in one of the alleles of the COL4A3 and COL4A4 genes is sufficient for its manifestation .
ALPORT SYNDROME LINKED TO CHROMOSOME X
X-linked Alport syndrome has its worst effects in male subjects.
This phenomenon is related to the sexual chromosome set that characterizes men and women; in the woman, in fact, there are two X chromosomes, which, in the presence of a mutation against one of the two, help each other (the healthy one compensates, more or less effectively, for the faults of the changed one); in humans, however, there is only one X chromosome (the other is a sex chromosome Y), which, if subjected to mutations, cannot count on the support of any other chromosome with equal functions.
AUTOSOMIC RECESSIVE ALPORT SYNDROME
Alport syndrome with autosomal recessive behavior causes symptoms and similar signs in both men and women.
DOMINANT AUTOSOMIC ALPORT SYNDROME
The syndrome of Alport with autosomal dominant behavior affects males and females with the same severity.
Symptoms and Complications
Due to the lack of adequate type IV collagen in the kidneys, inner ear and eyes, Alport syndrome classically determines:
- The progressive and inexorable loss of kidney function,
- A decrease in hearing ability e
- Ocular abnormalities combined with visual deficits .
In some rare cases, Alport syndrome has such extensive effects that, to the consequences indicated above, it also adds widespread leiomyomatosis of the esophagus and tracheobronchial tree, and serious vascular problems ( aortic dissection and abdominal or thoracic aortic aneurysm ).
Loss of kidney function: symptoms
Premise: with the expression "progressive loss of kidney function", doctors intend that the kidneys and their internal structures (eg, renal glomeruli) are subject to a gradual decrease in their filtering capacity and urine production.
In the presence of Alport syndrome, the symptoms related to the loss of renal function consist mainly of hematuria, that is blood in the urine, and proteinuria, that is the presence of protein in the urine.
Hematuria is a fairly early symptom, in the sense that, in subjects with Alport syndrome, it tends to appear at a young age; in most cases, its recognition is only possible through the microscope ( microscopic hematuria ).
In contrast, proteinuria is a later symptom, that is, that appears when Alport syndrome is in a more advanced stage.
Decreased hearing ability: details
At the hearing level, Alport syndrome causes partial deafness ; to be precise, it induces a sensorineural hearing loss, which prevents the patient from hearing the sounds at high frequencies (high frequency hearing loss ).
The development of hearing problems on the part of those suffering from Alport syndrome varies in relation to the gene subject to mutation and the type of inheritance; indeed:
- If the mutation resides in COL4A5, the males develop the hearing loss towards the end of childhood, while the females, in those rare circumstances in which they are interested, develop it in old age;
- If the mutation resides in COL4A4 or in COL4A3 and the disease is an autosomal recessive type, both the patient man and the woman patient complain of the first symptoms of a hearing loss in late childhood or early adolescence;
- If the mutation resides in COL4A4 or COL4A3 and the disease is autosomal dominant, both male and female patients develop sensorineural hearing loss in old age.
For reasons that are still unknown, Alport syndrome saves some patients from hearing problems; in other words, for unknown reasons, some of the carriers of Alport syndrome do not develop any sensorineural hearing loss.
Ocular anomalies and visual deficits: details
Observable only in a certain percentage of patients, the ocular anomalies induced by Alport syndrome are due to conditions such as: keratoconus, lenticonous, cataracts and presence of spots on the retinal macula .
Except for the presence of spots on the retinal macula, all these conditions just mentioned affect more or less profoundly the visual abilities of the patients.
Diffuse leiomyomatosis of the esophagus and tracheobronchial tree
The diffuse leiomyomatosis of the esophagus and that of the tracheobronchial tree are rare benign tumors which, in subjects with Alport syndrome, can cause:
- Dysphagia;
- Postprandial vomiting;
- Epigastric pain and retrosternal pain;
- Recurrent bronchitis;
- Dyspnoea;
- Cough;
- Screeching during the breath.
Complications
The main complication of Alport syndrome is the state of end-stage renal failure, resulting from the progressive and inexorable loss of renal function.
In medicine, the term "end-stage renal failure" indicates the end stage as well as the most serious stage of chronic renal failure, ie the condition in which the kidneys have lost all their functional capacity completely and definitively.
Responsible for very serious consequences (eg: hypertension, pulmonary edema, bone fragility, immunosuppression, damage to the nervous system, etc.), end-stage renal failure requires chronic treatment such as dialysis and is the most important indication for an operation surgical like kidney transplant .
OTHER COMPLICATIONS
Other possible complications of Alport syndrome, which also have a high mortality rate, are internal bleeding that follows the laceration of any aortic dissection or an eventual thoracic or abdominal aortic aneurysm.
Diagnosis
As a rule, for the diagnosis of Alport syndrome, doctors use information from:
- The physical examination .
- The anamnesis ;
- Renal biopsy ;
- A genetic test .
Physical examination
It is the medical observation of the symptoms and signs exhibited by the patient.
In a context of Alport syndrome, it reveals part of the kidney problems, hearing problems (if present) and ocular anomalies (if any).
history
It is the critical study of symptomatology through specific questions, combined with an examination of the patient's family history.
As part of the examination procedure that serves to recognize the Alport syndrome, the anamnesis allows the doctor to know the exact moment of the onset of the symptoms and to know if, in the family of the patient, some hereditary disease occurs.
Renal biopsy
It consists in the collection and laboratory analysis of a sample of renal cells.
In a context of Alport syndrome, it is useful for assessing the state of health of the kidneys and for ascertaining the absence of a functional type IV collagen.
Renal biopsy is an important step in the diagnosis of Alport syndrome, because, if timely, it allows the most appropriate therapy to be planned as soon as possible.
Genetic test
It is the DNA analysis aimed at detecting mutations of critical genes.
In a context of Alport syndrome, it represents the diagnostic confirmation test and the examination by which to establish the precise mutated gene and the type of inheritance.
Therapy
From Alport's syndrome it is impossible to cure ; however, those affected can rely on various symptomatic treatments, which allow to control the symptoms and postpone the onset of complications.
Did you know that ...
In order to be able to recover from an illness such as Alport's syndrome, it would be necessary to eliminate the genetic mutation or cancel its effects in such a way that type IV collagen is normal and functional.
Symptomatic therapy: what does it consist of?
The list of symptomatic treatments for the management of Alport syndrome includes:
- Pharmacological therapy based on ACE inhibitors ;
- The classic pharmacological therapies envisaged in the presence of chronic renal failure;
- Dialysis;
- Kidney transplantation;
- Use of a hearing aid ;
- Treatments for keratoconus, lenticonous and / or cataract.
ACE INHIBITORS
Normally indicated for the treatment of hypertension and some cardiovascular diseases, ACE inhibitors are used in the presence of Alport syndrome, by virtue of their demonstrated ability to slow down the progressive decline of renal function, typical of the aforementioned inherited disease.
Thanks to this ability, therefore, ACE inhibitors allow the postponement of renal failure and the need for important treatments such as dialysis or kidney transplantation.
For unknown reasons, in some individuals with Alport syndrome, ACE inhibitors are ineffective; this explains why doctors are looking for drugs with similar power.
PHARMACOLOGICAL THERAPIES FOR CHRONIC RENAL FAILURE
When Alport syndrome has resulted in chronic renal failure, there are several useful drugs, including:
- Medicines against hypertension (among these, include the already mentioned ACE inhibitors and ARBs, and diuretics);
- Calcium and vitamin D supplements (to protect bones from fractures);
- Sodium polystyrene sulfonate and analogues (to prevent the accumulation of potassium in the blood).
DIALYSIS AND KIDNEY TRANSPLANTATION
Dialysis is a treatment that artificially reproduces certain functions of the kidney, cleaning up the blood from excess waste products and water.
The kidney transplant, on the other hand, is the surgery to replace one or both kidneys with a healthy kidney, from a compatible donor (the donor may be non-living or living).
Both dialysis and kidney transplantation are indicated when Alport syndrome is in its most advanced stages, ie when there is end-stage renal failure.
HEARING AID
In the presence of Alport syndrome, the hearing aid is a remedy indicated for all those patients with partial deafness.
TREATMENT OF KERATOCON, LENTICON AND CATARACT
When Alport syndrome affects the eyes, causing keratoconus, lenticonous and / or cataracts, patients can rely on eye surgery, the results of which are more than satisfactory.
What medical figures does the symptomatic therapy of Alport syndrome involve?
The symptomatic treatment of Alport syndrome requires the coordinated intervention of several medical specialists, including: pediatricians, nephrologists, audiologists and ophthalmologists.
Prognosis
Alport syndrome has a different prognosis depending on the gene related to its presence; however, in general, it is never benevolent, since, incurability of the condition apart, each patient is destined to suffer the loss of renal function.
Prevention
Alport syndrome is an impossible condition to prevent .
