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Alport syndrome-Causes, Symptoms and treatment update on 2020

What is Alport syndrome-

Of the various diseases prevalent in children, Alport Syndrom is one such genetic disorder with a prevalence ratio of (1: 5000) or (1:10000). The disorder has quite a few characteristics such as glomerulonephritis, which is end-stage kidney disease and subsequent hearing loss.

It also has detrimental effects on the eyes, though significant damages to eyesight have not been observed, an exception to this case is the lens changes that occur to a person in his /her later stages of life. Chances are predominant in this case that the patient may have damages to his/her eyesight.

The universal factor of blood coming in urine is common in this case. As kidney disease progresses, Proteinuria becomes a common or prevalent symptom.

Discovery of the first symptoms of this disorder was done by physician Cecil A Alport in a British family way back in 1927.

It was also labeled as hereditary nephritis though this definition was later withdrawn as there were many cases of hereditary kidney disease and nephritis and this was not the only symptom that was associated with hereditary kidney disease.

It is quite surprising that Alport syndrome has an effect on seemingly different body parts which do not bear any interconnection between them, the prominently affected parts include ears, eyes, kidneys, etc. An inherited defect in Type iv collagen is the root cause of this disorder.

Type IV collagen is a structural material that is necessary for the normal functioning of different parts of the body. This material is found in abundance in ears, eyes, kidneys, which well explains the disorders caused to these body parts due to this syndrome.

Signs & Symptoms

The symptoms mentioned below pertains to the classical form of the disorder, which usually inflicts damage to patients in young adult or late childhood phase.

It is also been seen that some individuals develop this disease later in their lifetime which has milder mutations or carrier status. This lot of patients tend to show only limited features of the classical Alport syndrome.

Hematuria and proteinuria

The commonly prevalent feature of Alport Syndrome is traces of blood in urine which can be diagnosed by urine dipsticks and the problem occurs during early infancy. Episodes of visible haematuria may occur in young children.

As the disease progresses protein appearance in urine becomes visible. Protein appearance in urine is an indicative sign for the start of treatment with ACE inhibitors.

Hearing loss

Though the majority of patients are not affected hearing loss is observed in some patients with Alport syndrome. It has been found that patients with Alport syndrome have a fairly normal hearing at birth.

The progressive loss of hearing has been observed in affected patients, especially when there is substantial proteinuria but the kidney function is normal.

Instances of hearing loss are noted in some patients only when the kidney function has been lost. The early changes which characterize the situation are the significant reduction in the ability to hear high-frequency sounds or the term ‘high-tone hearing loss’ is apt for this description.

As the disease progresses this becomes more acute with patients' inability to hear low frequency sounds also.

The only respite is that there is no complete loss of hearing in Alport Syndrome and patients can maintain reasonable and good communication with the help of hearing aids.


Apart from the above-mentioned symptoms, some families with caltrop syndrome have shown signs of diffuse leiomyomatosis of the esophagus and apart from that, some have reportedly shown symptoms of the tracheobronchial tree.

The symptoms show a usual occurrence in late childhood inclusive of dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor.

The presence or confirmation of Leiomyomatosis is done by diagnostic techniques such as computerized tomography scan(CT Scan) or magnetic resonance imaging(MRI).

The diagnosis predominantly depends on the availability of such costly imaging techniques and proper medical guidance.

Eye Changes

This condition is also associated with various eye abnormalities of which lenticonus, keratoconus, cataracts are common and retinal flecks in the macula and mid-periphery can also be seen associated with this condition.

Loss of vision is a rare occurrence in this disorder. As far as the treatment of associated eye problems is concerned, Leticonus or Cone shaped lens can be treated by change or replacement of lens, as is done for cataracts.

Mild keratoconus is treated with piggyback, hard sclera or other specialty medical contact lenses. The eye cases which become progressive can be stopped by corneal collagen cross-linking and in more severe or acute cases, it may require corneal transplant surgery.

Other Abnormalities

A rare occurrence among other abnormalities associated with this disorder is Aortic dissection. Aortic dissection is seen in patients with early onset of the disease and generally not seen in later stages. Tumors of smooth muscle which have a direct impact on the esophagus and female genital tract and which are known as Leiomyomas may occur in a rare overlap syndrome which involves the adjacent COL4A5 and COL4A6 genes.



The mutations occurring in three of six human genes namely COL4A3, COL4A4, and COL4A5, which are located in the basement membrane and involved in collagen biosynthesis, are the causative factor in Alport syndrome.

Proper production or assembly of the specialized type IV collagen ‘345’ network is hampered by the gene mutations involving these three genes and it damages the important structural component of basement membranes in the kidney, inner ear and eye resulting in consequential impairment of the functions of these organs.

Basement membranes can also be found in other body parts such as alveoli of the lungs. The purpose of the basement membranes is to support cells in many tissues and the structures of the basement membranes are thin and sheet-like.

The collagen type which is found in both vertebrates and invertebrates is Type IV ‘112’ type and forms the major isoform in most human basement membranes.

Gene mutations prevent the formation of a 345 type IV collagen network in the glomerulus, it is replaced by the ‘112’ network which is formed in fetal development and persists into adult life.

Inheritance Patterns

Inheritance patterns associated with Alport syndrome depends on which specific mutation is present.
In about 85 percent of the cases with Alport syndrome, the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene.

If the gene involved in the disorder is located on the X chromosome, it is said to be an X-linked condition. In males possessing only one X chromosome, one altered copy of the COLA5 gene is enough to cause severe Alport syndrome, which predominantly explains the reason why most affected males eventually develop symptoms leading to kidney failure.

Females with two X chromosomes suffer from a mutation in one copy of the COLA5 gene which commonly results in blood in urine but most affected females do not develop chances of kidney failure.

Inheritance due to autosomal recessive patterns can also be attained in Alport syndrome if both copies of the COL4A3 or COL4A4 gene which is located on chromosome 2, have been mutated.

The parents of a child with an autosomal recessive disorder are not directly affected but they act as carriers of one copy of the altered gene.

Autosomal dominant forms that have been described in the past are no longer considered to be Alport variants. They have been categorized as other conditions.

The conditions associated with giant platelets and those associated with mutations of MYH9 are not any longer considered to be Alport variants.

Although diseases associated with mutations involving COL4A3 and COL4A4 which are autosomal dominant do occur and are apparently observed.


A combination of various factors such as clinical, biopsy criteria and family history can be used to diagnose this disease.

Biopsy of kidneys or skin

It is immensely helpful if kidney biopsies can be taken before the disease proceeds to an advanced stage. It cannot be diagnosed with changes in conventional or light microscopy and doesn’t show any significant characteristics with the help of an alight microscope.

The other possibilities for diagnosis include focal segmentation glomerulosclerosis(FSGS) which is helpful. “Basketweave” appearance is observed with the help of electron microscopy and it 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.

The early or local changes on this spectrum cannot be considered as to be of diagnostic value but the later changes are considered to be of a successful diagnosis.

 Other things that can be helpful are Immunohistochemistry or immunofluorescence studies which help to identify the COL3-4-5 proteins in GBM and have been found to be helpful.

In milder variants of patients with Alport syndrome, these techniques may show normal response.

Skin biopsies have shown the absence of the COL4A5 gene product because the skin contains type IV collagen in a ‘556’ network.

These techniques have also been found to be not straightforward and will apply only to patients with severe COL4A5 mutations and are not available widely. In the absence of a possible kidney biopsy, genetic testing is now considered to be a better alternative.

Family History

Family history can be traced for possible signs of Alport syndrome. A family history of endstage renal disease coupled with hearing impairment is a clear suggestive fact of Alport syndrome, but it is important to note that other conditions too are a causal factor of this type of combination of abnormalities.

Mostly it can be differentiated by clinical features associated with the patient's history. If any of the relatives have any findings of haematuria, it is suggestive of Alport syndrome.

The most common pattern is X-linked inheritance but genetic testings have revealed that atypical presentations can be more common that what is presently thought of.

Genetic Testing

An increasingly important role is being played by genetic testing in confirmation of the diagnosis where the clinical features have not been sufficiently able to prove the Alport syndrome.

The role of genetic testing has been sought to clear doubts with respect to the clinical features.
Other tests.

Eye examinations for the screening of Alport syndrome have been proposed in the category of other viable tests.


Kidney disease and renal failure

Among the various measures which include the measures for chronic kidney disease(CKD) of any cause, it has been found out that ACE inhibitors can reduce the deterioration or malfunctioning of kidney function in Alport syndrome, which can significantly delay the need for dialysis or transplantation.

Treatment should be commenced as soon as the development of proteinuria is seen and any further delay is not advisable.

Patients usually do well with dialysis or with a kidney transplant once the condition of kidney failure has developed.

There is a rare association of transplantation with the formation of antibodies to type IV collagen in the donor kidney which results in progressive graft failure as a result of Goodpasture syndrome.

Though there is considerable discussion regarding Gene therapy, yet delivering it to the podocytes in the glomerulus that normally produce the type IV collagen in the glomerular basement membrane remains a challenging aspect of this type of treatment.

Hearing loss

It is not well known or considerably proven fact that ACE inhibitors or other treatments can affect hearing loss.

Those persons who are infested with classic Alport syndrome do need to have hearing aids often in their teenage or young adult years.


Life expectancy studies on patients with Alport syndrome are rare and there are not sufficient statistical details about the same but a study which was conducted in the Year 2012 which comprised 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. However, since universal studies on the same phenomenon are absent nothing conclusive can be said about the variance analysis associated with kidney transplants and life expectancy.

Since the sample size of 456 is very small it is not reflective of the true traits of the problem.

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