INTRODUCTION:

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies. It is caused by mutations in the type IV collagen gene that is responsible for producing certain proteins that are essential for the normal structure and function of the kidneys' filtering units, known as glomeruli.¹Mutations in the α3, α4, or α5 chain of type IV collagen lead to the loss or disruption of the α3-α4-α5(IV) network, and dysfunction of the basement membranes.²It can be inherited as an autosomal recessive or dominant pattern by mutations in the COL4A3 or COL4A4 gene.It also follows an X-linked pattern of inheritance. As a result, the condition primarily affects males, while females are usually carriers of the gene³mutation and may have milder symptoms or remain asymptomatic.

Over time, the kidneys become less efficient at filtering waste products from the blood, leading to proteinuria and eventually to chronic kidney disease (CKD)⁴. Eventually, kidney failure may develop, requiring dialysis or kidney transplantation as the last option for survival. Along with kidney problems, individuals also tend to experience hearing loss that can vary in severity and may be present from birth or develop later in life. Eye abnormalities, such as lens dislocation, cataracts, and retinopathy, can also occur in some cases.⁵

DEFINITION:

It is an inherited disorder that damages the tiny blood vessels in the kidneys. It is a genetically and phenotypically heterogeneous disorder of glomerular, cochlear, and ocular basement membranes that results from the mutations in the genes encoding alpha-3, alpha-4, and alpha-5 of type 4 collagen (COL4A3, COL4A4, COL4A5) or collagen 4 α345 network.⁶

Alport syndrome is a hereditary genetic disorder that is characterized by progressive kidney disease, sensorineural hearing loss, and ocular abnormalities.

TYPES OF ALPORT SYNDROME:

Classified based on the mode of inheritance and the specific genetic mutation involved, there are three main types of Alport syndrome:

1. X-linked Alport syndrome (XLAS)⁷: It is caused by mutations in the COL4A5 gene, located on the X chromosome[Fig: 1(a) & 1(b)]. Since males have one X chromosome, they are more severely affected by XLAS compared to females, who have two X chromosomes.

Fig. 1(a). X-linked Recessive, Carrier Mother.

Fig. 1(b): X-linked Recessive, Carrier Father.

2. Autosomal recessive Alport syndrome (ARAS)⁸:

It is caused by mutations in both copies of the COL4A3 or COL4A4 genes, which are located on non-sex chromosomes (autosomes)[Fig: 2]. But unlike XLAS, ARAS affects both males and females equally occurring sporadically in one generation and its severity can vary widely.

Fig. 2: Autosomal Recessive.

Fig. 3: Autosomal Dominant.

3. Autosomal dominant Alport syndrome (ADAS)⁹:

It is caused by mutations in the COL4A3 or COL4A4 genes, similar to ARAS[Fig: 3]. However, in ADAS, only one copy of the gene needs to be affected for the condition to manifest. ADAS can affect both males and females although the severity of symptoms can vary.

Alport syndrome can also occur due to de novo mutations, where a new genetic mutation arises spontaneously in an affected individual without a family history of the condition. Genetic testing is necessary to determine the specific type of Alport syndrome in each affected individual and their family members.

INCIDENCE¹⁰

· XLAS:1 in 5,000 to 10,000 males.

· ARAS: 1 in 50,000 to 100,000 individuals

· ADAS: 1 in 5,000 to50,000 individuals

CLINICAL MANIFESTATIONS¹¹

The clinical manifestations and symptoms of Alport syndrome can vary in severity and may differ depending on the specific genetic type (X-linked, autosomal recessive, or autosomal dominant). The main symptoms specific to the affected organ are:

1. Kidney Symptoms:

· Hematuria: Detection of grossor microscopic hematuria is the hallmark symptom of this condition. It often starts in childhood and can be intermittent or persistent.

· Proteinuria: Excretion of excessive amounts of protein in the urine. Persistent proteinuria can be an indication of kidney damage.

· Progressive Kidney Dysfunction: Over time, Alport syndrome can lead to progressive deterioration of kidney function, ultimately resulting in chronic kidney disease (CKD) or end-stage renal disease (ESRD)¹². ESRD implies that the kidneys are permanently damaged and without renal replacement therapy the chance of survival is meagre¹³.Fatigue, fluid retention, decreased urine output, elevated blood urea nitrogen (BUN), and creatinine levels are the symptoms of advanced kidney disease.

· High blood pressure, a symptom as well as a contributing factor of kidney failure.¹⁴

· Lower limb edema

· The Glomerular Basement Membrane¹⁵ (GBM) lesions under electron microscopy (irregular thinning, thickening with splitting, and lamellation)

2. Hearing Loss:

· Sensorineural Hearing Loss: Progressive sensorineural hearing lossusually starts in childhood or adolescence. High-frequency hearing loss is typical, although it can eventually affect all frequencies.

3. Eye Abnormalities:

· Anterior Lenticonus: The front part of the lens in the eye becomes thin and bulges forward. [Fig. 4.]This can affect vision and may require corrective lenses.

· Retinopathy: Involves abnormalities in the blood vessels of the retinaleading to vision problems, including decreased visual acuity.

Fig. 4. Anterior Lenticonus

Diagnostic Evaluation¹⁶

· Medical History Collection: Review of the individual's medical history (Symptoms of hematuria, proteinuria, hearing loss, and any family history of kidney disease or hearing problems).

· Physical Examination: A physical examination to assess for signs of kidney disease, such as high blood pressure or fluid retention.

· Urine Tests

Ø Urinalysis:To assess the presence of hematuria and proteinuriain the urine.

Ø Microscopic examination may be performed to confirm the presence of red blood cells and evaluate other urine characteristics.

Ø Urine Protein-to-Creatinine Ratio:To determine the severity of proteinuria.

· Blood Tests:Kidney Function Tests (KFT),Blood tests, including CBC, serum creatinine indicating the Glomerular Filtration Rate (GFR), and blood urea nitrogen (BUN) levels, are performed to assess kidney function.

· Auditory Evaluation: To evaluate the individual's hearing thresholds and assess the type and severity of hearing loss (Pure-tone audiometry and speech audiometry).

· Eye Examination: Eye abnormalities, such as anterior lenticonus and retinopathy, may be present in individuals with Alport syndrome.

· Genetic Testing:To determine the inheritance pattern, guide family counseling, and potentially identify affected family members.¹⁷This can be done through the genetic testing registry (GTR)¹⁸.

· Kidney Biopsy: To evaluate the structure and integrity of the kidney's filtration system.

Management of Alport Syndrome¹⁹

Treatmentsto manage symptoms and slow down the progression of the diseaseare:

· Medications:

Ø Ramipril: Inhibits angiotensin-converting enzyme and decreases angiotensin II formation and consequently decreases blood pressure.

Ø Prednisolone: Reduces inflammation

Ø Diuretics: Promotes urine production and helps manage fluid retention.

Ø Angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE)inhibitors²⁰: To control blood pressure and decrease proteinuria.

· Kidney replacement therapy in adolescence or early adulthood such as dialysis.

· Kidney transplantation: In advanced stages, when kidney function significantly declines, a kidney transplant may be necessary.

· Hearing aids and cochlear implants: To improve hearing abilities if hearing impairment becomes significant.

· Regular check-ups with a nephrologist and other specialists:To monitor kidney function, blood pressure, and overall health.

· Monitoring includes periodic blood tests, urine tests, and imaging studies to assess kidney function and detect any complications.

· Genetic counseling is an important action for updating individuals and families with information on the nature and inheritance of genetic disorders, and also its implications to enable them in making informed medical and personal decisions. The counseling consists of genetic risk assessment and the use of family history and genetic testing to get a clear picture of genetic status among family members.²¹

· Consult with a healthcare professional who specializes in Alport syndrome to receive the most up-to-date and appropriate treatment recommendations.

Complications of Alport Syndrome²²

The severity of complications can vary depending on the specific genetic mutation and individual factors.

· Chronic kidney disease (CKD)

· End-stage renal disease (ESRD)

· Cataracts and retinopathy

· Mental retardation

· Cardiovascular complications (hypertension, increased risk of cardiovascular disease, and aneurysm).

· Thrombotic microangiopathy (formation of small blood clots in the vessels of the kidneys and other organs), in rare cases.

· Diffuse Leiomyomatosis (a severe form of Alport syndrome) is characterized by the development of smooth muscle tumors, particularly in the esophagus, tracheobronchial tree, and female genital tract.

CONCLUSION:

Alport syndrome is a genetic kidney disorder that can lead to progressive kidney damage, hearing loss, and eye abnormalities. Based on various studies and reports, it is now clear that a variant in COL4A3, COL4A4, and COL4A5 is a risk factor for CKD. Within the first three decades of life, most Alport syndrome patients develop ESRD and need dialysis. Early diagnosis, regular monitoring, and appropriate management of symptoms can help improve outcomes and quality of life for individuals with the condition as there is currently no cure for the disease. The ideal drug for Alport syndrome should replace the abnormal GBM and could be administered for many years in young adults and children. Research and advancements in genetic therapies hold promise for potential future treatments.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 05.06.2023 Modified on 19.10.2023

Asian J. Nursing Education and Research. 2024; 14(1):85-89.

DOI: 10.52711/2349-2996.2024.00017