Alport syndrome is a genetic disorder that primarily affects the kidneys, ear and eyes. It is caused by mutations in genes responsible for producing type IV collagen, a crucial component of the basement membranes in these organs. The syndrome is characterized by progressive kidney disease, leading to chronic kidney failure, sensorineural hearing loss and various eye abnormalities such as lens deformities and retinal changes. The disorder is most commonly inherited in an X-linked pattern, affecting males more severely but can also be inherited in autosomal recessive or dominant forms.

 Here’s an overview:

Genetics and Pathophysiology

  • Type IV Collagen: Alport syndrome is caused by mutations in genes responsible for producing type IV collagen, an essential structural protein in the basement membranes of the kidneys, inner ear and eyes. The mutations lead to abnormal or deficient collagen which compromises the structural integrity and function of these organs.
  • Key Genes Involved:
    • COL4A5: Mutation in this gene leads to X-linked Alport syndrome, the most common form.
    • COL4A3 and COL4A4: Mutations in these genes cause the autosomal recessive and dominant forms of Alport syndrome.

Clinical Features

Kidney Involvement:

Hematuria: One of the earliest signs, often detected in childhood, is microscopic or gross hematuria (blood in urine).

Proteinuria: As the disease progresses, protein begins to leak into the urine, an indicator of worsening kidney function.

Chronic Kidney Disease (CKD): Over time, patients develop chronic kidney disease, which can progress to end-stage renal disease (ESRD), requiring dialysis or a kidney transplant.

Hearing Loss:

Hearing loss typically affects high frequencies first and usually begins in late childhood to early adolescence. The hearing loss is sensorineural, meaning it results from damage to the inner ear structures.

Eye Abnormalities:

Anterior Lenticonus: A hallmark ocular feature where the lens becomes conical, leading to distorted vision.

Retinal Abnormalities: Patients may develop retinal changes, such as fleck retinopathy which generally doesn’t affect vision but can be detected on an eye exam.

Corneal Erosion: Some patients may experience recurrent corneal erosions, causing pain and sensitivity to light.

Other Features:

Leiomyomatosis: In rare cases, some individuals with Alport syndrome, particularly in certain genetic subtypes, can develop leiomyomas (benign smooth muscle tumors) affecting the esophagus, trachea or genital tract.

Inheritance Patterns

  • X-linked Alport Syndrome (XLAS): In X-linked Alport syndrome, males typically experience more severe symptoms, including earlier onset of kidney failure, due to having only one X chromosome. Females, who have two X chromosomes, might have milder symptoms but can still experience significant kidney disease.
  • Autosomal Recessive Alport Syndrome (ARAS): Both parents must carry a mutated gene to pass this form on to their children. Affected individuals typically show symptoms similar to those with X-linked Alport syndrome.
  • Autosomal Dominant Alport Syndrome (ADAS): This form is less common and generally milder but affected individuals can still develop significant kidney and hearing issues.

Causes

Genetics: Alport syndrome is usually inherited in an X-linked manner meaning the mutated gene is located on the X chromosome. This pattern is the most common but there are also autosomal recessive and autosomal dominant forms.

Mutated Genes: The most commonly affected gene in X-linked Alport syndrome is COL4A5. Autosomal recessive and dominant forms typically involve mutations in COL4A3 or COL4A4.

Symptoms

Kidneys: Progressive kidney disease is a hallmark of Alport syndrome. It often begins with blood in the urine (hematuria) and can progress to proteinuria and eventually kidney failure.

Eyes: Patients may develop anterior lenticonus (a cone-shaped lens), retinal abnormalities and other eye issues that can lead to vision problems.

Ears: Hearing loss, particularly of high-frequency sounds is common and usually begins in childhood or adolescence.

Diagnosis

  • Clinical Examination: Diagnosis often begins with the observation of characteristic symptoms, especially in individuals with a family history of Alport syndrome.
  • Genetic Testing: This is the most definitive method for diagnosing Alport syndrome, as it identifies the specific mutations in the COL4A3, COL4A4 or COL4A5 genes.
  • Kidney Biopsy: A biopsy can reveal characteristic changes in the kidney’s glomerular basement membrane such as thinning, splitting or lamellation (layering).
  • Hearing and Vision Tests: Audiometry and ophthalmologic exams can help detect hearing loss and eye abnormalities respectively.

Prognosis

Males with X-linked Alport Syndrome: They often face a more severe course, with many developing End Stage of Renal Disease (ESRD)by their 20s or 30s. Hearing loss typically begins in adolescence and eye abnormalities can emerge at various points.

Females with X-linked Alport Syndrome: They generally experience a milder course but still require careful monitoring as they can develop significant kidney disease, particularly later in life.

Individuals with Autosomal Recessive or Dominant Forms: The severity can vary widely with some individuals experiencing a course similar to X-linked males while others may have a milder disease

Early diagnosis and intervention can help manage symptoms and improve quality of life for individuals with Alport syndrome. Genetic counseling is also recommended for affected families.

By– Ms. Shivani Sinha
Faculty Of Biochemistry