Alport syndrome

Overview

Alport syndrome is a rare inherited genetic disorder that primarily affects the kidneys but can also impact hearing and vision. It is characterized by progressive kidney disease (often leading to kidney failure), sensorineural hearing loss, and ocular abnormalities. The condition results from mutations in genes responsible for producing type IV collagen, a key structural protein in the basement membranes of the kidneys, ears, and eyes.

Alport syndrome affects approximately 1 in 5,000 to 10,000 individuals and typically begins in childhood or adolescence, though its severity and progression vary depending on the genetic type.

Causes

Alport syndrome is caused by mutations in genes that encode the type IV collagen alpha chains, most commonly:

• COL4A5 (X-linked form): Accounts for about 80% of cases; inherited in an X-linked pattern

• COL4A3 and COL4A4 (autosomal forms): Can be inherited in autosomal recessive or autosomal dominant patterns

These genes are essential for the structural integrity of the glomerular basement membrane in the kidneys, cochlea in the ears, and lens and retina in the eyes. When mutated, they lead to weakening of these membranes, causing organ dysfunction over time.

Symptoms

Symptoms of Alport syndrome may vary depending on the individual and the inheritance pattern, but commonly include:

Renal (Kidney) Involvement:

• Hematuria (blood in the urine), often the first sign in childhood

• Proteinuria (protein in urine) as disease progresses

• Progressive loss of kidney function

• End-stage kidney disease (usually by adolescence or early adulthood in severe cases)

Hearing Impairment:

• Sensorineural hearing loss, typically affecting high frequencies

• Often begins in late childhood or early teens

Ocular (Eye) Abnormalities:

• Anterior lenticonus (cone-shaped lens) – a hallmark of Alport syndrome

• Dot-and-fleck retinopathy (pigment changes in retina)

• Corneal opacities (less common)

Diagnosis

Diagnosis of Alport syndrome involves a combination of clinical evaluation, family history, laboratory tests, and genetic studies:

• Urinalysis: Detection of persistent hematuria and proteinuria

• Kidney biopsy: May show characteristic changes in the glomerular basement membrane under electron microscopy

• Hearing tests: To detect sensorineural hearing loss

• Ophthalmologic exam: For anterior lenticonus or retinal abnormalities

• Genetic testing: Confirms the diagnosis by identifying mutations in COL4A3, COL4A4, or COL4A5

Treatment

There is no cure for Alport syndrome, but treatment focuses on slowing disease progression and managing symptoms. Key strategies include:

Renal Management:

• ACE inhibitors or ARBs: Help reduce proteinuria and slow kidney damage

• Regular monitoring of kidney function

• Dialysis or kidney transplantation: Required in end-stage renal disease

Hearing Support:

• Routine audiological assessments

• Hearing aids for significant loss

Ophthalmologic Care:

• Regular eye exams to detect and manage lenticonus or retinal issues

Genetic Counseling:

• Important for affected families to understand inheritance, recurrence risk, and testing options

Prognosis

The prognosis of Alport syndrome depends on the type of mutation, gender, and presence of symptoms. Males with X-linked Alport syndrome typically have a more severe course, often progressing to kidney failure by their 20s or 30s. Females and those with autosomal dominant forms may have a milder progression, though kidney impairment can still occur.

With early diagnosis, use of ACE inhibitors, and appropriate management, disease progression can be slowed, and quality of life can be significantly improved. Advances in gene therapy and molecular treatments may offer future options for managing this condition.