CORE Kidney

What is Alport syndrome?

Disease Overview

Alport syndrome is a genetically inherited condition characterized by kidney disease, sensorineural hearing loss, and ocular abnormalities. There are three modes of inheritance for Alport syndrome: X-linked inheritance caused by a gene mutation in the COL4A5 gene which accounts for approximately 80% of diagnoses, autosomal recessive inheritance by mutations in the COL4A3 or COL4A4 genes making up approximately 15% of diagnoses, and autosomal dominant inheritance by mutations in COL4A3 or COL4A4 genes which account for approximately 5% of diagnoses. All modes of inheritance for Alport syndrome damage the kidneys’ glomeruli, preventing the body from filtering excess fluid and waste.

Alport syndrome is categorized as a rare disease, affecting 30,000-60,000 people in the United States and approximately 1 out of every 50,000 newborns. Due to the prevalence of the X-linked mode of inheritance, Alport syndrome more severely affects the male population with 50% of males requiring dialysis or kidney transplantation by age 25 and 90% developing End-Stage Renal Disease (ESRD) before age 40. In females, 12% develop ESRD by age 40 and about 30% by age 60.

Symptoms

Kidneys

Microscopic hematuria: blood not directly visible in urine, but red blood cells present upon microscopic inspection. Earliest and most common symptom
Proteinuria: abnormal amounts of protein in urine
Abnormal urine color
Blood in urine that is visible during a cold or flu or exercise
Flank pain: pain between the upper abdomen and back, on one side of the body
Hypertension: high blood pressure
Edema: swelling near the eyes and in the lower extremities
Fatigue
Poor appetite
Excessive thirst

Ears

Hearing loss in both ears
- Common in males with X-linked inheritance by early teenage years
- With autosomal recessive inheritance, boys and girls have hearing loss during childhood
- With autosomal dominant inheritance, hearing loss occurs later in life
- Hearing loss usually occurs before kidney failure

Eyes

In those with X-linked Alport syndrome and autosomal recessive Alport syndrome:
- Abnormal shape of the lens, which can lead to a slow decline in vision as well as cataracts
- Corneal erosion in which there is damage to the outer layer of the covering of the eyeball
  - Pain
  - Itching
  - Redness of the eye
  - Blurred vision
- Dot-and-fleck Retinopathy (abnormal coloring of the retina)
- Macular hole in which there is thinning or a break in the macula
  - Blurred or distorted central vision

Symptoms may vary among individuals depending on gender, age, and mode of inheritance for Alport syndrome.

Causes: Genetics

Alport syndrome is a genetic disorder caused by mutations in the COL4A3, COL4A4, or COL4A5 genes. When functioning normally, these genes code for collagen IV, which is essential for the structure and function of the basement membrane in the glomeruli of the kidney, cochlea, and eye.

All males who develop Alport syndrome in an X-linked manner develop proteinuria and, eventually, progressive renal insufficiency, which leads to ESRD. Overall, an estimated 60% reach ESRD by age 30, and 90% by age 40. There is much more variability in the female population with symptoms ranging from isolated hematuria (the presence of blood in the urine without any other abnormalities or other signs of kidney problems) to ESRD. Approximately, 12% of females with X-linked Alport syndrome develop ESRD before age 40, increasing to 30% by age 60 and 40% by age 80. Because the disorder is X-linked, females who inherit one mutated and one normal X chromosome will have a mix of cells—some expressing the mutated gene and others expressing the functional gene. As a result, disease severity in females can vary, depending on the proportion of cells in which the mutated X chromosome is active.

X-Linked affected father inheritance diagram

In about 15% of cases, Alport syndrome is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the altered gene and are called carriers. Some carriers are unaffected, while others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria.

Diagram illustrating autosomal recessive inheritance in parents and children.

Alport syndrome is inherited in an autosomal dominant pattern in about 5%. With this inheritance pattern, there is typically a delay in the development of ESRD until middle age.

Diagram illustrating autosomal dominant inheritance pattern in parents and children.

Affected Populations

Alport syndrome impacts all races and ethnic populations as well as both males and females. Alport syndrome is categorized as a rare disease, affecting 30,000-60,000 people in the United States and approximately 1 out of every 50,000 newborns.

Diagnosis

Alport syndrome can be diagnosed by a healthcare professional through various methods of testing. A urine test may be conducted to determine if blood and/or protein is present in the urine, hearing tests and vision tests can indicate any abnormalities in vision or hearing, and a genetic test can confirm whether one has Alport syndrome and determine its mode of inheritance. A kidney biopsy may be performed as well. Laboratory blood testing may be conducted to measure levels of waste and protein in the blood, and to determine one’s glomerular filtration rate (GFR).

Therapies, Treatment, and Management

There are currently no specific and approved therapies for Alport syndrome, but clinical trials are underway. The standard of care currently is symptomatic management alongside traditional CKD-management methods to decrease the rate of decline in kidney function.

Since Alport syndrome is linked to CKD, measures can be taken to control CKD. These include ACEi (ACE inhibitors) and ARBs (Angiotensin II receptor blockers), which both help delay the progression of CKD and control hypertension. Just like Alport syndrome, CKD tends to be a silent disease, so early diagnosis is critical.

Flowchart outlining optimal care for chronic kidney disease (CKD) management.

The figure above shows optimal care for a CKD patient. ACEi and ARBs help delay the progression of CKD. Other measures to slow the progression of Alport syndrome include the use of diuretics and dietary modifications to decrease sodium intake. Dialysis or a kidney transplant may be necessary if kidney failure occurs as a result of Alport syndrome.

Alport Syndrome: What You Need to Know

Disclaimer: The UCLA Health System cannot guarantee the accuracy of such information. The information is provided without warranty or guarantee of any kind. Please speak to your Physician before making any changes.