Alport Syndrome

Article Author:
Simon Watson
Article Editor:
Jeffrey Bush
Updated:
12/1/2017 1:43:51 PM
PubMed Link:
Alport Syndrome

Introduction

Alport syndrome is a genetic condition. It is identified by kidney disease, hearing loss, and eye abnormalities. Patients with Alport syndrome will experience progressive loss of kidney function. Almost all patients experience blood in their urine (hematuria) as well as proteinuria at symptom onset. The kidneys lose function as this condition progresses, resulting in kidney failure. In 1927, the syndrome of hereditary nephritis and deafness was described by a British physician, A. Cecil Alport. At the time, he observed that hematuria was the most common symptom and males were affected more often than females. After multiple families were described with similar problems, the disease was named Alport syndrome in 1961.

Etiology

In 80% of cases, Alport syndrome is inherited in an X-linked mode and caused by COL4A5 gene mutations, although other inheritance patterns exist. It may be inherited in either an autosomal recessive, or less commonly, an autosomal dominant manner caused by COL4A3 or COL4A4 gene mutations. By the time patients are in their teens, approximately 80% of men with the X-linked inherited form develop some degree of hearing loss.

Epidemiology

Alport syndrome affects about 1 in 50,000 newborns and males are more likely to be symptomatic than females. It is estimated that approximately 30,000 to 60,000 people in the United States (US) have the disorder. In the US, approximately 3% of children with chronic kidney disease and 0.2% of adults with end-stage renal disease (ESRD) will end up being diagnosed with Alport syndrome.

Pathophysiology

This COL4A5, COL4A3, and COL4A4 genes each encode part of a protein called type-IV collagen. This protein performs a vital function in the glomeruli of the kidney. Glomeruli are a cluster of capillaries around the end of a kidney tubule, where waste products are filtered from the blood. Mutations in these genes result in abnormal type-IV collagen in glomeruli, which causes improper filtering of the blood and allows blood and/or protein to pass into the urine. Gradual injury to the kidneys occurs, eventually leading to kidney failure in many people with Alport syndrome.

During late childhood, people with Alport syndrome also frequently develop sensorineural hearing loss caused by abnormalities of the inner ear. Hearing loss is never present at birth. Type-IV collagen is an important element of certain inner ear structures, especially the organ of Corti, involved with the conduction of sound waves into electrical signals for the brain. This can lead to abnormal inner ear function and subsequent hearing loss. Hearing loss becomes apparent in late childhood or early adolescence, usually before the onset of kidney failure. Hearing loss is less common and occurs later in life in women with X-linked Alport syndrome.

Multiple ocular findings can be present in patients with Alport syndrome. Affected individuals may also have malformed lenses in the eyes (anterior lenticonus) which causes the lens to become cone shaped. This irregular shape can lead to abnormal refraction and a decrease in visual acuity. This cannot be corrected with glasses or contact lenses.  Other abnormalities include aberrant coloration of the light-sensitive tissue in the retina. The retina develops abnormal pigmentary changes caused by the development of yellow or white flecks (dot-and-fleck retinopathy). Fortunately, these retinal changes do not appear to affect vision. The cornea may also be affected, although the specific abnormalities can vary. Recurrent corneal erosions may develop. These can cause eye pain, an abnormal sensitivity to light (photophobia), blurred vision, or a persistent foreign body sensation. Some individuals may experience a maculopathy, resulting in a hole in the macula, which can affect the central vision.

History and Physical

Individuals with Alport syndrome may develop symptoms of blood in the urine (hematuria), protein in the urine (proteinuria), edema, and hypertension. Symptoms may be different based on age, gender, and subtype of the disease. 

Evaluation

Initial diagnosis is made from clinical symptomatology and family history. Laboratory evaluation would include evaluation of renal function and urinalysis. Renal biopsy can be considered to look for the presence of abnormal type-IV collagen and abnormal glomeruli. Any patient with suspected Alport syndrome should be referred to ophthalmology for an eye exam as well as for a hearing test. Genetic testing can help establish the diagnosis and determine the inheritance pattern of an individual and their family members.

Treatment / Management

Unfortunately, there is not a specific treatment for Alport syndrome. Treatment is focused on symptom control and limiting the progression of the kidney disease. Options include ACE inhibitors (angiotensin-converting enzyme), Angiotensin receptor blockers for blood pressure, diuretics, and a salt-restricted diet. Although the listed treatment options may delay the onset of renal impairment, most people affected by Alports will ultimately require dialysis or a kidney transplant.

For those patients with ocular involvement, specifically anterior lenticonus, clear lens phacoemulsification with intraocular lens implantation can be considered. For patients with the concomitant hearing loss,  hearing aids are usually very effective. Of course, hearing loss is not impacted by kidney transplantation. As with any hereditary disease, psychosocial support for all of the affected family members is important.

Differential Diagnosis

Collagen IV related nephropathies include another disorder, closely related to Alport syndrome, called thin basement membrane nephropathy (TBMN).  In many individuals with the disorder, the same genes appear to be involved. Unlike those with Alport syndrome, few extra-renal findings are present, and symptoms are less severe, with progression to renal impairment rarely found. Differentiating these disease processes is a challenge, particularly in younger or female patients who are less likely to have other associated symptoms.

Prognosis

In the X-linked disease form, the most common type of Alport syndrome, about 50% of males require dialysis or kidney transplantation by age 25 years, and approximately 90% develop ESRD before age 40. Female patients with X-linked Alport syndrome have a better prognosis with about 12% developing end-stage renal disease (ESRD) by age 40. By age 60, this rate increases to about 30% and by 60 years of age, the rate of ESRD approaches 40%. In the female population, proteinuria and hearing loss are found to be risk factors for the progression to ESRD. In comparison, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20 while the autosomal dominant form of the disease typically has a delay in ESRD until middle age.