BASICS

DESCRIPTION

• Alport syndrome is a genetic disease characterized by glomerulonephritis, sensorineural hearing loss, and ocular changes.

• Patients often progress to end-stage renal failure and high-tone deafness by age 40.

• Common ocular associations include a dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy.

• Less common ocular associations include other corneal dystrophies, ulceration, microcornea, arcus, iris atrophy, cataracts, spontaneous lens rupture, spherophakia, a poor macular reflex, fluorescein angiogram hyperfluorescence, electrooculogram and electroretinogram abnormalities, and retinal pigmentation.

EPIDEMIOLOGY

Prevalence

• 1 in 5000 people has one of the forms of Alport syndrome.

• Alport syndrome accounts for approximately 2.1% of pediatric patients with end-stage renal failure.

• Over 85% of Alport syndrome patients are male.

RISK FACTORS

Genetics

• Alport syndrome is usually X-linked recessive.

• Less common autosomal recessive and autosomal dominant forms exist.

• Patients typically harbor a mutation in one of the genes for type IV collagen.

– COL4A5 (most common)

– COL4A4

– COL4A3

GENERAL PREVENTION

Genetic counseling

PATHOPHYSIOLOGY

Type IV collagen is the major structural component of basement membranes found in the glomerulus, cochlea, cornea, and retina.

ETIOLOGY

Many different mutations involving disruption of tertiary and quaternary structure of type IV collagen cause Alport syndrome. The most common mutation involves a substitution for glycine in the a5(IV) chain of type IV collagen that results in a misshapen protein.

COMMONLY ASSOCIATED CONDITIONS

• Hematuria:

– Most common presenting symptom

• Proteinuria

• Nephrotic syndrome

• End-stage renal failure:

– Due to chronic glomerulonephritis

– Associated anemia and osteodystrophy

• Hypertension:

– Due to chronic renal failure

• High-frequency sensorineural hearing loss:

– Begins by late childhood or early adolescence

– Extends to low frequency as the disease progresses

• Myopia

• Posterior polymorphous corneal dystrophy

• Dot-and-fleck retinal dystrophy:

– Usually asymptomatic

• Anterior lenticonus:

– Highly suggestive of Alport syndrome once trauma has been excluded

• Other ocular conditions as mentioned above

• Diffuse leiomyomatosis of the esophagus and trachea

• Vulvar and clitoral leiomyomatosis in females

DIAGNOSIS

HISTORY

• Hematuria is the most common presenting symptom.

– Childhood microscopic hematuria

– Episodes of gross hematuria associated with upper respiratory infections

• Hearing loss

• Poor vision

• Family history of juvenile renal failure, hearing loss, or vision loss

PHYSICAL EXAM

• Hypertension

• Edema from nephrotic syndrome

• Evidence of known ophthalmic manifestations

DIAGNOSTIC TESTS & INTERPRETATION

Diagnostic Procedures/Other

• Urine analysis:

– Microscopic or gross hematuria

– Dysmorphic RBCs with casts

– Proteinuria

• Electrolytes, BUN, creatinine:

– Reflect level of renal insufficiency

• Renal ultrasound:

– Rule out other conditions

– Normal early in disease course, may show progressive atrophy

• High-frequency audiometry

• Ophthalmologic examination

• Renal biopsy

• Genetic analysis:

– Can diagnose the carrier state as well

Pathological Findings

Nonspecific renal histology. Electron microscopy, however, reveals a characteristic thickening of the glomerular basement membrane that is directly proportional to the patient’s age and severity of proteinuria.

DIFFERENTIAL DIAGNOSIS

• Dot-and-fleck retinopathy must be differentiated from other inherited retinopathies, hypertensive changes, choroidal infarcts, and vasculitic changes.

• Anterior lenticonus must be differentiated from age-related nuclear sclerosis.

• Differential diagnosis of posterior polymorphous corneal dystrophy includes Fuchs corneal dystrophy, congenital hereditary corneal dystrophy, Axenfeld-Rieger syndrome, and congenital glaucoma.

TREATMENT

ADDITIONAL TREATMENT

General Measures

• Address refractive error with glasses or contact lenses

• Cataract surgery for visually significant lenticular changes

• Complications from posterior polymorphous corneal dystrophy should be managed on an individual basis. Some patients are asymptomatic while others require corneal transplantation for severe visual impairment.

• Dot-and-fleck retinal changes are asymptomatic and do not require treatment.

• Kidney transplant or dialysis for renal failure

• Hearing aids for sensorineural hearing loss

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Ophthalmologist

• Nephrologist

• Audiologist

• Screen family members for microscopic hematuria

PATIENT EDUCATION

• The Alport Syndrome Foundation (www.alportsyndrome.org)

PROGNOSIS

• 90% of male patients with X-linked Alport syndrome develop renal failure and are deaf by age 40.

• Progression to renal failure and deafness in females is less likely.

• Visual impairment is variable.

COMPLICATIONS

• Visual loss

• Renal failure

• Sensorineural hearing loss

ADDITIONAL READING

• Govan JA. Ocular manifestations of Alport syndrome: A hereditary disorder of basement membranes. Br J Ophthalmol 1983;67:493–503.

• Colville DJ, Savige J. Alport syndrome: A review of the ocular manifestations. Ophthalmic Genet 1997;18(4):161–173.

• Flinter F. Alport syndrome. J Med Genet 1997;34(4):326–330.

• Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 1998;9(9):1736–1750.

CODES

ICD9

• 362.10 Background retinopathy, unspecified

• 743.36 Congenital anomalies of lens shape

• 759.89 Other specified congenital anomalies

CLINICAL PEARLS

• Anterior lenticonus and posterior polymorphic corneal dystrophy are highly suggestive of Alport syndrome.

• Patients with an established diagnosis of Alport syndrome should have regular ophthalmologic exams.

• Renal failure and sensorineural hearing loss are the most common associations.

• Hematuria is the most common presenting symptom.