Causes and genetics

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes.

Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, and eye.

The 3 genetic forms of Alport syndrome are as follows:

• X- Linked Alport syndrome (XLAS) - The most common form (85%) that results from mutations in the encoding of the alpha-5 (IV) chain of type IV collagen
• Autosomal recessive Alport syndrome (ARAS) - Caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains and is responsible for approximately 10-15% of cases
• Autosomal dominant Alport syndrome (ADAS) - Rare form that is caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains

10 criteria for diagnosis of alports syndrome

• Family history of nephritis of unexplained haematuria in first degree relatives
• Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy.
• Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years.
• A mutation in COL4An (where n = 3, 4 or 5).
• Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.
• Widespread GBM ultrastructural abnormalities, in particular thickening, thinning and splitting.
• Ocular lesions including anterior lenticonus, posterior sub capsular cataract, posterior polymorphous dystrophy and retinal flecks.
• Gradual progression to ESRD in the index case of at least two family members.
• Macrothrombocytopenia or granulocytic inclusions.
• Diffuse leiomyomatosis of esophagus or female genitalia, or both.

Signs and symptoms

Renal manifestations

• Gross or microscopic haematuria is the most common and earliest manifestation of Alport syndrome.
• Proteinuria is usually absent in childhood but eventually develops in males with XLAS and in both males and females with ARAS.
• Hypertension is usually present in males with XLAS and in males and females with ARAS.

Hearing manifestations

• Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with Alport syndrome.
• Some families with Alport syndrome have severe nephropathy but normal hearing.
• Hearing loss is never present at birth. Usually, hearing loss becomes apparent by late childhood or early adolescence, generally before the onset of renal failure.
• Hearing impairment is always associated with renal involvement.

Ocular manifestations

• The most common ocular manifestation of patients with Alport syndrome, that is, dot-and-fleck retinopathy, occurs in approximately 85% of males with XLAS.
• Dot-and-fleck retinopathy is usually asymptomatic with no associated visual impairment or night blindness.
• Anterior lenticonus is the pathognomonic feature of Alport syndrome and manifests by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently. 
  
• Lenticonus occurs in approximately 25% of patients with XLAS and is not present at birth, but it worsens with increasing age.
• Posterior polymorphous corneal dystrophy is a rare ocular manifestation in patients with Alport syndrome.

Leiomyomatosis

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome.

AD- Alport syndrome

Clinical features confined to ADAS include bleeding tendency, macrothrombocytopenia, abnormalities of platelet aggregation (Epstein syndrome), and, occasionally, neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechner syndrome.

Complications

• Chronic renal failure
• Decrease or loss of vision
• End-stage renal disease
• Permanent deafness

Tests and diagnosis

• Urinalysis – for haematuria, and Proteinuria
• Renal function test
• Renal ultrasound
• Skin and renal biopsy
• Audiometry for nerve deafness
• Genetic screening for mutations in collagen

Treatment

Medical management

• ACE inhibitors or angiotensin-receptor blockers (enalapril, lisinopril, losartan, candesartan, and irbesartan) should be administered to patients with Alport syndrome who have proteinuria with or without hypertension.
• Help to reduce proteinuria by decreasing intraglomerular pressure; moreover, angiotensin II is a growth factor that is implicated in glomerular sclerosis.
• By inhibiting angiotensin II, these drugs have a potential role in slowing down glomerular sclerosis.

Gene therapy for Alport syndrome is being studied

Surgical care

• Renal transplantation is usually offered to patients with Alport syndrome who develop ESRD.
• The allograft survival rate in these patients is similar to patients with other renal diseases.
• Recurrent disease does not occur in the transplant; however, approximately 3-5% of patients with Alport syndrome who undergo transplant develop anti-GBM nephritis.
• In view of excellent graft survival rates and a very low incidence of anti-GBM disease, renal transplantation is not contraindicated in patients with Alport syndrome.
• Surgical repair of cataracts (cataract extraction), or repair of the anterior lenticonus in the eye is possible.

Prognosis

Approximately 90% of patients with Alport syndrome develop ESRD by age 40 years. Approximately 75% of patients younger than 30 years develop ESRD (ie, juvenile type).

The disease is consistently severe in males and is much less severe in females.

Women usually have a normal life span with no signs of the disease except for blood in the urine.

Rarely, women will have high blood pressure, swelling, and nerve deafness as a complication of pregnancy.