Epidemiology

Alport's syndrome (AS) is rare; however, it does account for 3% of end-stage renal failure (ESRF) in childhood and is the most common of several types of hereditary nephritis.

Gene frequency is estimated at 1:5,000.^[2] Males are more severely affected than females.

Inheritance is variable and may be either:^[3]

• X-linked dominant - approximately 85%.
• Autosomal recessive - approximately 15%.
• Autosomal dominant - approximately 1%.

Different mutations in type IV collagen genes can lead to a broad spectrum of disease phenotypes.^[4] Up to 20% have no family history due to high spontaneous mutation rate.

Pathogenesis

• Alport's syndrome (AS) is caused by defects in type IV collagen, a major structural component of the basement membranes in the kidney, ear, and eye.
• X-linked AS is caused by defects in the COL4A5 gene which encodes collagen alpha-5 (IV) chain, located at Xq22.^[5]
• Autosomal recessive AS is caused by mutations in either the COL4A3 or the COL4A4 gene.
• Accumulation of types V and VI collagen chains in the glomerular basement membrane (GBM) occurs as a compensatory response.
• These proteins spread and result in GBM thickening and impairment of selectivity with subsequent glomerular sclerosis, interstitial fibrosis, and renal failure.

AS associated with leiomyomatosis is a distinct entity. Diffuse leiomyomatosis of the oesophagus and tracheobronchial tree has been reported in some families with AS. Symptoms usually appear in adolescence and include dyspnoea, cough, stridor, recurrent bronchitis, dysphagia, vomiting and epigastric pain. The diagnosis is made by CT or MRI scanning.

Clinical features

• Progressive haematuric nephritis. Microscopic haematuria is reported in almost 100% of patients with Alport's syndrome (AS). Proteinuria is found in 85-95% of patients.^[6]
• Sensorineural deafness: this feature is commonly, but not universally, observed in patients with AS. Hearing loss is never present at birth, but usually becomes apparent by late childhood or early adolescence, generally before the onset of renal failure.
• Ocular abnormalities: lens - cataracts, microspherophakia, posterior or anterior lenticonus. Anterior lenticonus is the pathognomonic feature of AS. It is a slow, progressive deterioration of vision. Patients need to change the prescription of their glasses frequently. There is no eye pain, redness, or night blindness.

A strong relationship has been demonstrated between mutations at the 5' end of the gene and younger age at onset of end-stage renal failure (ESRF), hearing loss and ocular changes.^[6]

Investigations

• Urinalysis:
  • Gross or microscopic haematuria is the most common and earliest sign in Alport's syndrome (AS).
  • The condition is usually persistent in males, whereas it can be intermittent in females.
  • Proteinuria usually worsens with age.
• Microscopy:
  • This shows a glomerular pattern of damaged red blood cells (RBCs) and RBC casts.
• Renal biopsy:
  • Light microscopy shows mesangial cell proliferation and capillary wall thickening, progressing to glomerular sclerosis and tubulo-interstitial changes.
• Electron microscopy:
  • This shows GBM changes including splitting of lamina densa and lamellation.
• Gingival biopsy:
  • Changes in gingival tissues have been reported as a consequence of AS and may prove to be be an alternative initial diagnostic tool.^[7]

Management

There is no definitive treatment for Alport's syndrome (AS).

Control hypertension

This is usually present in males with X-linked AS and in males and females with autosomal recessive AS. Incidence and severity increase with age and degree of kidney disease. Angiotensin-converting enzyme (ACE) inhibitors reduce proteinuria and progression of renal disease.^[8] They should be considered in patients with AS (particularly children) who have proteinuria with or without hypertension.^[9]

Supportive management of renal failure

This may include dialysis and transplantation. Renal transplantation is not contra-indicated in patients with AS. Approximately 1-5% of patients with AS who undergo transplant develop anti-GBM nephritis.^[5] However, graft survival rates are excellent.

Genetic counselling

Incomplete penetrance of AS in females must be considered; genetic tests may soon be available for gene-carrier status in most families.

Complications

• Nephritic syndrome: oedema, hypertension, uraemia and oliguria.
• Nephrotic syndrome: oedema, hypoalbuminaemia, hyperlipidaemia.
• End-stage renal failure (ESRF): occurs at an average age of 16-37 years.^[6]

Prognosis

Prognosis depends on the type of inheritance, the sex of the patient, and the type of mutations in type IV collagen genes.