Alport's Syndrome

Synonym: Familial hereditary nephritis.
This is a familial nephritis first described in 1927 by Cecil Alport. It comprises haematuria, progressive renal failure, neurosensory hearing loss, and several ocular abnormalities. It is a progressive disease that ultimately leads to renal failure.

1:5000.¹ Males are more severely affected than females.
Inheritance is variable and may be either:

• X-linked dominant; (Xq22)²
• Autosomal recessive; approximately 15%
• Autosomal dominant; approximately 1%³

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.

The glomerular basement membrane (GBM) is a sheetlike structure between the capillary endothelial cells and the visceral epithelial cells of the renal glomerulus. The major constituent of the GBM is type IV collagen. AS is caused by defects in the genes encoding type IV collagen of the basement membrane.
Accumulation of types V and VI collagen chains in the 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.

There are other indeterminate types of Alport's Syndrome (AS) which are unclassifiable as types I-VI in the above scheme.
Alport's Syndrome associated with leiomyomatosis is another 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.

• Progressive haematuric nephritis.
• Sensorineural deafness; this feature is commonly observed, but not universally, 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.

• Nephritic Syndrome; oedema, hypertension, uraemia and oliguria.
• Nephrotic Syndrome; oedema, hypoalbuminaemia, hyperlipidaemia.
• End stage renal failure (ESRF).

It accounts for 3% ESRF in childhood,¹ and is the most common of several types of hereditary nephritis.

• Urinalysis; haematuria and proteinuria. Gross or microscopic haematuria is the most common and earliest sign in AS. Microscopic haematuria is seen in all males and in 95% of females. This condition is usually persistent in males, whereas it can be intermittent in females. Proteinuria usually worsens with age and can occur in the nephrotic range in up to 30% patients.
• Microscopy; glomerular pattern - damaged red blood cells (RBC) 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 shows glomerular basement membrane changes (splitting of lamina densa, lamellation)

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There is no definitive treatment for AS.

• Control blood pressure. This is usually present in males with X-linked AS and in males and females with autosomal recessive AS. Incidence and severity increases with age and degree of renal failure. Animal studies suggest that angiotensin-converting enzyme (ACE) inhibitors may reduce proteinuria and progression of renal disease.⁶ ACE inhibitors use should be considered in patients with AS (particularly children) who have proteinuria with or without hypertension.⁷
• Supportive management of renal failure; dialysis; transplantation. Renal transplantation is not contraindicated in patients with AS. Approximately 3-5% of patients with AS who undergo transplant develop anti-GBM nephritis. However graft survival rates are excellent.
• Arrange genetic counselling

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

• Prognosis depends on the type of inheritance, the sex of the patient, and the type of mutations in type IV collagen genes.
• Approximately 90% of patients with AS develop ESRD by age 40 years.¹
• Males usually require renal replacement therapy by age 20 to 30yrs.
• Females have a normal life span and subclinical hearing loss, but may develop haematuria during the stress of illness or pregnancy.