Alport’s syndrome is a rare hereditary nephropathy occurring due to mutations to genes encoding type IV collagen.
Alport’s may demonstrate different inheritance patterns though it is most commonly X-linked due to mutations of COL4A5 on the X chromosome.
The disease affects the glomerular basement membrane (GBM) leading to nephritis. Other features may include sensorineural hearing loss and ocular defects.
Alport’s may arise from a number of mutations to genes responsible for type IV collagen.
It may occur due to mutations to alpha-3, alpha-4 and alpha-5 chains of type IV collagen. Type IV collagen is important to basement membranes and mutations lead to impaired function. This affects basement membranes in the kidneys (GBM), eyes and ears.
Inheritance may be X-linked (most common), autosomal dominant or autosomal recessive. Rarely autosomal digenic inheritance is seen.
The majority of patients are affected by the X-linked form. It occurs due to mutations of COL4A5. Female carriers (i.e. heterozygotes) of the X-linked form are not unaffected due to lyonisation, they have an increased risk of hypertension and renal impairment. Up to 20% will be affected by sensorineural hearing loss.
NOTE: Lyonisation refers to the process of inactivation of one of the X chromosomes on a cellular level in females.
Accounts for around 20-30% of cases. Occurs due to mutations to COL4A3 or COL4A4. Typically has a mild phenotype.
Accounts for around 15% of cases. Occurs due to mutations to COL4A3 or COL4A4, may be associated with parental consanguinity.
Alport’s syndrome leads to microscopic haematuria, progressive renal failure and hypertension.
The first identifiable sign is asymptomatic microscopic haematuria that manifests in childhood. Unless specifically screened for or episodes of macroscopic haematuria occur this is unlikely to be picked up.
As affected individuals grow up renal impairment and proteinuria develop. Renal impairment causes a secondary hypertension.
Bilateral sensorineural hearing loss, initially affecting high frequencies, is often seen.
There are a number of ocular pathologies seen in patients with Alport’s:
Patients may develop leiomyomas and arterial aneurysms amongst other manifestations.
The diagnosis of Alport’s can be confirmed with genetic testing or biopsy (of the skin or kidneys).
Molecular genetic testing can confirm the diagnosis of Alport’s syndrome and the underlying mutation type.
There are two tissue types that may be biopsied:
Kidney transplant offers a chance of ‘cure’ in patients with Alport’s.
Patients require lifelong care under a nephrologist. Regular monitoring of renal function, proteinuria and blood pressure is required amongst other investigations.
In patients with hypertension and proteinuria, ACE inhibitors are the preferred initial therapy. Genetic counselling should be offered to all patients (including prior to genetic testing).
Transplant offers a chance at a ‘cure’ in patients with chronic kidney disease. Patients typically respond well and it alleviates the need for dialysis.
Though Alport’s cannot recur in the transplant kidney, approximately 1-5% will develop anti-GBM disease.
Patients with sensorineural hearing loss or ocular pathology should be referred to audiology/ENT and ophthalmology. Interventions are typically supportive and may include hearing aids.
Patients with leiomyomas will occasionally require surgical resection.
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