Alport syndrome

Alport syndrome or hereditary nephritis is a group of diseases caused by mutations that cause defects in the glomerular basement membrane (GBM) of the kidney. It consists of a triad of nephritis, deafness and eye disorders. The deafness is of sensorineural type and the eye disorders include dot and fleck retinopathy, anterior lenticonus (lens protrusion) and posterior polymorphous corneal dystrophy.

Pathogenesis

The GBM of the reanl glomerulus is a sheet like structure mainly constituted by type IV collagen. This collagen is crucial for normal functioning of the glomerulus, the eye lens and the cochlea. Each molecule of type IV collagen is composed of 3 subunits called alpha chains which intertwine to form a triple helical structure. The alpha chains (alpha-1, 2, 3, 4, 5 and 6) are encoded by the genes, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6. The genes are located on different chromosomes and can undergo different mutations.

Genes and the chromosomes
Alpha chain Gene Chromosome
Alpha-1 COL4A1 13
Alpha-2 COL4A2 13
Alpha-3 COL4A3 2
Alpha-4 COL4A4 2
Alpha-5 COL4A5 x
Alpha-6 COL4A6 x

Alport syndrome is caused due to mutation in any one of these genes coding the alpha chains. The mutation will lead to defective heterotrimer assembly and production of a defective type IV collagen network resulting in the disease.

Clinical features

The inheritance is most commonly X-linked and as a result of mutations of the COL4A5 gene which encodes the alpha 5 chain of type IV collagen. Due to the X-linked nature of the disease males are more among the affected. The individuals usually present at an age of 5 to 20 years with gross or microscopic hematuria and proteinuria and in many cases overt renal failure occurs between 20 and 50 years of age. In few instances, a heterozygous defect in the alpha 3 or alpha 4 chains is associated with persistent, often familial hematuria and a benign course (benign familial hematuria or thin basement membrne lesion). Alport syndrome may be associated with ocular manifestations like dot and fleck retinopathy and sensorineural hearing loss. In certain families, leiomyomatosis of oesophagus and tracheobroncheal tree have been reported. Depending on the type and extent of mutations in type IV collagen genes, the disease can present with symptoms of varying intensities. For example, some of the affected people may present with minimal ocular and minimal hearing defects, but with a severe renal disease.

Morphology

Interstitial cells of kidney take up a foamy appearnce due to the accumulation of mucopolysaccharides. In severe cases, glomeruloscrelosis, vascular sclerosis and tubular atrophy can be seen. Under electron microscope, basement membrane has a 'basket-weave' apperance due to irregular thickening with pronounced splitting and lamination of the lamina densa of the renal glomerulus.

Differential diagnosis

Other conditions which can mimic Alport syndrome are
  • IgA nephropathy
  • Pulmonary renal syndrome

Investigations

  • Urine analysis for detecting hematuria and proteinura.
  • Renal ultrasound scan.
  • Genetic analysis for detecting mutation of COL4A5 genecan be done.
  • Audiometry to detect sensorineural deafness.

Treatment

There is no definite cure available for Alport syndrome. The effects of gene therapy are being studied. The current treatment plans are mostly aimed at controlling progression of the disease and treating the symptoms. ACE Inhibitors are useful to treat the proteinuria. Dialysis and fluid restriction may become necessary if chronic renal failure sets in. Surgical repair of the eye defects like lenticonus and cataract can be performed with good results. The hearing loss on the other hand is likely to be permanent. Hearing aids along with development of new skills of conversation and use of sign languages will be helpful. And, to prevent new cases of this rare genetic disorder, genetic counseling may be recommended.



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