Alport’s syndrome

Classic Alport syndrome is inherited as an X-linked disorder.

The diagnosis of classic alport syndrome is based on X-linked inheritance of hematuria, sensorineural hearing loss, and lenticonus. The lenticonus together with hematuria is pathognomonic of classic Alport syndrome. 

The light microscopic findings are not characteristic in alport syndrome.
It will be normal in early years of life.

In older patients the changes seen are
1. Interstitial fibrosis,
2. Tubular atrophy,
3. Foam cells,
4. Segmental proliferative

The presence of interstitial foam cells has been considered as suggestive of Alport syndrome.

Ref: Dan Med Bull 2009;56:105-52

Typical electron microscopic changes in Alport syndrome:

1. Irregular thickening of the GBM of up to 4 or 5 times the normal
thickness,
2. Multi Lamellation of the lamina densa forming a “basket weave” pattern by inclusion of electron lucent areas, often containing round, dense granules, measuring 20-60 nm in diameter.
The earliest manifestation of the GBM is irregular thinning, and the extent and severity of thickening and multi lamellation increases with age.

These changes are often widespread especially in adults.

Ref: Dan Med Bull 2009; 56:105-52.

Deafness in alport syndrome:

1. High-tone sensorineural deafness occurs in 55-83% of males
2. Deafness is never congenital
3. Always accompanied by renal impairment
4. The hearing defect is clinically apparent at an average age of 11 years
5. Deafness is slowly progressive in childhood, but usually static in adult life

Audiometry reveals a bilateral reduction in sensitivity to tones in the 2,000-8,000 Hz range (high-tone)

Ref: Dan Med Bull 2009;56:105-52

The typical ophthalmological manifestations of the X-linked form of AS are

1. Dot-and-fleck retinopathy which occur in about 85% of affected adult males
And
2. Anterior lenticonus which occur in about v25%

Other additional ocular abnormalities are:
1. Recurrent corneal epithelial erosions
2. Posterior polymorphous corneal dystrophy
3. Posterior lenticonus
4. Macular holes
5. Retinal detachment
The ocular manifestations presents after renal abnormalities manifest
The dot-and-fleck retinopathy is not associated visual impairment or night blindness.

Ref: Dan Med Bull 2009;56:105-52

Diagnostic criteria for classical X-linked Alport syndrome.
At least three of the following four criteria must be fulfilled for a diagnosis
of Alport syndrome to be made clinically:

In a patient with microscopic hematuria

• A positive family history of hematuria with or without chronic
• renal failure.
• Typical ultrastructural GBM changes in a renal biopsy specimen.
• High-tone sensorineural deafness.
• Characteristic ophthalmological signs (lenticonus and/or macular
• flecks)

Ref: Dan Med Bull 2009; 56:105-52

Alport Syndrome (AS)
AS, X-linked- COL4A5
AS, autosomal recessive – COL4A3 and COL4A4
AS, autosomal dominant – COL4A3 and COL4A4
Benign familial hematuria – COL4A3 and COL4A4
AS with diffuse leiomyomatosis- COL4A5 and COL4A6

Ref: Dan Med Bull 2009; 56:105-52

Ans. is ‘a’ i.e., Foamy cells in interstitium

Histological characteristics of Alport – syndrome :

o Diffuse basement membrane thinning

o Foam cell in interstitium -4 Due to accumulation of neutral fat and mucopolysaccharide

o In advanced stage there is focal or global glomerulosclerosis.

o Vascular sclerosis

o Tubular atrophy

o Interstitial fibrosis

o The GBM shows irregular foci of thickening alternating with thinning, with pronounced splitting and lamination of the lamina densa, often with a distinctive basket – weave appearance.

Ans. is ‘a’ i.e., X linked

o Alport syndrome, when fully developed, is manifest by nephritis progressing to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and conical dystrophy.

o In the most common X-linked form, males express the full syndrome, and females are carriers in whom manifestations of disease are typically limited to hematuria.

Answer is A (Haematuria):

Most patients with Alports syndrome present with haematuria.

Alport syndrome is the ‘most common hereditary nephritis’ and it is characterized by haematuria – Harrison

Manifestations

– Renal manifestations

– Extrarenal manifestations

– Microscopic haematuria

– Sensorineural hearing loss

– Proteinuria (nephrotic range – 30%)

– Bilateral anterior lenticonus (15 to 30%)

–  Progressive renal insufficiency

– Recurrent corneal erosions

• Sensorineural deafness is primarily in the high tone range and can frequently be detected only by an audiogram.
• It is thus unlikely to be a presenting symptom. (It is usually non progressive)
• Proteinuria  by itself is again unlikely to be a presenting symptom.
• Olizuria would develop with progressively increasing renal insufficiency

Ans. is ‘b’ i.e., Autosomal dominant

• Autosomal dominant form also exist, but it is very rare. Thus, among the given options, it is the best answer. 
• Other three options are classical features of Alport’s syndrome.

Alport’s syndrome

• Alport’s syndrome is a type of hereditary nephritis characterized by –
• Glomerulonephritis progressing to chronic renal failure.
• Nerve deafness
• Eye defects    lenticonus, lens dislocation, posterior cataract, corneal dystrophy.
• Most commonly it is inherited as X-linked form.
• Rare autosomal – recessive and autosomal-dominant pedigrees also exist.
• Pathogenesis
• There is defective GBM synthesis because of production of abnormal collagen type IV underlies the renal lesions. 
• The defect is caused by mutation in the gene encoding a _c-chain of collagen type IV.