Thin basement membrane disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Marufa Marium, M.B.B.S[2]

Thin basement membrane disease is usually caused by Heterozygous mutation in COL4A3 and COL4A4 gene in autosomal nonprogressive dominant pattern and heterozygous mutation in COL4A5 gene in X-chromosome may cause Thin basement membrane disease in female.. Alport syndrome, IgA nephropathy are among the most common to have association with Thin basement membrane disease. Gross pathology usually shows no distinctive features although Diffuse thinning of GBM in electron microscopy, Erythrocytes in between renal tubules ad bowman’s membrane, Minimal glomerular change or mesangial expansion on light microscopy are seen on microscopic histopathological analysis.

Physiology

Glomerular Basement membranee consists of laminin, Type 4 collagen, heparan sulfate proteoglycan and nidogen. Type 4 collagen is generally composed of Gly-X-Y amino acids rich in six alpha chains (alpha 1-6) that gives type 4 collagen a trimeric shape. The nascent GBM is made up of alpha 1 and 2 initially, then alpha 3-4 trimers are secreted after glomerular capillaries formation which becomes the major component of type 4 collagen and giving the GBM its stability.^[1]

Pathology

Heterozygous mutation in COL4A3 and COL4A4 gene is responsible for causing autosomal dominant pattern of 40-50% of Thin basement membrane disease in which people have defective alpha 3, alpha 4 , alpha 5 chains. ^[1] And heterozygous mutation in COL4A5 gene in X-chromosome may cause Thin basement membrane disease in female..

Genetics

Thin basement membrane disease is an inherited pattern disease affecting successive generations. It may be due to-

• Autosomal dominant inheritance due to heterozygous mutation in COL4A3 and COL4A4 gene
• Heterozygous mutation in COL4A5 gene in X-chromosome causing Thin basement membrane like disease in female
• ‘De novo‘ mutation.^[2]

Associated condition

Condition associated with Thin basement membrane disease include:

• Alport syndrome
  • Alport syndrome is caused by homozygous or heterozygous mutation of both or either COL4A3, COL4A4 and COL4A5 gene, thus 36% of cases of TBMD with COL4A3, COL4A4 mutation are shown to be associated with Alport syndrome.^[3]
• IgA nephropathy.

Gross pathology

On gross pathology, there is no distinctive features suggesting TBMD.

Microscopic pathology

On microscopic histopathological analysis, the followings features are noted:

• Erythrocytes in between renal tubules ad bowman’s membrane^[4]
• Diffuse thinning of GBM in electron microscopy in around 50% of population with TBMD.^[5] Occassionally, segmental thinning of GBM is present in TBMD.^[6]
• Minimal glomerular change or mesangial expansion may be present on light microscopy.^[7]

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