Alport Syndrome

Alport Syndrome

Helen Liapis, MD

Joseph Gaut, MD, PhD

This kidney biopsy is from a 2-year-old boy who presented with proteinuria and a family history of X-linked Alport syndrome. The glomeruli show mild mesangial hypercellularity but are generally unremarkable.

This GBM segment in a boy with X-linked AS shows classic splitting and multilamellation (“basket weaving”), diagnostic of AS. The GBM also contains microparticles (“bread crumbs”) image.



  • Alport syndrome (AS)


  • Hereditary nephritis


  • Inherited glomerular disease secondary to mutations in the α3, α4, or α5 chains of type IV collagen, characterized by hematuria with hearing and eye abnormalities



  • COL4A5

    • Encodes α5 type IV collagen chain

    • X-linked form

      • Maps to chromosome Xq26-48

    • 85% of patients

      • 10-15% are de novo mutations

      • Female carriers may show disease depending on degree of mosaicism following lyonization

    • Mutations in adjacent COL4A6 gene result in diffuse leiomyomatosis

  • COL4A3

    • Encodes α3 type IV collagen chain

    • Autosomal recessive inheritance

      • Maps to chromosome 2q35-37

    • Autosomal dominant inheritance has been described but is rare

    • Disease may result from compound heterozygous or homozygous mutations

  • COL4A4

    • Encodes α4 type IV collagen chain

    • Autosomal recessive inheritance

      • Maps to chromosome 2q35-37

      • Heterozygote phenotype in thin basement membrane disease

    • Autosomal dominant inheritance has been described but is rare

    • Disease may result from compound heterozygous or homozygous mutations

  • Mutations of COL4A3 and COL4A4 account for 15% of AS patients


  • Normal GBM and distal TBM composed primarily of α3α4α5 trimeric collagen IV molecules

    • Deficiency in any 1 of the 3 chains leads to failure of formation of trimer and lack of other 2 chains

    • Bowman capsule contains α5α5α6 trimers, so expression of α5 not dependent on α3 or α4

    • α1α1α2 collagen IV chains, minimally present in subendothelial side of normal GBM, increased in AS

  • Mutations may result in protein misfolding, truncation, or absence of chain

    • Protein misfolding may lead to degradation of α3α4α5 type IV collagen

  • Nature of mutation in X-linked form influences age of onset of ESRD

    • Earliest onset (mean: 25 years) with truncating mutation

    • Intermediate onset (mean: 28 years) with splice site mutations

    • Later onset (mean: 37 years) with missense mutations

    • Mutation at 5′ end with earlier onset and more extrarenal manifestations



  • Incidence

    • 1:5,000-1:10,000 gene frequency in USA

    • Cause of 3% of ESRD in children

    • Associated with 1-2% of ESRD in Western countries

  • Age

    • X-linked males (hemizygotes)

      • Median: 33 years

    • X-linked female heterozygote carriers

      • Median: 37 years

    • Autosomal recessive

      • Median: 35 years

  • Ethnicity

    • None specific


  • Hematuria

    • Males typically present with gross hematuria

    • Females typically present with microscopic hematuria

    • Tends to be persistent in males and intermittent in females

    • Exacerbated by exercise, infection

  • Proteinuria, 1-2 g/d

    • Tends to develop later in disease course

    • Variable in X-linked AS

    • Common in autosomal recessive AS

      • Nephrotic syndrome in 30%

  • Sensorineural deafness

    • 90% of X-linked hemizygotes by age 40

    • 10% of X-linked heterozygotes by age 40

    • 67% of AR homozygotes before age 20

  • Hypertension

  • Eye abnormalities

    • Anterior lenticonus in ˜ 22% of patients < 25 years old

      • Pathognomonic of AS

      • Associated with rapid ESRD and hearing loss

    • Retinal flecks in ˜ 37% of patients < 25 years old

  • Leiomyomatosis (rare)

    • Mutations in COL4A6 and COL4A5

Laboratory Tests

  • Direct DNA sequencing or linkage analysis of COL4A3/A4/A5

  • Sensitivity of linkage analysis reported to be ˜ 60%


  • None available to reverse

  • Transplantation for ESRD

    • Rarely, anti-GBM disease may develop post transplant


  • X-linked males

    • 90% develop ESRD by age 40

  • X-linked carrier females

    • 12% develop ESRD by age 40

    • 60% develop ESRD by age 60

  • Autosomal recessive

    • Earlier and more rapid progression to ESRD

  • Autosomal dominant

    • Slower progression to ESRD


Histologic Features

  • Glomeruli

    • Early changes

      • Minimal changes

      • Mild mesangial hypercellularity

      • Small capillary diameter

      • Lamination of GBM hard to appreciate by light microscopy (LM)

    • Late changes

      • Focal segmental glomerulosclerosis (FSGS)

      • Global glomerulosclerosis

  • Interstitium and tubules

    • Interstitial fibrosis and tubular atrophy

    • Interstitial foamy macrophages

  • Vessels

    • Arteriosclerosis



  • No specific deposition of IgG, IgA, IgM, C3, C1q, kappa, or lambda

  • Segmental IgM and C3 typical in FSGS lesions

Electron Microscopy

  • Transmission

    • Multilamellation of the GBM lamina densa imparting a “basket weave” appearance

    • GBM microparticles or “bread crumbs” between laminations

    • Scalloping or “outpouching” of subepithelial surface of GBM

    • Irregular, variable GBM thickness, both thick and thin

    • Podocyte foot process effacement

    • Thin GBM measuring < 200 nm as only lesion

      • X-linked carrier females

      • Autosomal recessive carriers

      • Identical to thin basement membrane disease

      • Typically have milder clinical course

Demonstration of Collagen IV α Chains

  • Normal distribution

    • α5 is present in GBM, Bowman capsule (BC), distal TBM, collecting duct, and EBM of skin

    • α3 and α4 are normally expressed in GBM and basement membrane of distal tubules

    • α1 is abundant in GBM during development; decreases with normal GBM maturation

  • X-linked AS: Male

    • Absent α5(IV) staining in GBM, TBM, BC

    • Absent α3(IV) staining GBM, TBM

    • α1(IV) increased in GBM

  • X-linked AS: Female (heterozygote)

    • α5 and α3 expression may be preserved, decreased, or may show mosaic pattern in GBM and TBM

  • Autosomal recessive AS

    • Absent or severely decreased α3 and α5 staining in GBM and distal TBM

    • Preserved α5 staining in BC

  • Skin biopsy

    • EBM shows absent α5(IV) in males with X-linked AS

    • EBM shows mosaic α5(IV) staining in X-linked female heterozygotes

    • Normal α5(IV) in autosomal recessive AS


Thin Basement Membrane Disease

  • Normal collagen IV α3-5 staining pattern

  • Generally no structural damage to glomeruli

IgA Nephropathy

  • Mesangial IgA deposits

  • May have laminations of GBM as part of repair

Nail-Patella Syndrome

  • Type III collagen deposition in GBM by EM

    • Highlighted using phosphotungstic acid

  • Lamina densa electron-lucent areas on EM

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Alport Syndrome

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