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.


TERMINOLOGY


Abbreviations



  • Alport syndrome (AS)


Synonyms



  • Hereditary nephritis


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


Genetics



  • 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


Pathogenesis



  • 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


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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%


Treatment



  • None available to reverse


  • Transplantation for ESRD



    • Rarely, anti-GBM disease may develop post transplant


Prognosis



  • 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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunofluorescence



  • 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


DIFFERENTIAL DIAGNOSIS


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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