Alport Syndrome

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Males with unexplained, persistent hematuria or chronic kidney disease
  • Females with unexplained, persistent hematuria or chronic kidney disease and a family history of adult chronic kidney disease
  • Diagnostic, presymptomatic, or carrier testing of individuals with a family history of X-linked Alport syndrome when the familial mutation is unknown

Laboratory Testing

  • Detailed patient and family history should be used to rule out other possible disease/syndrome as etiology for renal disease
  • Diagnosis is established by combination of the patient’s history and a physical exam, including a hearing test, skin biopsy specimen (immunohistochemical staining), and renal biopsy specimen (electron microscopy)

Genetic Testing

  • Diagnostic testing for symptomatic individuals – COL4A5 gene sequencing and deletion/duplication analysis is most sensitive
    • Sequencing alone – reasonable first-line test
  • Use to exclude diagnosis of Alport syndrome in patients with thin basement membrane nephropathy
  • Should not be used for prenatal testing
  • For more information on COL4A5 gene variants and their clinical significance, refer to ARUP's Alport syndrome and COL4A5 mutation database

Other Testing

  • Hearing and vision

Histology

  • Immunohistochemical analysis of collagen IV expression using renal or skin biopsy specimen
    • Skin biopsy specimens have a higher incidence of false negatives than renal biopsy specimens
  • Electron microscopy of renal biopsy specimen

Differential Diagnosis

  • Presymptomatic and carrier testing for at-risk individuals with previously diagnosed family members

Alport syndrome is a hereditary, progressive renal disease characterized by abnormalities in the glomerular basement membrane (GBM) and commonly associated with cochlear and/or ocular involvement.

Epidemiology

  • Incidence – 1/5,000-50,000 births
  • Age – variable
    • Autosomal recessive – earliest onset
    • X-linked – later onset, but earlier than autosomal dominant form
    • Autosomal dominant – onset in middle age
  • Sex
    • M>F for X-linked Alport syndrome – 100% penetrance in males, variable in females
    • M:F, equal for autosomal dominant and autosomal recessive forms

Inheritance

  • Autosomal recessive and autosomal dominant forms
    • Mutation(s) in the COL4A3 or COL4A4 gene
    • 15-20% of Alport syndrome
  • X-linked form (end-stage renal disease after 30 years)
    • Mutation(s) in the COL4A5 gene
    • 80% of Alport syndrome
    • Sequencing of COL4A5 gene identifies 70% of mutations in affected females and 80% of mutations in affected males regardless of age
    • 75% of adult X-linked Alport syndrome cases caused by mutations C1564S, L1649R, or R1677Q in the COL4A5 gene
  • De novo mutations in 10-15% of affected males

Pathophysiology

  • Type IV collagen laminin, nidogen, and perlecan – major proteins of GBM
  • Alport defects in alpha 5 chain of type IV collagen – leads to loss of type IV collagen in the basal lamina
  • Weakened basal lamina results in focal ruptures of glomerular capillary walls

Clinical Presentation

  • Renal
    • Microscopic hematuria and proteinuria, progressive renal insufficiency, end-stage renal disease (ESRD)
      • 95% of females and 100% of males have microscopic hematuria in early childhood
    • ESRD
      • X-linked – 60% of males have ESRD <30 years and 90% by 40 years
      • Autosomal recessive – most individuals have ESRD <30 years
      • Autosomal dominant – usually middle-age onset of ESRD
  • Cochlear
    • Sensorineural hearing loss
      • X-linked – usually presents in late childhood
        • 85% of males – sensorineural deafness by 40 years
      • Autosomal recessive – juvenile onset
      • Autosomal dominant – associated with later adult onset
  • Ocular
    • Lenticonus, maculopathy, corneal endothelial vesicles, recurrent corneal abrasions
    • Ocular lesions uncommon in adult-onset disease
  • Gastrointestinal and bronchopulmonary
    • Leiomyomatosis occasionally associated with Alport syndrome
    • Thoracic and abdominal aortic aneurysms

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Alport Syndrome, X-linked (COL4A5) Sequencing and Deletion/Duplication 2002398
Method: Polymerase Chain Reaction/ Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

Rare diagnostic errors can occur due to primer- or probe-site mutations

Not detected – deep intronic mutations, promotor mutations, COL4A3 and COL4A4 gene mutations associated with autosomal recessive or dominant disease, deletions/duplications in exons 8, 25, 40, 42, and 43 of the COLA5 gene

Alport Syndrome, X-linked (COL4A5) Sequencing 0051786
Method: Polymerase Chain Reaction/Sequencing

Limitations

Rare diagnostic errors can occur due to primer-site mutations

Not detected – deep intronic mutations, promotor mutations, COL4A3 and COL4A4 gene mutations associated with autosomal recessive or dominant disease, deletions/duplications in exons 8, 25, 40, 42, and 43 of the COLA5 gene

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Limitations

Mutations other than the one targeted will not be identified

Collagen IV by Immunohistochemistry 2003839
Method: Immunohistochemistry

Related Tests

General References

Beicht S, Strobl-Wildemann G, Rath S, Wachter O, Alberer M, Kaminsky E, Weber LT, Hinrichsen T, Klein H, Hoefele J. Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. Gene. 2013; 526(2): 474-7. PubMed

Haas M. Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis. Arch Pathol Lab Med. 2009; 133(2): 224-32. PubMed

Joosten H, Strunk AL M, Meijer S, Boers JE, Ariës MJ H, Abbes AP, Engel H, Beukhof JR. An aid to the diagnosis of genetic disorders underlying adult-onset renal failure: a literature review. Clin Nephrol. 2010; 73(6): 454-72. PubMed

Kashtan C. Alport Syndrome and Thin Basement Membrane Nephropathy. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Feb 2013; Accessed: Nov 2015]

Kashtan CE, Segal Y. Genetic disorders of glomerular basement membranes. Nephron Clin Pract. 2011; 118(1): c9-c18. PubMed

Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013; 24(3): 364-75. PubMed

Thorner PScott. Alport syndrome and thin basement membrane nephropathy. Nephron Clin Pract. 2007; 106(2): c82-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Crockett DK, Pont-Kingdon G, Gedge F, Sumner K, Seamons R, Lyon E. The Alport syndrome COL4A5 variant database. Hum Mutat. 2010; 31(8): E1652-7. PubMed

International Alport Mutation Consortium, Savige J, Ars E, Cotton RG H, Crockett D, Dagher H, Deltas C, Ding J, Flinter F, Pont-Kingdon G, Smaoui N, Torra R, Storey H. DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. Pediatr Nephrol. 2014; 29(6): 971-7. PubMed

Pont-Kingdon G, Sumner K, Gedge F, Miller C, Denison J, Gregory M, Lyon E. Molecular testing for adult type Alport syndrome. BMC Nephrol. 2009; 10: 38. PubMed

Medical Reviewers

Last Update: July 2016