Alport Syndrome

Diagnosis

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

Screening

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

Clinical Background

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 age 30)
    • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Alport Syndrome, X-linked (COL4A5) Sequencing and Deletion/Duplication 2002398
Method: Polymerase Chain Reaction/ Sequencing/Multiplex Ligation-dependent Probe Amplification

Most sensitive genetic test for the detection of mutations causing X-linked Alport syndrome

Clinical sensitivity ~90% in males, >80% in females with X-linked Alport; ~80% in males, >70% in females for sequencing; 10% for deletion/duplication

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

Regulatory region and deep intronic mutations will not be detected

Breakpoints of deletions/duplications will not be determined

Mutations in genes other than COL4A5 are not evaluated

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

Acceptable first-line genetic test for the detection of mutations causing X-linked Alport syndrome

Clinical sensitivity 80% in males and 70% in females

Rare diagnostic errors can occur due to primer-site mutations

Regulatory and deep intronic mutations will not be detected

Large deletions/duplications will not be detected in females

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

Identify familial COL4A5 mutation

Must provide copy of laboratory report of affected family member detailing the specific mutation

Mutations other than the one targeted will not be identified

 
Collagen IV by Immunohistochemistry 2003839
Method: Immunohistochemistry

Aid in histological diagnosis of Alport syndrome   

Stained and returned to client pathologist; if consultation is required, contact anatomic pathology, surgical consult, or hematopathology

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Alport Syndrome, X-linked (COL4A5) Deletion/Duplication 2002394
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Detect large coding region deletions/duplications in COL4A5 gene

Clinical sensitivity 10% for X-linked Alport syndrome in males and females