Alport Syndrome

Diagnosis

Indications for Testing

  • Unexplained hematuria or chronic kidney disease – particularly in men
  • Unexplained hematuria in women with a family history of chronic kidney disease
  • Diagnostic presymptomatic or carrier testing in individuals with family history of Alport syndrome when the familial mutation is not known

Laboratory Testing

  • Diagnosis is established by combination of history and physical, audiologic exam, skin biopsy, and electromicroscopy of renal biopsy
  • COL4A5 genetic testing
    • Diagnostic testing for symptomatic individuals – COL4A5 sequencing and deletion/duplication testing is most sensitive
      • Sequencing alone is reasonable first-line test
    • Use to exclude diagnosis of Alport syndrome in patients with positive thin basement membrane nephropathy on biopsy
    • 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
  • Detailed family and personal history to rule out other possible diseases
  • Audiologic and ophthalmologic exams – may be abnormal

Histology

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

Differential Diagnosis

Screening

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

Clinical Background

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

Epidemiology

  • Incidence – varies from 1/5,000-50,000 births
  • Age – variable  
    • Autosomal recessive – earliest onset 
    • X-linked – next onset 
    • 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 recessive forms

Inheritance

  • Alport syndrome forms
    • 80% X-linked, 15-20% autosomal recessive or autosomal dominant
  • Autosomal recessive and dominant forms – mutations in the COL4A3 and COL4A4genes
  • X-linked form (end-stage renal disease after age 30) – mutations in the COL4A5 gene
    • Sequencing of COL4A5 identifies 70% of mutations in affected females and 80% of mutations in affected males regardless of age
    • 75% of adult X-linked Alport syndrome caused by mutations C1564S, L1649R, and R1677Q
    • 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
      • 95% of females and 100% of males have microscopic hematuria in early childhood
    • X-linked Alport syndrome – 60% of males have end-stage renal disease by age 30 and 90% by age 40
    • Autosomal recessive Alport syndrome – most individuals have end-stage renal disease before age 30
    • Autosomal dominant Alport syndrome – end-stage renal disease usually delayed until middle age
  • Cochlear
    • Sensorineural hearing loss
    • X-linked Alport syndrome – usually presents in late childhood  
      • 85% of males – sensorineural deafness by age 40
    • Autosomal recessive Alport syndrome – juvenile onset
    • Autosomal dominant Alport syndrome – associated with later adult onset
  • Ocular
    • Lenticonus, maculopathy, corneal endothelial vesicles, recurrent corneal abrasions
    • Ocular lesions uncommon in adult-onset disease
  • Gastrointestinal
    • Leiomyomatosis occasionally associated with Alport syndrome

Treatment

  • Early disease – antihypertensive drugs and angiotensin converting enzyme inhibitors
  • Renal transplantation for end-stage disease
    • Antibodies may redevelop, but repeat renal failure uncommon
    • Genetic testing of family members for Alport syndrome critical when selecting eligible donors

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

Confirm diagnosis of 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

Confirm diagnosis of X-linked Alport syndrome

Clinical sensitivity 80% in males and 70% in females

Rare diagnostic errors can occur due to prime 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 histologic diagnosis of Alport syndrome   

Stained and returned to client pathologist; if consultation 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 COL4A5 coding region deletions/duplications

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