Alport Syndrome

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. Genetic testing is used to confirm the diagnosis; COL4A5 variants are responsible for the majority of cases.

Diagnosis

Indications for Testing

  • X-linked Alport syndrome
    • Unexplained, persistent hematuria, proteinuria, or progressive decline in kidney function, with accompanying hearing loss and eye abnormalities (males)
    • Unexplained, persistent hematuria or chronic kidney disease and a family history of adult chronic kidney disease (females)
    • A family history of X-linked Alport syndrome (diagnostic, presymptomatic, or carrier testing)
  • Autosomal Alport syndrome
    • Unexplained, persistent hematuria, proteinuria, or progressive decline in kidney function, with accompanying hearing loss and eye abnormalities (males and females)

Criteria for Diagnosis

  • Clinical signs and symptoms
    • Changes in renal function (eg, hematuria, proteinuria)
    • Sensorineural hearing loss
    • Eye abnormalities
    • Thinning of basement membrane, as determined by renal biopsy with electron microscopy
    • Abnormalities in type IV collagen protein, as determined by immunohistochemical analysis of renal or skin biopsy and/or electron microscopy of renal biopsy
  • Family history of X-linked Alport syndrome
  • Confirmation by genetic testing

Laboratory Testing

  • Initial tests
    • Urinalysis         
      • Gross hemoglobinuria (often first clinical sign)
      • Proteinuria
    • Urine albumin
      • Often manifests after hematuria, prior to gross proteinuria
      • Testing for albuminuria should be used, rather than standard urinalysis
    • Urine protein quantification
      • Urine protein:creatinine ratio >0.2 mg/mg, or
      • Urinary protein excretion >4 mg/m2 per hour in timed collection (4 g over 24 hours)
    • Glomerular filtration rate
      • Standard calculations (Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) based on serum creatinine concentrations provide rough estimate of degree of kidney injury (chronic kidney disease [CKD] level 1 to 5)

Genetic Testing

  • Use to confirm diagnosis
    • COL4A5 gene sequencing and deletion/duplication analysis detects ~92% of COL4A5 variants, if present
      • COL4A5 variants are responsible for 80-85% of all Alport cases
      • The remaining 15-20% of Alport cases are due to variants in COL4A3 or COL4A4 genes (testing not offered at ARUP Laboratories)
    • Sequencing alone – reasonable first-line test
  • Use to exclude diagnosis of Alport syndrome in patients with thin basement membrane nephropathy
  • For more information on COL4A5 gene variants and their clinical significance, refer to ARUP's Alport syndrome and COL4A5 mutation database

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 is recommended for at-risk individuals with previously diagnosed family members.

Monitoring

Proteinuria and albuminuria testing should be initiated by age 1 in children at risk and repeated annually (Kashtan, 2013).

Background

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 – middle-age onset
  • 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
    • 15-20% of Alport syndrome cases
    • Pathogenic variant(s) in the COL4A3 or COL4A4 genes
  • X-linked form (end-stage renal disease [ESRD])
    • 80% of Alport syndrome cases
    • Pathogenic variant(s) in the COL4A5 gene
      • Sequencing of COL4A5 gene identifies >80% of pathogenic variants, regardless of age
  • X-linked heterozygotes (Kashtan, 2015)
    • Females with heterozygous COL4A5 variants
    • 95% appear to have hematuria, and there may be an increased lifetime risk of ESRD (probability of developing ESRD by age 60 is 30%)
    • Carriers are better described as “affected” (Savige, 2013) because they exhibit signs/symptoms
  • 10-15% of affected males have de novo variants

Pathophysiology

  • Type IV collagen α3, α4, α5 chains in kidney, cochlea, cornea, lens, and retina (Kashtan, 2015) exhibit defects
  • Defects lead to loss of type IV collagen in the basement membranes in these structures
  • In the kidney, weakened basal lamina results in focal rupture of glomerular capillary walls, resulting in scarring and progressive loss of function

Clinical Presentation

  • Renal
    • Hematuria and proteinuria, progressive renal insufficiency
      • 95% of females and 100% of males have microscopic hematuria in early childhood
    • ESRD
      • X linked
        • 60% of males have ESRD by 30 years and 90% have ESRD by 40 years (Kashtan, 2015)
        • 30% of females have ESRD by 60 years and 40% by 80 years (Kashtan, 2015)
      • Autosomal recessive – most individuals have ESRD before 30 years
      • Autosomal dominant – ESRD onset usually in middle age
  • Cochlear
    • Sensorineural hearing loss
      • X linked
        • Usually presents in late childhood
        • 85% of males have 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

ARUP Lab Tests

Primary Tests

Preferred genetic test for the detection of variants causing X-linked Alport syndrome

Diagnostic errors can occur due to rare sequence variations

Regulatory region variants and deep intronic variants will not be detected

Breakpoints of deletions/duplications will not be determined

Variants in genes other than COL4A5 are not evaluated

Deletions/duplications in exons 8, 25, 40, 42, and 43 of the COL4A5 gene will not be detected

Refer to Additional Technical Information document for further content

Acceptable genetic test for the detection of variants causing X-linked Alport syndrome

Diagnostic errors can occur due to rare sequence variations

Regulatory region and deep intronic variants will not be detected

Large deletions/duplications will not be detected in females

Variants in genes other than COL4A5 are not evaluated

Refer to Additional Technical Information document for further content

Consultation with a genetic counselor is advised

Useful when a pathogenic familial variant identifiable by sequencing is known

Aid in histological diagnosis of Alport syndrome   

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

Related Tests

Screen for various metabolic and kidney disorders

Detect early kidney disease in those with diabetes or other risk factors (eg, hypertension)

Panel to evaluate kidney function

Components include estimated glomerular filtration rate and urine albumin-creatinine ratio

Medical Experts

Contributor

Mao

Rong Mao, MD, FACMG

Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories

Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®