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

• Thin basement membrane nephropathy
• Other glomerular diseases
• Inherited hearing loss syndromes
• Fechtner-Epstein syndrome

Screening

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Alport Syndrome, X-Linked (COL4A5) 3 Mutations 0051710 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Confirm diagnosis of type X-linked Alport syndrome by examining three common COL4A5 mutations: C1564S (c.4992G>A), L1649R (c.4946T>G), and R1677Q  (c.5030G>A) Clinical sensitivity 75% for adult type X-linked Alport syndrome Analytical sensitivity and specificity are 99%
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