Alport Syndrome

 

Clinical Background

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

Epidemiology

  • Incidence – 1/50,000 live 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 of Alport syndrome

Inheritance

  • 80% X-linked, 15% autosomal recessive and <5% autosomal dominant
  • Autosomal recessive and dominant forms of Alport syndrome are due to gene mutations in COL4A3 and COL4A4
  • X-linked form is due to mutations in the COL4A5 gene
    • Sequencing of COL4A5 identifies 70% of mutations in affected females and 80% of mutations in affected males of all ages
    • Three common mutations, C1564S, L1649R, and R1677Q, are causative for 75% of adult (end stage renal disease after age 30) X-linked Alport syndrome
    • de novo mutations in 10-15% of affected males

Pathophysiology

  • Caused by defects in type IV collagen alpha chain
  • Leads to loss of type IV collagen in the basal lamina

Clinical Presentation

  • Renal
    • Microscopic hematuria and proteinuria, progressive renal insufficiency, end-stage renal disease
    • 60% of males with X-linked Alport syndrome reach end-stage renal disease by age 30 and 90% by age 40
    • Most individuals with autosomal recessive Alport syndrome reach end-stage renal disease before age 30
    • End-stage renal disease is usually delayed until middle age in autosomal dominant Alport syndrome
  • Cochlear
    • Sensorineural hearing loss
      • Usually presents in late childhood in X-linked Alport syndrome
      • 85% of males with X-linked Alport syndrome have sensorineural deafness by age 40
      • Individuals with autosomal recessive Alport syndrome have juvenile onset
      • Autosomal dominant Alport syndrome is associated with later adult onset
  • Ocular – lenticonus, maculopathy, corneal endothelial vesicles and recurrent corneal abrasions
    • Ocular lesions are uncommon in adult-onset disease

Treatment

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