Alport syndrome (AS) is a progressive, hereditary renal disease with cochlear and ocular involvement.

Epidemiology

• Incidence - 1/50,000 live births
• Age - presentation of the disease is variable with autosomal recessive AS having the earliest onset followed by the X-linked form; autosomal dominant AS usually has onset in middle age
• Sex - male predominance for X-linked AS but equal in autosomal dominant and recessive forms of AS

Inheritance

• Eighty percent X-linked, 15% autosomal recessive and <5% autosomal dominant
• Autosomal recessive and dominant AS is due to gene mutations in COL4A3 and COL4A4
• X-linked form is due to mutations in the COL4A5 gene
  • Three common mutations associated with adult AS - C1564S, L1649R, and R1677Q

Sequencing of COL4A5 identifies 80% of mutations in individuals of all ages with X-linked AS

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 AS reach end-stage renal disease by age 30 and 90% by age 40
  • Most individuals with autosomal recessive AS reach end-stage renal disease before age 30
  • End-stage renal disease is usually delayed until middle age in autosomal dominant AS
• Cochlear
  • Sensorineural hearing loss
    • Usually presents in late childhood in X-linked AS
    • 80% of males with X-linked AS have sensorineural deafness by age 40
    • Individuals with autosomal recessive AS have juvenile onset
    • Autosomal dominant AS 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 AS is critical when selecting eligible donors

Diagnosis

• Indications for testing
  • Unexplained hematuria or chronic kidney disease in men
  • Unexplained hematuria in women with a family history of chronic kidney disease
• Detailed family and personal history
• Audiologic and ophthalmologic exams - usually abnormal at presentation if symptomatic
• Histology
  • Immunohistochemical analysis of basement membrane type IV collagen expression using renal or skin biopsies
  • Electron microscopy of renal biopsy specimen
• Genetic testing
  • Diagnostic testing for symptomatic individuals
  • Presymptomatic and carrier testing for at-risk individuals who have previously diagnosed family members
  • Exclude diagnosis of AS in patients with thin basement membrane nephropathy

Differential Diagnosis

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