Alport Syndrome

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Alport syndrome (AS), also referred to as hereditary nephritis, is an inherited progressive form of glomerular disease that is typically associated with sensorineural hearing loss and ocular abnormalities.
  • It is a primary basement membrane disorder with defects in one of several subunits of type IV collagen.

EPIDEMIOLOGY

  • AS accounts for up to 2% of pediatric end-stage kidney disease (ESKD) in the United States.
  • Affects an estimated 30,000 to 60,000 persons in the United States

RISK FACTORS

Genetics

Modes of inheritance:

  • X-linked dominant inheritance (XLAS)
    • Accounts for ~80% of affected patients
    • Mutations in the COL4A5 gene encoding the α-5(IV) collagen chain on the X chromosome
  • Autosomal recessive inheritance (ARAS)
    • Accounts for 10–15% of patients
    • Mutations in both alleles of COL4A3 or COL4A4 gene encoding the 3(IV) or 4(IV) chain, respectively
  • Autosomal dominant inheritance (ADAS)
    • Accounts for 5% of patients
    • Mutations in one allele of COL4A3 or COL4A4 gene encoding the 3(IV) or 4(IV) chain, respectively
  • Some families exhibit digenic inheritance due to transmission of variants or mutations in two of the three genes (COL4A3, COL4A4, COL4A5).

PATHOPHYSIOLOGY

  • Impaired production and deposition of collagen
  • 4 (a.k.a. Type IV collagen) alpha-3, alpha-4, and alpha-5 in the basement membrane of the glomeruli, cochlea (inner ear), and eye
  • Glomerular basement membranes (GBMs) thicken unevenly, split, and ultimately deteriorate; GBM in AS is more prone to proteolytic injury leading to activation of adhesion kinase in podocytes, endothelial receptors, glomerular inflammation, and tubulointerstitial fibrosis, resulting in ESKD.
  • Different factors can affect clinical outcomes.
    • Mode of inheritance: XLAS males and ARAS have a more severe disease than ADAS
    • Type of mutation in type IV collagen genes: Truncating mutations have worse prognosis than splice site and missense mutations.
    • Genetics: ARAS and ADAS affect equally in males and females
    • Family history: Juvenile type is associated with ESKD <20 years; adult type: variable course of ESKD

COMMONLY ASSOCIATED CONDITIONS

  • Hearing impairment
    • Frequent but not universally present
    • Starts in late childhood to early adolescence
    • Initially high-frequency hearing loss, which progresses to low-frequency hearing loss
  • Ocular manifestations
    • Anterior lenticonus (thinning and bulging of lens capsule, which creates a conical lens shape)
      • 25% of patients with XLAS
      • Not present at birth; progressive deterioration of vision, requiring glasses
    • Dot-and-fleck retinopathy
      • Most common in males with XLAS
      • Asymptomatic
    • Posterior polymorphous corneal dystrophy
      • Rare
  • Leiomyomatosis
    • Affects esophagus and tracheobronchial tree
    • Appears in late childhood
    • Present with dysphagia, vomiting, and recurrent bronchitis
    • Diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI)
  • Bleeding tendency, macrothrombocytopenia, abnormal platelet and neutrophil inclusions
    • Confined to ADAS

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