Description

• A group of genetic diseases with defects in one of several subunits of type IV collagen that cause progressive hematuric nephritis and sensorineural deafness
• Genetically heterogeneous defined as three types:
  • X-linked trait (XLAS): 80%
  • Autosomal recessive (ARAS): 15%
  • Autosomal dominant (ADAS): 5%

Epidemiology

• Varies according to genetics. Gene frequency is 1:5,000.
  • Gender
  • XLAS is more severe in males than females.
  • ARAS is equally severe in males and females.
• Age
  • Hematuria: 1st year of life (XLAS)
  • Hearing loss and ocular abnormalities: late childhood or early adolescence
  • End-stage kidney disease (ESKD) by age 40 years in 90% of XLAS

Prevalence

• In the United States, 3% of children and 0.2% of adults with ESKD:
  • 0.02% of the population
• In Europe: 2.3% of patients with ESKD

Etiology and Pathophysiology

• Mutations arrest the normal development of collagen in glomerular basement membrane (GBM) in cochlea and lens capsule:
  • Glomerular membranes thicken unevenly, split, and ultimately deteriorate.
  • This leads to mild proteinuria and sclerosis, with progression from concomitant interstitial nephritis and renal fibrosis.
• X-linked dominant inheritance (XLAS)
  • Mutations in the COL4A5 gene encoding the α-5(IV) collagen chain on chromosome Xq26-48
• Autosomal recessive inheritance (ARAS)
  • Mutations in the COL4A3 or COL4A4 gene encoding the 3(IV) or 4(IV) chain, respectively, on chromosome 2q35-37

Genetics
See “Description.”

Risk Factors

• For renal deterioration:
  • Clinical manifestations
    • Hypertension
    • Presence of nephrotic syndrome
• Family history
  • Juvenile type: stereotypical course ESKD <20 years
  • “Nonprogressive” or adult type: variable course ESKD: age 40 years
• Gender
  • XLAS is more severe; male > female; 90% males versus 15% females go to ESKD
  • ARAS: male = female
• Type of inheritance
  • XLAS males and ARAS have a more severe disease than ADAS.
• Type of mutations in type IV collagen genes

General Prevention

• Genetic counseling
  • Genotype if possible (1)[C]
• Renal follow-up
  • BP control
  • Monitoring of microalbuminuria by age 1 year (1)[C]
• Hearing follow-up

Commonly Associated Conditions

• Hearing defects
  • Sensorineural deafness
    • Frequent but not universal
    • Cochlear lesion
• Ocular manifestations
  • Anterior lenticonus
    • 25% of patients
    • Pathognomonic feature
  • Dot-and-fleck retinopathy
  • Posterior polymorphous corneal dystrophy
• Leiomyomatosis: 2–5% of families