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- 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%
- Varies according to genetics. Gene frequency is 1:5,000.
- XLAS is more severe in males than females.
- ARAS is equally severe in males and females.
- 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
- In the United States, 3% of children and 0.2% of adults with ESKD:
- 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
- For renal deterioration:
- Clinical manifestations
- Presence of nephrotic syndrome
- Family history
- Juvenile type: stereotypical course ESKD <20 years
- “Nonprogressive” or adult type: variable course ESKD: age 40 years
- 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
- 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
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