For Physicians

Alport syndrome encompasses a group of heterogeneous inherited disorders involving the basement membranes of the kidney, the cochlea and the eye. These disorders are the result of mutations in type IV collagen genes. The mode of inheritance is X-linked in 80%, autosomal recessive in 15%, and autosomal dominant in about 5% of individuals with Alport syndrome.
 
In 1927, Alport first described the combination of progressive hereditary nephritis with sensorineural deafness. The presence of 2 of the following diagnostic criteria establishes the diagnosis of Alport syndrome:
 
Family history of hematuria, progressing mostly in males to end-stage renal disease (ESRD)
Characteristic thickening and splitting of the glomerular basement membrane detected by electron microscopy
  • Progressive, high-frequency, sensorineural deafness
  • Anterior lenticonus and perimacular flecks
  • Characteristic abnormalities of basement membrane expression of type IV collagen a3, a4, and a5 chains
  • Mutations in genes encoding the type of IV collagen a3, a4, and a5 chains
Children with Alport syndrome may initially present with only persistent hematuria and a family history of hematuria. Auditory or ocular manifestations may appear later in life. The typical changes of the glomerular basement membrane are also age dependent and may be absent from initial biopsy samples obtained from young children with Alport syndrome.
 
Pathophysiology
Recent advances in study of the cellular and molecular biology of proteins of the basement membrane have been instrumental in clarifying the pathophysiology of Alport syndrome. Basement membranes are sheetlike structures that support endothelial and epithelial cells. They are composed of various proteins that these cells secrete, including type IV collagen. The family of type IV collagens consists of six chains designated a1 through a6(IV).
 
The genes for type IV collagen are distributed in pairs on three chromosomes. The genes COL4A1 and COL4A2 on chromosome 13 encode the a1 and a2 chains, changes, COL4A3 and COL4A4 on chromosome 2 encode the a3 and a4 chains, and COL4A5 and COL4A6 on the X chromosome encode the a5 and a6 chains. The a1 and a2 chains are present in all basement membranes. The a3 -  a6 chains exhibit more restricted patterns of distribution.
 
Patients with Alport syndrome have mutations in COL4A3, COL4A4, or COL4A5, with consequent abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and ESRD), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks).
 
Children with Alport syndrome usually have normal development and intelligence. However, a rare contiguous gene-deletion syndrome involving chromosome Xq22.3 was recently described; this has been named Alport syndrome and mental retardation (ATS-MR).  These patients carry deletions of the COL4A5 gene that extend beyond the 3' end of the gene.  Mid-face hypoplasia and elliptocytosis are seen in some of these patients.
 
In a small number of families X-linked Alport syndrome is associated with smooth muscle tumors of the esophagus, tracheobronchial tree and, in affected females, the external genitalia.  This constellation is known as the Alport syndrome - diffuse leiomyomatosis complex (AS-DL) and results from deletions that include the COL4A5 gene and extend into the second intron of the adjacent COL4A6 gene.
 
Frequency
In the US: The gene frequency for Alport syndrome is estimated to be 1 in 5000. According to the 2005 annual report of the United States Renal Data System, Alport syndrome accounts for approximately 2.5% of pediatric patients with ESRD.
 
Internationally: In Europe, Alport syndrome may be responsible for as many as 2.3% of cases of ESRD.
 
Outcomes
Males with X-linked Alport syndrome and people of both genders with autosomal recessive disease have increasing proteinuria, hypertension, and progression to ESRD, and hearing loss during the second to fourth decades of life.
 
About 50% of males with X-linked disease require dialysis or kidney transplantation by age 25 years, and about 90% develop end-stage renal disease (ESRD) before 40 years of age.
In female patients, progression to ESRD was previously thought to be rare. However, recent observations have shown that as many as 12% of female patients also develop ESRD by the age of 40 years; this rate increases to 30% by the age of 60 years and 40% by age 80 years. Among female patients, risk factors for progression to ESRD include proteinuria and hearing loss.
 
Gender effects
All males with X-linked Alport syndrome eventually develop ESRD.
Many female patients with X-linked Alport syndrome have mild disease, but recent studies have shown significant renal morbidity in female patients who develop proteinuria and hearing loss.The uncommon autosomal recessive form of Alport syndrome affects both genders equally.
 
Age
Hematuria, the cardinal feature of Alport syndrome, is first detectable in early childhood in both affected males and females.The rate of progression to ESRD in males with X-linked Alport syndrome is heavily influenced by the nature of the COL4A5 mutation.
 
Large deletions and nonsense mutations are typically associated with progression to ESRD by age 30.Missense mutations may be associated with relatively slow progression, with delay in onset of ESRD to 40 - 60 years of age.In males with X-linked disease, hearing loss is typically detectable in late childhood.

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