Excerpt from Alport Syndrome

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Background

Alport syndrome encompasses a group of heterogeneous inherited disorders involving the basement membranes of the kidney and frequently involving 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 is reported 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 3 of the following 4 proposed diagnostic criteria establishes the diagnosis of Alport syndrome:

1. Family history of hematuria, progressing mostly in males to end-stage renal disease (ESRD)
2. Thickening and splitting of the glomerular basement membrane detected by electron microscopy
3. Progressive, high-frequency, sensorineural deafness
4. Anterior lenticonus and perimacular flecks

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 elucidating the pathophysiology of Alport syndrome. Basement membranes are sheetlike structures that support endothelial and epithelial cells. They are composed of various proteins that these cell secret, including a network of type IV collagen. The family of type IV collagens consists of 6 chains designated a1 through a6(IV) that share a collagenous domain and a carboxy-terminal noncollagenous (NC1) domain.

The genes for type IV collagen are distributed in pairs on 3 chromosomes. The genes COL4A1 and COL4A2 on chromosome 13 encode for the a1 and a2 changes, COL4A3 and COL4A4 on chromosome 2 encode for the a3 and a4 chains, COL4A5 and COL4A6 on the X chromosome encode for a5 and a6. The a1 and a2 chains are present in all basement membranes. The a3 and a4 chains are restricted to the basement membranes of the glomerulus, cochlea, and eye. The a5 chain is expressed in the glomerulus, cochlea, eye, and epidermis.

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).

Frequency

United States

The genetic frequency for Alport syndrome is estimated to be 1 case in 5000 population. According to the 2005 annual data report of the United States Renal Data System, Alport syndrome accounts for approximately 2.5% of pediatric patients with ESRD.

International

In Europe, Alport syndrome may be responsible for as many as 2.3% of cases of ESRD.

Mortality/Morbidity

• Male individuals with X-linked Alport syndrome and both people of sexes with autosomal recessive disease have increasing proteinuria, hypertension, progression to ESRD, and hearing loss during the second to fourth decades of life.
• Male patients with the typical X-linked disease have a renal half-life of about 25 years, and about 90% develop 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 the degree of proteinuria and hearing loss.

Race

No racial predilection is reported.

Sex

• The common X-linked form of Alport syndrome leading to ESRD predominantly affects male individuals.
• 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 sexes equally.
• See also Mortality/Morbidity above.

Age

• Most patients with Alport syndrome present with persistent microscopic hematuria and episodic gross hematuria during the first 2 decades of life.
• Two clinical subtypes of Alport syndrome have been distinguished on the basis of their rates of progression.
  • The first is a juvenile type in which ESRD occurs when an individual is approximately 20 years of age. Its course is fairly constant within a given family.
  • The second is an adult variety in which ESRD occurs when the individual is older than 40 years. This form has notable intrakindred variability.
• See also Mortality/Morbidity above.

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