ASF is an Alport syndrome patient-led 501(c)(3) non-profit based in the US. ASF regularly
communicates with thousands of Alport syndrome patients, caregivers, researchers,
clinicians, and industry stakeholders in the US and internationally. ASF created its
Alport Patient Registry in partnership with Pulse Infoframe Inc. Together, ASF and Pulse
Infoframe Inc. are committed to ensuring patients' data entered in the Registry remain
secure and under the control of the patients themselves.
Alport syndrome is a genetic disease stemming from pathogenic variants in the COL4A3
gene, the COL4A4 gene (both located on the 2 chromosome), and the COL4A5 gene (located on
the X chromosome). These 3 genes encode for the 3 individual collagenous strands (⍺3, ⍺4,
and ⍺5 respectively) that "braid" to form the triple-helix protein
collagen-typeIV⍺3,⍺4,⍺5. Collagen-typeIV⍺3,⍺4,⍺5 is an extracellular structural protein
that supports and gives form and function to multiple organs and organ sub-structures in
the human body including the glomeruli of the kidney, the inner ear, the eyes, skin,
lungs, and blood vessels.
The primary phenotypical manifestations of Alport syndrome are:
Progressive glomerulonephritis leading to kidney failure. In the glomeruli of the
nephrons of the kidneys, collagen-typeIV⍺3,⍺4,⍺5 is formed in specialized podocyte
cells and then excreted into the extracellular matrix space between the podocytes
and the endothelial (blood vessel) cells where it cross-links to form a mature
glomerular basement membrane (GBM). In Alport syndrome, the GBM's structural
integrity and support of podocyte viability is compromised because of the absence of
healthy, functional cross-linked collagen-typeIV⍺3,⍺4,⍺5 matrix. Establishment of
the cross-linked collagen-typeIV⍺3,⍺4,⍺5 matrix in the GBM starts only after birth
and takes years. As such, all Alport syndrome patients are born healthy and progress
to kidney failure at different rates depending on the pathogenicity of their
genotype and variant. Notably, X-linked male and autosomal recessive Alport syndrome
patients typically experience kidney failure in their teenage and young adult years.
Also, notably, X-linked female and autosomal dominant Alport syndrome patients also
suffer from kidney disease - just at a slower rate of progression - and the term
"carrier" is no longer clinically accepted.
Often, but not always, progressive bilateral sensorineural hearing loss,
particularly in the mid-to-higher frequencies.
Sometimes lenticonus (a bulging of the lens capsule and underlying cortex of the
lenses of the eyes) and/or fleck retinopathy (yellowish-white lesions of the retinas
of the eyes).
For patients with certain large deletion variants of the COL4A5 gene, diffuse
esophageal leiomyomatoses ("benign", tumor-like growths that can cause discomfort
and can interfere with swallowing).
Other phenotypical characteristics that are less understood and hypothesized include, but
are not limited to, diffuse uterine leiomyomatoses, increased risk of aortic aneurysm,
increased risk of preeclampsia, and the inability to recover from retinal delamination or
corneal abrasions.
Because Alport syndrome stems from 3 genes that are located on both autosomal and somatic
chromosomes, it exists in heterozygous, homozygous, and hemizygous forms as well as
digenic and trigenic forms. Added to this complexity, pathogenic variants can present as
mutations that are described as missense, nonsense, frameshift, intronic, exonic,
collagenous-domain, non-collagenous-domain, or other mutations. Therefore, Alport
syndrome is best characterized as a "spectrum" syndrome that encompasses tens of
thousands of potential genotypical variants along with an equally diverse set of
phenotypical expressions, and includes dependencies related to the patient's age, sex,
treatment history, diet, and environment.
The ASF Alport Patient Registry's goals are to help understand the above described
complexity of Alport syndrome by:
A) Help assessing which genetic variants influence the rate of kidney function decline.
B) Quantifying and qualifying understudied aspects of Alport syndrome.
C) Documenting medications patients are currently taking and how well they are working.
D) Supporting exploration of new therapies and potential genetic cures.