ASF Alport Patient Registry

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.

Inclusion criteria

• Confirmed diagnosis of Alport syndrome by a certified genetic counselor, treating physician or nephrologist.
• Signed informed consent/assent must be provided by the subject and/or caregiver (parent/legal guardian) including compliance with the restrictions listed in the informed consent/assent form and in the study protocol. (Separate age-appropriate assent forms are provided for ages 7-12 years and ages 13-17 years.)
• Must reside in the USA or US territories and outlying islands. (This criterium may change at an as-yet undetermined future date.)

Exclusion criteria

[none]