Page 77 - GPD-4-2

Gene & Protein in Disease Alport syndrome: Genetics, variability, and management

often following upper respiratory infections. Proteinuria examination is recommended for both XLAS and ARAS
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develops as glomerular damage progresses secondarily to at the time of diagnosis, as well as periodic monitoring for
impaired GMB, along with hypertension and a gradual potential ocular complications. 6
decline in renal function. The progression rate varies A small subset of AS patients with contiguous deletions
according to the inheritance pattern. encompassing the 5’ ends of the COL4A5 and COL4A6

3.1. X-linked inheritance may develop leiomyomatosis, a condition characterized
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by benign smooth muscle tumors. These tumors may
Variants in the COL4A5 gene account for approximately occur in the esophagus, tracheobronchial tree, or female
80% of AS cases and, together with ARAS, are associated reproductive tract, leading to symptoms such as dysphagia,
with the most severe phenotypic manifestations. respiratory distress, or clitoral hypertrophy. This rare
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Approximately 70% of males develop ESKD by the age of manifestation occurs in 2 – 5% of patients with XLAS who
30, and 90% by the age of 40. 2,3 have the specific chromosomal deletion. 18
In females with XLAS, X-chromosome activity results
in a mosaic state, where segments of the GBM may 3.2. Autosomal recessive inheritance
have normal collagen α-chains or regions affected by Variants in the COL4A3 or COL4A4 genes lead to ARAS,
the pathogenic COL4A5 variant. This GBM mosaicism a form of disease that presents with comparable severity
underlies their typically milder and more variable clinical in both males and females and is responsible for 10 –
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presentations compared to males. Initial studies failed 15% of all AS cases. Clinically, ARAS shares many
3,13
to show a correlation between genotype mutations and characteristics similar to males with XLAS, with nearly all
clinical outcomes in females with XLAS, being historically presenting with hematuria and proteinuria and with 60%
labeled as “carriers.” However, recent evidence recognizes progressing to ESKD. The median age for ESRD in ARAS
them as part of the AS spectrum due to their potential for is approximately 21 years, while sensorineural hearing
significant disease progression, with approximately 20% loss typically manifests earlier, with a median onset age of
developing ESKD by the age of 60. Factors associated 13 years. 19,20 Unlike XLAS, there are no known differences
6,13
with a higher likelihood of kidney failure in heterozygous between females and males in ARAS. 20
females include early proteinuria, episodic gross hematuria, Nonsense mutations in COL4A3 or COL4A4 genes
and hearing loss. lead to the complete absence of collagen IV α3α4α5
Sensorineural hearing loss is a common extrarenal heterotrimers in the GBM, whereas missense mutations
manifestation of AS, particularly in XLAS and ARAS, where result in structurally abnormal, but not necessarily
it affects up to 90% of male patients. Hearing loss typically deleterious, GBM. Studies have shown that ARAS patients
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begins in the high-frequency range during childhood or lacking missense mutations experience an earlier onset
adolescence and progresses to involve frequencies used in of AS-related manifestations, such as kidney failure and
conversational speech. Although complete deafness is rare, sensorineural hearing loss. 20,21 A different study found that
early detection is essential to provide timely interventions patients with nonsense mutations or mutations resulting
such as hearing aids or cochlear implants. in stop codons were associated with earlier onset of kidney
failure. 22
Ocular disease is another characteristic feature of AS
due to the expression of type IV collagen in ocular tissue, These studies suggest that both truncated mutations
affecting the lens, cornea, and retina. It is observed in 30% and the absence of missense mutations are associated
– 40% of males and approximately 15% of females with with the worst renal prognosis, as in the XLAS patients.
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XLAS. Anterior lenticonus is pathognomonic for AS and Furthermore, there are currently over 80 pathogenic
is present in 20 – 50% of patients with XLAS or ARAS. variants identified in ARAS that make up for only 15%
This condition often requires surgical correction due to of AS patients, making it hard to obtain valid results in
progressive loss of visual acuity. Dot-and-fleck retinopathy, cohorts due to a low number of patients and requiring an
another common ocular finding, is characterized by additional study on this correlation. 22
bilateral retinal granulations and is detectable through
ophthalmoscopy or slit-lamp examination. While this 3.3. Autosomal dominant AS
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finding is diagnostic in the presence of a positive family ADAS exhibits significant variability in its clinical
history or ESKD, it does not typically impair vision. Other presentation. While some individuals experience isolated
ocular abnormalities include posterior polymorphous hematuria or only minimally symptomatic disease,
corneal dystrophy, recurrent corneal erosions, macular others progress to kidney failure. Heterozygous variants
holes, and subcapsular cataracts. A full ophthalmologic of COL4A3 or COL4A4 are highly prevalent, affecting
2,16

Volume 4 Issue 2 (2025) 3 doi: 10.36922/gpd.7656