Page 79 - GPD-4-2

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

variants in COL4A3 and COL4A4 exhibit a clinical course MYH9-related disorders, which can also present with kidney
intermediate between ARAS and ADAS. For instance, in failure and both hearing loss and ocular abnormalities.
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a cohort of 32 patients with autosomal digenic disease, the However, the pattern on electron microscopy is different,
median time to develop ESKD was 54 years, which was as MYH9-related disorders do not exhibit the same GBM
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later than in ARAS but earlier than in ADAS. Regarding abnormalities. Other important differential diagnoses
extrarenal manifestations, it was shown that over 25% of include thin basement membrane nephropathy, which
patients presented hearing loss – once again, with this is characterized by diffuse GBM thinning but lacks the
prevalence being between those for ARAS and ADAS progressive structural disorganization seen in AS, and IgA
– and none had ocular abnormalities. Differences in the nephropathy, where immunofluorescence findings play a
extrarenal manifestations among patients with this disease key role in establishing the diagnosis. 31
were not observed, regardless of their gender. These findings, in combination with clinical
4. Diagnosis manifestations as well as family history, aid in the selection
of those who might benefit from genetic testing for
The diagnosis of AS is made with the aid of molecular genetic arriving at a definite diagnosis. Skin biopsy might also be
testing, kidney, and/or skin biopsy. Figure 1 provides a useful, particularly in settings without access to genetic
recommended approach to diagnosing AS. Genetic testing testing and with an elevated clinical suspicion of XLAS.
is the gold-standard method for AS diagnosis, providing However, as the epidermal basement membrane lacks
a non-invasive diagnostic route with results of a relatively α3 and α4 collagen chains, this method is unsuitable for
2
high degree of specificity and sensitivity. COL4A3/4/5 diagnosing ARAS or ADAS. Once a molecular diagnosis
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gene testing is recommended in the following: 6 of AS is established in an index case, genetic testing for
• Young individuals, particularly females of childbearing that variant could be offered to adult relatives at risk
age, who present with isolated, persistent hematuria of of inheriting the disease. It has to be taken into account
glomerular origin; that 10 – 15% of pathogenic variants in COL4A5, and an
• Persistent hematuria and a family history of either unknown percentage of those in COL4A3 and COL4A4,
hematuria or unexplained kidney disease in at least occur de novo. This is particularly important to consider
one first- or second-degree relative; when evaluating patients with no known family history
• Cases where kidney biopsy findings suggest AS; of AS. The known prevalence for de novo variants is even
• Patients with persistent hematuria and high-frequency weaker in individuals without any clinical manifestations
sensorineural hearing loss and/or characteristic eye of the disease, such as abnormal renal function, hematuria,
abnormalities, such as fleck retinopathy or anterior proteinuria, hearing loss, or ocular findings. 6
lenticonus; It is important to first offer testing to first-degree relatives
• Individuals indicated for genetic testing for before proceeding with testing of second-degree relatives.
investigation of focal segmental glomerulosclerosis For couples undergoing preconception counseling, genetic
(FSGS) or kidney disease of unknown etiology. testing can be offered to the partner if it may influence
In cases of ARAS or digenic AS, testing the parents of reproductive decisions or guide interventions. 6
index individuals is important to assess the pathogenicity It is essential to point out that no targeted gene panel
of the variant. Access to genetic testing remains limited achieves complete sensitivity for detecting all genetic
6
in many parts of the world due to disparities in health- changes associated with AS, with the sensitivity of COL4A3,
care resources and reimbursement policies. In such COL4A4, and COL4A5 gene analysis in well-designed
cases, kidney biopsy plays a crucial role in the diagnosis panels being estimated to exceed 85%, providing a reliable
of AS and in distinguishing it from other hereditary or diagnostic tool for most pathogenic variants. However,
acquired nephropathies with similar clinical features. if there is a negative result and the presence of a strong
Histopathological findings on biopsy – particularly those clinical suspicion, genome sequencing might be useful. 6
stemming from transmission electron microscopy (EM) Despite strong evidence supporting early intervention,
– can reveal characteristic alterations of the GBM, such implementing newborn screening for AS is still not part of
as thinning or lamellation. In addition, electron-dense routine clinical practice. The lack of a simple and detectable
deposits distinct from immune complexes and abnormal biomarker – such as an enzyme deficiency in Fabry disease
immunostaining for collagen IV chains can further support or cysts on imaging in polycystic kidney disease – has
the diagnosis. 6
hindered the incorporation of AS into routine newborn
This is particularly useful in differentiating AS with screening panels. Despite this limitation, advances in
conditions with overlapping clinical features, such as next-generation sequencing might provide a promising

Volume 4 Issue 2 (2025) 5 doi: 10.36922/gpd.7656