More Studies Urged to Classify Gene Mutations Before Diagnosing Alport Syndrome

More studies are needed for the accurate classification of cases of heterozygous — only one gene copy affected — COL4A3 or COL4A4 mutations causing kidney failure, according to an editorial. In the meantime, diagnosing these patients as Alport syndrome should be avoided.

The editorial, “Should we diagnose autosomal dominant Alport syndrome when there is a pathogenic heterozygous COL4A3 or COL4A4 variant?,” was written by Judy Savige, PhD, a professor at The University of Melbourne, and was published in the journal Kidney International Reports.

Research has shown that up to 30% of patients with AS have a single mutation in the COL4A3 or COL4A4 genes, describing the condition as autosomal dominant (AD), which means that having only one mutated gene copy (out of the two gene copies we inherit from our parents) is sufficient to cause the condition.

Those who favor the classification of Alport syndrome in cases of heterozygous COL4A3 or COL4A4 consider that the risk of kidney failure is high enough to consider the diagnosis and that patients should be informed of this risk and receive ongoing medical supervision. They also consider that there is little evidence supporting the frequently used alternative — thin basement membrane nephropathy (TBMN), a rare, inherited disorder.

However, the panel working on the “Expert guidelines for the diagnosis and management of Alport syndrome and Thin basement membrane nephropathy,” led by Savige, did not recommend the adoption of AD Alport syndrome.

About 85% of families with Alport syndrome have pathogenic (disease-causing) COL4A5 gene variants inherited in an X-linked pattern, which refers to alterations in the X chromosome, while 15% have autosomal recessive (AR, both gene copies are mutated) with two variants in COL4A3 or COL4A4.

X-linked Alport syndrome leads to end-stage renal failure in 90% of men by age 40 but only 15-30% of women by age 60. This difference may be explained by the fact that men only have one X chromosome, thereby not being able to compensate for the COL4A5 change. Also, those with AR disease develop renal failure by age 40.

In contrast, those with heterozygous COL4A3 or COL4A4 variants typically have a thinner but not layered (lamellation) glomerular basement membrane (GBM) — essential to the kidney’s filtration barrier – together with normal renal function, and unchanged hearing and eyesight. As a result, they are diagnosed with TBMN (most often with a benign course), not with Alport syndrome.

According to the expert guidelines panel, the primary advantage of using TBMN for these patients is that this diagnosis and its implications are widely understood. However, the fact that renal biopsies are rarely performed in suspected cases makes TBMN not a fully satisfactory term, they cautioned.

Heterozygous COL4A3 or COL4A4 mutations are normally only associated with hematuria, or blood in the urine. Most patients have normal or nearly normal renal function, even if a family member has one such mutation and develops renal failure. Cases of renal failure in members of consecutive generations are scarce, if any, Savige noted.

Also, cases of renal failure and hearing loss in people with heterozygous COL4A3 or COL4A4 variants may have other explanations, such as poorly controlled hypertension, diabetes, and obesity. Evidence that these gene alterations are sufficient to cause layered GBM, as well as hearing and eye abnormalities, is limited. Scientists were unable to find heterozygous COL4A3 or COL4A4 mutations in dogs with AD Alport syndrome.

Studies employing next generation gene sequencing revealed further complexity in the genetics of Alport syndrome, with additional combinations of variants of COL4A3 and/or COL4A4.

“We expect soon to be able to explain why some, but relatively few, heterozygous COL4A3 or COL4A4 mutations cause kidney failure. We expect then that the Alport community will develop more accurate terminology for these variants and the combinations that occur,” the researcher said.

In the meantime, Savige suggested using “heterozygous pathogenic variants,” possibly adding “consistent with the diagnosis of TBMN or the carrier state of AR Alport syndrome.” This would avoid unnecessary anxiety in people with low risk of renal failure and confusion with a premature change in terminology, the author wrote.