Genetic testing, not hematuria (blood in urine), is the more accurate method to diagnose Alport syndrome and determine its mode of inheritance within a family, a review of eight related cases reports.
The review study, titled “Alport syndrome: deducing the mode of inheritance from the presence of haematuria in family members” was published in the journal Pediatric Nephrology.
Alport syndrome can be caused by three different types of genetic defects: a mutation in one copy of the COL4A5 gene, called X-linked inheritance; two mutations in both copies — one copy inherited from the mother and one from the father — of the COL4A3 or the COL4A4 gene, called autosomal recessive inheritance; and in rare cases a mutation in a copy of either COL4A3 or COL4A4, called autosomal dominant inheritance.
It is important to distinguish among each type of inheritance, particularly X-linked inheritance, which occurs in 85 percent of the families, and autosomal recessive inheritance, which accounts for the remaining 15 percent.
“This distinction is important because different modes of inheritance mean that different family members are at risk of being affected,” the review report stated.
Some clinicians have deduced the pattern of inheritance using hematuria, or the presence of blood in urine — a primary symptom of Alport syndrome — as a marker of affected individuals within a family. The presence of hematuria in family members is a sign that the disease has been inherited and helps doctors determine the pattern of disease transmission.
However, using hematuria to determine Alport syndrome inheritance has several pitfalls, said the author of the study, Judy Savige, PhD, a group leader and professor at Australia’s Royal Melbourne Hospital.
Savige said clinicians at the hospital have been using hematuria to construct family trees and determine inheritance patterns in more than 75 families over the past 20 years.
But in some of these families, hematuria was not enough or even misleading to identify the mode of inheritance; rather, genetic testing was able to unequivocally determine it.
The report describes eight families, each illustrating different possible pitfalls of using hematuria to determine the mode of inheritance.
The families included sporadic cases of Alport syndrome with no prior family history, subjects with hematuria only or hematuria plus renal failure, a consanguineous family and a family with two different kidney diseases.
In many of the cases, a diagnosis of Alport syndrome or thin basement membrane nephropathy (also a cause of hematuria, but normally not harmful to kidney function) had been confirmed by a renal biopsy. However, kidney biopsies have become less common and cannot alone identify disease inheritance reliably.
The cases show that deducing inheritance based on hematuria may be ambiguous or incorrect, particularly in families with few members or where too few have been tested for hematuria; in families comprising mainly women who lack the typical symptoms or signs of Alport syndrome; families where the father is not available for testing for hematuria; or when other renal diseases may coexist within the family.
Genetic testing “not only enables the diagnosis of Alport syndrome to be made, but also indicates whether inheritance is X-linked or autosomal recessive,” the researcher stressed.
She added that the “Expert guidelines for the management of Alport syndrome and Thin basement membrane nephropathy” advocates genetic screening as the most accurate method to determine the type of Alport syndrome inheritance.
Tests have also shown that Alport syndrome’s genetic basis may be more complicated than once thought. Advanced DNA sequencing technologies, for instance, have demonstrated that some people have mutations in other kidney-related genes, such as NPHS2.