Recognition of Inheritance Patterns in XLAS Critical for Proper Diagnosis, Care, Case Report Shows

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by Alice Melão |

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rare mutation, severe X-linked Alport Syndrome

Genetic evaluation of direct family members of Alport syndrome patients is an important step to better understanding the underlying features of the disease, as well as to provide proper counseling to the family, a case report shows.

The case of a young boy with Alport syndrome, described in the study, “Germline mosaicism is a pitfall in the diagnosis of “sporadic” X-linked Alport syndrome,” highlights the relevance of extended genetic profiling in suspected cases of spontaneous disease. The study was published in the Journal of Nephrology.

At a year old, the boy was evaluated by a clinical team at the regional hospital due to acute ear inflammation. He was found to have small amounts of blood cells present in the urine (hematuria), which got worse as the inflammation progressed, but without changes in protein urine levels.

When he was 3, the clinicians decided to evaluate his kidneys, because his renal condition had gradually progressed, with increased levels of proteins in the urine (proteinuria), in addition to the sustained hematuria.

The kidney evaluation revealed that, despite the symptoms, he had a normal filtration rate, with no significant changes in total blood protein levels.

A tissue biopsy analysis showed some minor structural alterations in the kidneys’ filtration structures (glomerulus and Bowman’s capsule) that were lacking alpha 5 chains of type IV collagen — a critical structural component affected in patients with X-linked Alport syndrome (XLAS).

Still, his vision and hearing, which are often affected in patients with this genetic disease, were within normal values.

Because all the findings pointed to a genetic disease, the team evaluated the family’s clinical history. The boy’s parents were found to have normal kidney function without any urinary symptoms; however, his younger sister had very mild hematuria.

To confirm the suspected diagnosis of Alport syndrome, the team performed a genetic analysis of the three genes linked to the disease — COL4A3, COL4A4, and COL4A5.

They found that the boy had one mutation affecting COL4A5 that had not been previously described but could be the cause of all his symptoms, including the lack of alpha 5 chains of type IV collagen.

The parents, however, did not have the genetic variant, which was consistent with a diagnosis of sporadic Alport syndrome rather than inherited. But when the researchers evaluated the genetic profile of the boy’s sister, they found she also had the same COL4A5 mutation, which once more pointed to an inherited disorder.

The team performed a new genetic evaluation of the mother, since the father had no disease symptoms, and this type of mutation is often linked to the X chromosome inherited from the mother — X-linked Alport syndrome.

Despite analyzing different cells, including immune cells collected from peripheral blood and saliva and urinary cells, they failed to find that the origin of the mutation was from the mother.

Still, all the gathered information suggested the disease had been inherited from the mother who was carrying the causative mutation through a mechanism called mosaicism — in which just a few cells have the alteration.

“Germline mosaicism is thought to be rare, but our case reminds us that even for asymptomatic parents of a child with ‘sporadic’ XLAS, the possibility that one of the parents may [have] mosaicism should be considered,” the researchers said. So, “we can never eliminate the possibility that the next baby will not have the same genetic disease.”


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