Atypical presentation of Alport syndrome is common among mothers of children with the disease, researchers reported in a study published in the journal Nephron.
This finding suggests that screening for Alport syndrome in those with persistent renal symptoms, in particular those with a family history of renal diseases, may enable earlier diagnosis and treatment of their offspring.
The study, “Diagnosing Alport Syndrome: Lessons from the Pediatric Ward,” was conducted by researchers at the Erasmus University and Maastricht University in The Netherlands.
Alport syndrome is a genetic condition that causes reduced production of collagen fibers, which are essential for sustaining the normal function of the kidney’s filtrating units, and also important structures in the eye and ear.
At least 1,422 genetic mutations have been associated with Alport syndrome, 976 of which were identified in the COL4A5 gene (located in the X chromosome) and affect 85% of patients. COL4A3 and COL4A4 genes are the other two genes known to cause the disease.
Approximately 90% of Alport cases are caused by genetic mutations inherited from one or both parents. Only 10% of cases have what are called de novo mutations, which were not inherited from the parents but instead occurred during the child’s development.
The Dutch research team reviewed the clinical records of 21 children (14 boys and seven girls) with genetically proven Alport syndrome who had been identified in the last 20 years at the Pediatric Nephrology department of the Erasmus MC Sophia Children’s Hospital in Rotterdam.
The most common symptom in these children (17 of 21) was persistent increased levels of red blood cells in the urine (hematuria). One patient had severe progressive hearing loss, and three sought medical attention to evaluate for Alport syndrome before becoming symptomatic due to family history.
Genetic analysis revealed that 87% of the patients had X-linked COL4A5-driven Alport syndrome. In 17 cases, the identified mutations were new, and all families had different private mutations.
From the 21 patients, 16 were found to have a family history of renal disease; eight were Alport syndrome and eight were other kidney diseases. In five cases, the child was the first family member to be diagnosed with Alport syndrome. All the children’s mothers were found to be carriers of the same mutation as the child.
The family history reveals that for many, the opportunity to identify Alport syndrome may have been missed “either because of an incomplete evaluation or an atypical presentation,” the researchers said.
The researchers noted that half the children, all girls, were diagnosed after the onset of symptoms. “This low proportion of intentionally screened children may reflect parental unawareness of the disease heritability in their child,” they said.
“Parents may erroneously assume that Alport syndrome cannot present as severe renal disease in women, or that early recognition of the disease does not benefit the child, since effective treatment is not available,” the researchers said.
However, Alport disease management has improved in recent years. Treatments such as angiotensin convert enzyme inhibitors or angiotensinogen receptor blocking agents; their timely initiation can delay renal function decline.
Supported by these findings, the team suggests that adult patients with Alport syndrome should receive genetic counseling “on the risk of passing the disease to their offspring” as well as on the importance of early treatment options and benefits.
Alport syndrome should be considered as a possible diagnosis “in every patient male or female with prolonged hematuria or unexplained severe renal disease at a young age,” they said. They epecially stressed this “for women in their childbearing age and in individuals with a positive family history of [any] renal disease.”