A genetic mutation affecting the COL4A4 gene was linked for the first time to a rare, vision-threatening event in a woman with Alport syndrome.
The case of the 40-year-old Portuguese woman was reported in the study “Bilateral giant macular holes: A rare manifestation of Alport syndrome,” published in the European Journal of Ophthalmology.
Alport syndrome is caused by mutations in the genes that encode type IV collagen alpha chains, particularly the COL4A3, COL4A4, and COL4A5 genes.
Kidney problems are one of the main symptoms of Alport, affecting all men with the disease and 95 percent of women. But the production of impaired type IV collagen can also lead to hearing loss in about 73 percent of patients and eye abnormalities in about 57 percent.
Researchers at the Centro Hospitalar e Universitário de Coimbra, in Portugal, presented the woman’s case after she complained of progressive, painless vision loss that affected both eyes.
The woman was diagnosed with Alport syndrome at 28 and had a clinical history of hearing loss, renal failure, elevated blood pressure, and high blood calcium levels due to the enlargement of her parathyroid glands. She also had a family history of kidney disease and hearing loss on her father’s side.
At her initial diagnosis, genetic testing was performed and a type of mutation was detected in both copies of the COL4A4 gene — meaning they were inherited from both her mother and father. This resulted in an early “stop signal” that prevented the production of full-length protein.
Reduced amounts of type IV collagen can lead to thinner light-sensitive membrane in the eyes. In this case, the patient had developed a large hole in the retina, which was initially detected only in the right eye. Surgical treatment was unsuccessful.
After a new evaluation, the clinical team detected large holes in the retina of both eyes, causing reduced bilateral visual acuity that was more pronounced in her right eye. No additional Alport-related visual alterations were found. An evaluation of the eyes’ networks of blood vessels showed normal structures with no noteworthy alterations.
Because initial surgical treatment failed to close the hole in the retina, and other effective treatment options were lacking, the team decided to adopt a conservative approach after discussing it with the patient. The nephrology department continued to monitor her kidney disease.
Based on the findings, genetic counseling was offered to the patient and her husband, and genetic testing was recommended to other family members who were at risk.
The woman had a 7-year-old daughter who was also tested for a possible Alport-associated genetic alteration. The daughter was found to have one copy of the same COL4A4 mutation inherited from the mother. Her genetic alteration led to a non-progressive, mild increase of blood cells in the urine, known as hematuria.
“Holes [in the retina] are a rare but vision-threatening alteration associated with Alport syndrome,” the researchers noted. Unfortunately, no therapies are available to protect patients from these ocular manifestations or from hearing loss. Therefore, it is critical to provide patients and their families with information about the course of the disease, therapeutic options, and genetic counseling, researchers said.